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Johanna Maria Catharina BLOM
Professore Associato
Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze sede ex-Sc. Biomediche
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Pubblicazioni
2024
- Low TGF-β1 plasma levels are associated with cognitive decline in Down syndrome
[Articolo su rivista]
Grasso, Margherita; Fidilio, Annamaria; L’Episcopo, Francesca; Recupero, Marilena; Barone, Concetta; Bacalini, Maria Giulia; Benatti, Cristina; Giambirtone, Maria Concetta; Caruso, Giuseppe; Greco, Donatella; Di Nuovo, Santo; Romano, Corrado; Ferri, Raffaele; Buono, Serafino; Cuello, A. Claudio; Blom, Johanna Maria Catharina; Tascedda, Fabio; Piazza, Pier Vincenzo; De La Torre, Rafael; Caraci, Filippo
abstract
2024
- New Psychometric Strategies for the Evaluation of Affective, Cognitive,
and Psychosocial Functioning in Unipolar versus Bipolar Depression:
Impact of Drug Treatment
[Articolo su rivista]
Guerrera, Claudia Savia; Platania, Giuseppe Alessio; Varrasi, Simone; De Vivo, Simona; Pirrone, Concetta; Vezzosi, Venera Francesca; Tascedda, Fabio; Drago, Filippo; Di Nuovo, Santo; Blom, Johanna M. C.; Castellano, Sabrina; Caraci, Filippo
abstract
Background: Different studies have been conducted to understand how patients with unipolar and bipolar depression differ in terms of cognitive and affective symptoms as well as in psychosocial function. Furthermore, the impact of antidepressants, second-generation antipsychotics, and mood stabilizers on these dimensions needs to be characterized, as well as the best psychometric approach to measure changes after pharmacological treatment. Objectives: This study aims to analyze the impact of psychotropic drugs on cognitive, affective, and psychosocial functioning in MDD and BD patients; to test the sensitivity of psychometric tools for measuring those changes; also, to understand how psychosocial abilities are associated with affective and cognitive dimensions in patients with MDD and BD. Methods: A total of 22 patients with MDD and 21 patients with BD in the depressive phase were recruited. Several psychometric tests were administered to assess affective, cognitive, and psychosocial symptoms before and after 12 weeks of drug treatment (T0 and T1) with different psychotropic drugs including second-generation antidepressants, second-generation antipsychotics and mood stabilizers (lamotrigine). Results: MDD patients showed significant improvement in MoCA, Delayed Recall of Rey's 15 Words and HDRS, while a significant worsening was detected on Digit Span Backwards and on FAST scores. Instead, patients with BD showed significant improvements in the MoCA as the MDD patients, but only a trend of improvement (non-statistically significant) on the BDI-II. A positive correlation was detected in both groups between FAST and HDRS and BDI-II scores, especially in BD patients. Conclusion: Our results demonstrate that drug treatment with psychotropic drugs can improve cognitive and affective symptoms, but not all psychometric tools may be equally sensitive to detect those changes in MDD vs. BD patients. Moreover, we found that affective and cognitive dimensions can be considered as different psychopathological dimensions both in unipolar and bipolar depression.
2024
- Snails go on a fast when acetylsalicylic acid comes along with heat stress: A possible effect of HSPs and serotonergic system on the feeding response
[Articolo su rivista]
Batabyal, A.; Rivi, V.; Benatti, C.; Blom, J. M. C.; Tascedda, F.; Lukowiak, K.
abstract
: A novel food followed by sickness, causes a taste-specific conditioned aversion, known as the 'Garcia effect'. We recently found that both a heat shock stressor (30 °C for 1 h - HS) and the bacterial lipopolysaccharide (LPS) can be used as 'sickness-inducing' stimuli to induce a Garcia effect in the pond snail Lymnaea stagnalis. Additionally, if snails are exposed to acetylsalicylic acid (ASA) present in aspirin tablets before the LPS injection, the formation of the Garcia effect is prevented. Here, we hypothesized that exposing snails to crushed aspirin before the HS (ASA-HS) would prevent the HS-induced 'sickness state' and - therefore -the Garcia effect. Unexpectantly, the ASA-HS procedure induced a generalized and long-lasting feeding suppression. We thus investigate the molecular effects underlying this phenomenon. While the exposure to the HS alone resulted in a significant upregulation of the mRNA levels of the Heat Shock Protein 70 (HSP 70) in snails' central ring ganglia, the ASA-HS procedure induced an even greater upregulation of HSP70, suggesting that the ASA-HS combination causes a severe stress response that inhibits feeding. Additionally, we found that the ASA-HS procedure induced a significant downregulation of the mRNA levels of genes involved with the serotoninergic system which regulates feeding in snails. Finally, the ASA-HS procedure prevented HS-induced upregulation of the mRNA levels of key neuroplasticity genes. Our study indicates that two sickness-inducing stimuli can have different physiological responses even if behavioral outcomes are similar under some learning contexts.
2023
- A European comparison of screening and referral by childcare professionals of maltreatment in children aged 0–3: A wild goose chase or maybe not
[Articolo su rivista]
Bisagno, E.; Cadamuro, A.; Dierickx, S.; Mosleh, D. B.; Linde-Ozola, Z.; Kandate, A.; Varga-Sabjan, D.; Morva, D.; Laszlo, N.; Rozsa, M.; Gruber, A.; De Fazio, G. L.; Wuyts, D.; Blom, J. M. C.
abstract
Framed within the European project ECLIPS (Enhancing the Capacity to combat chiLd abuse through an Integral training and Protocol for childcare professionalS), this study aims at understanding the needs related to the screening and referral of child maltreatment by childcare professionals working with children aged 0-3 in daycare settings of four European countries (Belgium, Hungary, Italy and Latvia). While children in this age group display the highest risk of abuse compared to older children, research and practice are less focused on them. Given their daily exposure, childcare professionals are in a unique position to identify and refer child maltreatment of infants and toddlers. However, data from desk research and focus groups held in the four countries revealed significant gaps in both processes. Screening for abuse is not mandatory for childcare professionals, and many barriers limit its effectiveness, such as the lack of training and the absence of standardised practices. Referral is mainly undermined by psychological barriers, namely fear and lack of self-efficacy. This is a fundamental first step to developing strategies to face underreporting and filling knowledge gaps while supporting the fundamental competencies necessary to safeguard the young child's best interest, which is the final goal of the ECLIPS project.
2023
- A Novel Behavioral Display in Lymnaea Induced by Quercetin and Hypoxia
[Articolo su rivista]
Rivi, V.; Batabyal, A.; Benatti, C.; Tascedda, F.; Blom, J. M. C.; Lukowiak, K.
abstract
The pond snail Lymnaea stagnalis employs aerial respiration under hypoxia and can be operantly conditioned to reduce this behavior. When applied individually, a heat shock (30 7C for 1 h) and the flavonoid quercetin enhance long-term memory formation for the operant conditioning of aerial respiration. However, when snails are exposed to quercetin before the heat shock, long-term memory is no longer enhanced. This is because quercetin prevents the heat-induced upregulation of heat-shock proteins 70 and 40. When we tested the memory outcome of operant conditioning due to the simultaneous exposure to quercetin and 30 7C, we found that Lymnaea entered a quiescent survival state. The same behavioral response occurred when snails were simultaneously exposed to quercetin and pond water made hypoxic by bubbling nitrogen through it. Thus, in this study, we performed six experiments to propose a physiological explanation for that curious behavioral response. Our results suggest that bubbling nitrogen in pond water, heating pond water to 30 7C, and bubbling nitrogen in 30 7C pond water create a hypoxic environment, to which organisms may respond by upregulating the heat-shock protein system. On the other hand, when snails experience quercetin together with these hypoxic conditions, they can no longer express the physiological stress response evoked by heat or hypoxia. Thus, the quiescent survival state could be an emergency response to survive the hypoxic condition when the heat-shock proteins cannot be activated.
2023
- A network study to differentiate suicide attempt risk profiles in male and female patients with major depressive disorder
[Articolo su rivista]
Sarti, P.; Colliva, C.; Varrasi, S.; Guerrera, C. S.; Platania, G. A.; Boccaccio, F. M.; Castellano, S.; Pirrone, C.; Pani, L.; Tascedda, F.; di Nuovo, S.; Caraci, F.; Blom, J. M. C.
abstract
Suicide attempts are a possible consequence of Major Depressive Disorder (MDD), although their prevalence varies across different epidemiological studies. Suicide attempt is a significant predictor of death by suicide, highlighting its importance in understanding and preventing tragic outcomes. Researchers are increasingly recognizing the need to study the differences between males and females, as several distinctions emerge in terms of the characteristics, types and motivations of suicide attempts. These differences emphasize the importance of considering gender-specific factors in the study of suicide attempts and developing tailored prevention strategies. We conducted a network analysis to represent and investigate which among multiple neurocognitive, psychosocial, demographic and affective variables may prove to be a reliable predictor for identifying the 'suicide attempt risk' (SAR) in a sample of 81 adults who met DSM-5 criteria for MDD. Network analysis resulted in differences between males and females regarding the variables that were going to interact and predict the SAR; in particular, for males, there is a stronger link toward psychosocial aspects, while for females, the neurocognitive domain is more relevant in its mnestic subcomponents. Network analysis allowed us to describe otherwise less obvious differences in the risk profiles of males and females that attempted to take their own lives. Different neurocognitive and psychosocial variables and different interactions between them predict the probability of suicide attempt unique to male and female patients.
2023
- ADOLESCENCE AS A CRITICAL TIME-WINDOW FOR NEUROINFLAMMATION IN THE MOUSE: WHY SEX
MATTERS
[Abstract in Rivista]
Toscano, Ylenia; Benatti, Cristina; Alboni, Silvia; Ciani, Miriam; Rigillo, Giovanna; Tascedda, Fabio; Blom, Johanna Maria Catharina; Brunello, Nicoletta
abstract
2023
- Behavioral and Transcriptional Effects of Short or Prolonged Fasting on the Memory Performances of Lymnaea stagnalis
[Articolo su rivista]
Rivi, Veronica; Benatti, Cristina; Actis, Pietro; Tascedda, Fabio; Blom, Johanna Maria Catharina
abstract
Introduction: The Garcia effect, a solid learning paradigm, was used to investigate the molecular and behavioral effects induced by different lengths of fasting on the cognitive functions in the pond snail Lymnaea stagnalis, a valid model systemMethods: Three experimental groups were used: Moderately hungry snails, food-deprived for 1 day (D1 snails), severely hungry snails (D5 snails), fasting for 5 days, and satiated snails with ad libitum access to food (AL snails). In the Garcia effect, a single pairing of an appetitive stimulus with a heat stressor results in a learned taste-specific negative hedonic shift. D5 snails were injected with bovine insulin and D1 snails with the insulin receptor antibody (Ab). As a control group, AL snails were injected with saline. Gene expression analyses were performed by Real-time PCR in snails' central nervous system (CNS).Results: AL snails are 'average learners', D1 snails are the best performers, whereas the D5 ones do not show the Garcia effect. Severely fasting snails injected with insulin 3h before the training procedure, show the Garcia effect, whereas injecting 1-day fasting snails with insulin receptor Ab blocks their ability to express memory. The differences in memory performances are associated with changes in the expression levels of selected targets involved in neuronal plasticity, energy homeostasis, and stress response.Discussion: Our results suggest that short-term fasting creates an optimal internal state in L. stagnalis' CNS, allowing a spike in insulin release and an upregulation of genes involved in neuroplasticity. Long-term fasting, instead, upregulates genes involved in energy homeostasis and animal survival.
2023
- Care When It Counts: Establishing Trauma-Sensitive Care as a Preventative Approach for 0–3-Year-Old Children Suffering from Trauma and Chronic Stress
[Articolo su rivista]
Dierickx, S.; Malisse, L.; Bisagno, E.; Cadamuro, A.; Van Haeken, S.; Wuyts, D.; Linde-Ozola, Z.; Kandãte, A.; Morva, D.; Rozsa, M.; Gruber, A.; Blom, J. M. C.; De Fazio, L. G.; Mosleh, D. B.; Varga-Sabján, D.; Groenen, A.
abstract
Adverse childhood experiences are an important societal concern. Children aged 0-3 are particularly vulnerable to unpredictable chronic stress due to the critical period for brain development and attachment. Trauma-sensitive care is a preventative approach to reduce the burden of stressful experiences by committing to positive relationships. Professional caregivers are ideally placed to offer trauma-sensitive care; however, earlier research reveals that the tools they need to consciously apply trauma-sensitive care principles are missing. The current study organized living labs (co-creative research method) to present trauma-sensitive care as a preventative approach aimed at children aged 0-3. Two living labs were organized in Belgium and Hungary, where professional caregivers collaborated to create a protocol that offers guidelines on how to implement trauma-sensitive care. The resulting protocol included a theoretical foundation on trauma as well as a translation of these guidelines into practical recommendations. The protocol was evaluated by incorporating it into a training intervention delivered to 100 professional caregivers from childcare organizations across four European countries. The protocol received positive feedback from participants, with results indicating a self-reported increase in knowledge, attitude and practice of trauma-sensitive care principles. We conclude that this trauma-sensitive care protocol is a promising answer to the needs of professional caregivers working with children aged 0-3.
2023
- Comparison of behavioural and transcriptional responses to a heat stressor between freshly collected and an inbred strain of Lymnaea
[Articolo su rivista]
Rivi, V.; Batabyal, A.; Benatti, C.; Tascedda, F.; Blom, J. M. C.; Lukowiak, K.
abstract
Different populations of organisms occurring across varying thermal regimes show diversity in responses to heat stress. We use a "common garden experimental" approach designed to deal with phenotypic plasticity to study in Lymnaea stagnalis (Linnaeus, 1758) the behavioural and molecular responses to a heat shock in laboratory-inbred snails (W-strain) and freshly collected snails (Stony strain) from ponds. In the W-strain, which has been reared under standardized temperatures for generations, the exposure to 30 degrees C for 1 h (heat shock, HS) when experienced after a novel "taste" results in a taste-specific aversion known as the "Garcia effect". This learned avoidance requires the upregulation of heat shock proteins (HSPs). In contrast, freshly collected Stony strain, which experiences temperature fluctuations regularly, does not exhibit a Garcia effect. Here, we found that (1) Stony-strain snails have higher basal mRNA levels of HSPs than W-strain ones; (2) in the W-strain, the training procedure to cause the Garcia effect upregulates the mRNA levels of HSPs and key neuroplasticity-related genes such as CREB1 and GRIN1; (3) in Stony-strain snails, the same training procedure fails to alter the mRNA levels of those targets. These data suggest that Stony-strain snails do not perceive the HS as a stressor because of the higher HSP basal mRNA levels, which may confer a higher thermal tolerance.
2023
- Dysbindin, D3 receptors, and their genetic interaction differently regulate neuroplasticity genes in the mouse brain
[Abstract in Atti di Convegno]
Rivi, V.; Benatti, C.; Blom, J. M. C.; Pani, L.; Brunello, N.; Drago, F.; Papaleo, F.; Torrisi, S.; Leggio, G.; Tascedda, F.
abstract
2023
- Emotional, Behavioral, and Physical Health Consequences in Caregivers of Children with Cancer: A Network Analysis Differentiation in Mothers’ and Fathers’ Reactivity
[Articolo su rivista]
Scarponi, D.; Sarti, P.; Rivi, V.; Colliva, C.; Marconi, E.; Pession, A.; Blom, J. M. C.
abstract
Background: Pediatric cancer presents mental and physical challenges for patients and their caregivers. However, parental distress has been understudied despite its negative impact on quality of life, disability, and somatic disorders. Parents of oncopediatric patients experience high levels of suffering with their resilience tested throughout their children’s illness. Identifying at-risk parents and offering specific treatments is crucial and urgent to prevent or alleviate negative outcomes. Methods: This study used statistical and network analyses to examine symptom patterns assessed by the Kellner Symptom Questionnaire in 16 fathers and 23 mothers at different time points: diagnosis, treatment, and discharge. Results: The results indicated significantly higher distress levels in parents of oncopediatric children compared to the control reference population. Gender-specific differences in symptom profiles were observed at each time point, and symptoms showed a gradual but non-significant decrease over time. Conclusions: The network analysis yielded valuable insights that, when applied in clinical practice, can guide the implementation of timely treatments to prevent and manage parental distress, thus addressing long-term, stress-related issues in primary caregivers of children diagnosed and treated for cancer.
2023
- Invertebrates as models of learning and memory: investigating neural and molecular mechanisms
[Articolo su rivista]
Rivi, Veronica; Benatti, Cristina; Rigillo, Giovanna; Blom, Johanna M C
abstract
: In this Commentary, we shed light on the use of invertebrates as model organisms for understanding the causal and conserved mechanisms of learning and memory. We provide a condensed chronicle of the contribution offered by mollusks to the studies on how and where the nervous system encodes and stores memory and describe the rich cognitive capabilities of some insect species, including attention and concept learning. We also discuss the use of planarians for investigating the dynamics of memory during brain regeneration and highlight the role of stressful stimuli in forming memories. Furthermore, we focus on the increasing evidence that invertebrates display some forms of emotions, which provides new opportunities for unveiling the neural and molecular mechanisms underlying the complex interaction between stress, emotions and cognition. In doing so, we highlight experimental challenges and suggest future directions that we expect the field to take in the coming years, particularly regarding what we, as humans, need to know for preventing and/or delaying memory loss. This article has an associated ECR Spotlight interview with Veronica Rivi.
2023
- Investigating the interactions between multiple memory stores in the pond snail Lymnaea stagnalis
[Articolo su rivista]
Rivi, V.; Batabyal, A.; Benatti, C.; Blom, J. M. C.; Tascedda, F.; Lukowiak, K.
abstract
The pond snail Lymnaea stagnalis exhibits various forms of associative learning including (1) operant conditioning of aerial respiration where snails are trained not to open their pneumostome in a hypoxic pond water environment using a weak tactile stimulus to their pneumostome as they attempt to open it; and (2) a 24 h-lasting taste-specific learned avoidance known as the Garcia effect utilizing a lipopolysaccharide (LPS) injection just after snails eat a novel food substance (carrot). Typically, lab-inbred snails require two 0.5 h training sessions to form long-term memory (LTM) for operant conditioning of aerial respiration. However, some stressors (e.g., heat shock or predator scent) act as memory enhancers and thus a single 0.5 h training session is sufficient to enhance LTM formation lasting at least 24 h. Here, we found that snails forming a food-aversion LTM following Garcia-effect training exhibited enhanced LTM following operant condition of aerial respiration if trained in the presence of the food substance (carrot) they became averse to. Control experiments led us to conclude that carrot becomes a ‘sickness’ risk signal and acts as a stressor, sufficient to enhance LTM formation for another conditioning procedure.
2023
- LPS-Induced Garcia Effect and Its Pharmacological Regulation Mediated by Acetylsalicylic Acid: Behavioral and Transcriptional Evidence
[Articolo su rivista]
Rivi, V.; Batabyal, A.; Lukowiak, K.; Benatti, C.; Rigillo, G.; Tascedda, F.; Blom, J. M. C.
abstract
Lymnaea stagnalis learns and remembers to avoid certain foods when their ingestion is followed by sickness. This rapid, taste-specific, and long-lasting aversion—known as the Garcia effect—can be formed by exposing snails to a novel taste and 1 h later injecting them with lipopolysaccharide (LPS). However, the exposure of snails to acetylsalicylic acid (ASA) for 1 h before the LPS injection, prevents both the LPS-induced sickness state and the Garcia effect. Here, we investigated novel aspects of this unique form of conditioned taste aversion and its pharmacological regulation. We first explored the transcriptional effects in the snails’ central nervous system induced by the injection with LPS (25 mg), the exposure to ASA (900 nM), as well as their combined presentation in untrained snails. Then, we investigated the behavioral and molecular mechanisms underlying the LPS-induced Garcia effect and its pharmacological regulation by ASA. LPS injection, both alone and during the Garcia effect procedure, upregulated the expression levels of immune- and stress-related targets. This upregulation was prevented by pre-exposure to ASA. While LPS alone did not affect the expression levels of neuroplasticity genes, its combination with the conditioning procedure resulted in their significant upregulation and memory formation for the Garcia effect.
2023
- Narrative Review of the Complex Interaction between Pain and Trauma in Children: A Focus on Biological Memory, Preclinical Data, and Epigenetic Processes
[Articolo su rivista]
Rivi, V.; Rigillo, G.; Toscano, Y.; Benatti, C.; Blom, J. M. C.
abstract
The incidence and collective impact of early adverse experiences, trauma, and pain continue to increase. This underscores the urgent need for translational efforts between clinical and preclinical research to better understand the underlying mechanisms and develop effective therapeutic approaches. As our understanding of these issues improves from studies in children and adolescents, we can create more precise preclinical models and ultimately translate our findings back to clinical practice. A multidisciplinary approach is essential for addressing the complex and wide-ranging effects of these experiences on individuals and society. This narrative review aims to (1) define pain and trauma experiences in childhood and adolescents, (2) discuss the relationship between pain and trauma, (3) consider the role of biological memory, (4) decipher the relationship between pain and trauma using preclinical data, and (5) examine the role of the environment by introducing the importance of epigenetic processes. The ultimate scope is to better understand the wide-ranging effects of trauma, abuse, and chronic pain on children and adolescents, how they occur, and how to prevent or mitigate their effects and develop effective treatment strategies that address both the underlying causes and the associated physiological and psychological effects.
2023
- Neuropsychological Outcomes of Children Treated for Brain Tumors
[Articolo su rivista]
Pancaldi, Alessia; Pugliese, Marisa; Migliozzi, Camilla; Blom, Johanna; Cellini, Monica; Iughetti, Lorenzo
abstract
Central nervous system (CNS) neoplasms are the most common solid tumors diagnosed in children. CNS tumors represent the leading cause of cancer death and cancer-related morbidity for children less than 20 years of age, although there has been a moderate increase in survival rates over the past several decades. The average survival at 5 years now nearly reaches 75%, and for some, non-malignant histology approximates 97% at 20 years from diagnosis. Neurological, cognitive, and neuropsychological deficits are the most disabling long-term effects of brain tumors in children. Childhood is a time of extreme brain sensitivity and the time of life in which most brain development occurs. Thus, the long-term toxicities that children treated for CNS tumors experience can affect multiple developmental domains and day-to-day functioning, ultimately leading to a poor quality of survival (QoS). We reviewed literature focusing on the risk factors for cognitive and neuropsychological impairment in pediatric patients treated for brain tumors with the aim of better understanding who is at major risk and what the best strategies for monitoring these patients are.
2023
- No food for thought: An intermediate level of food deprivation enhances memory in Lymnaea
[Articolo su rivista]
Kagan, Diana; Rivi, Veronica; Benatti, Cristina; Tascedda, Fabio; Blom, Johanna M C; Lukowiak, Ken
abstract
: Nutritional status plays an important role in cognitive functioning but there is disagreement on the role that food deprivation plays in learning and memory. In this study, we investigated the behavioral and transcriptional effects induced by different lengths of food deprivation: 1 day, which is a short-time period of food deprivation, and 3 days, which is an 'intermediate' level of food deprivation. Snails were subjected to different feeding regimens and then trained for operant conditioning of aerial respiration where they received a single 0.5h training session followed by a long-term memory (LTM) test 24h later. Immediately after the memory test, snails were sacrificed and the expression levels of key genes for neuroplasticity, energy balance, and stress response were measured in the central ring ganglia. We found that 1 day of food deprivation was not sufficient to enhance snails' LTM formation and subsequently did not result in any significant transcriptional effects. However, 3 days of food deprivation resulted in enhanced LTM formation and caused the upregulation of neuroplasticity and stress-related genes and the downregulation of serotonin-related genes. These data provide further insight into how nutritional status and related molecular mechanisms impact cognitive function.
2023
- Novel taste, sickness, and memory: Lipopolysaccharide to induce a Garcia-like effect in inbred and wild strains of Lymnaea stagnalis
[Articolo su rivista]
Rivi, V.; Batabyal, A.; Benatti, C.; Blom, J. M.; Tascedda, F.; Lukowiak, K.
abstract
Food is not only necessary for our survival but also elicits pleasure. However, when a novel food is followed sometime later by nausea or sickness animals form a long-lasting association to avoid that food. This phenomenon is called the ‘Garcia effect’. We hypothesized that lipopolysaccharide (LPS) could be used as the sickness-inducing stimulus to produce a Garcia-like effect in inbred and wild populations of Lymnaea stagnalis. We first demonstrated that the injection of 25 μg (6.25 µg/mL) of Escherichia coli-derived LPS serotype O127:B8 did not by itself alter snails’ feeding behavior. Then we showed that the presentation of a novel appetitive stimulus (i.e., carrot slurry) and LPS resulted in a taste-specific and long-lasting feeding suppression (i.e., the Garcia-like effect). We also found strain-specific variations in the duration of the long-term memory (LTM). That is, while the LTM for the Garcia-like effect in W-strain snails persisted for 24h, LTM persisted for 48h in freshly collected Margo snails and their F1 offspring. Finally, we demonstrated that the exposure to a non-steroidal anti-inflammatory drug, aspirin (acetylsalicylic acid) before the LPS injection prevented both the LPS-induced sickness state and the Garcia-like effect from occurring. The results of this study may pave the way for new research that aims at (1) uncovering the conserved molecular mechanisms underlying the Garcia-like effect, (2) understanding how cognitive traits vary within and between species, and (3) creating a holistic picture of the complex dialogue between the immune and central nervous systems.
2023
- Predictors of functional outcome in patients with major depression and bipolar disorder: A dynamic network approach to identify distinct patterns of interacting symptoms
[Articolo su rivista]
Platania, Giuseppe Alessio; Savia Guerrera, Claudia; Sarti, Pierfrancesco; Varrasi, Simone; Pirrone, Concetta; Popovic, Dina; Ventimiglia, Andrea; De Vivo, Simona; Cantarella, Rita Anna; Tascedda, Fabio; Drago, Filippo; Di Nuovo, Santo; Colliva, Chiara; Caraci, Filippo; Castellano, Sabrina; Blom, Johanna M C
abstract
: The purpose of this study is to use a dynamic network approach as an innovative way to identify distinct patterns of interacting symptoms in patients with Major Depressive Disorder (MDD) and patients with Bipolar Type I Disorder (BD). More precisely, the hypothesis will be testing that the phenotype of patients is driven by disease specific connectivity and interdependencies among various domains of functioning even in the presence of underlying common mechanisms. In a prospective observational cohort study, hundred-forty-three patients were recruited at the Psychiatric Clinic "Villa dei Gerani" (Catania, Italy), 87 patients with MDD and 56 with BD with a depressive episode. Two nested sub-groups were treated for a twelve-week period, which allowed us to explore differences in the pattern of symptom distribution (central vs. peripheral) and their connectedness (strong vs weak) before (T0) and after (T1) treatment. All patients underwent a complete neuropsychological evaluation at baseline (T0) and at T1. A network structure was computed for MDD and BD patients at T0 and T1 from a covariance matrix of 17 items belonging to three domains-neurocognitive, psychosocial, and mood-related (affective) to identify what symptoms were driving the networks. Clinically relevant differences were observed between MDD and BD, at T0 and after 12 weeks of pharmacological treatment. At time T0, MDD patients displayed an affective domain strongly connected with the nodes of psychosocial functioning, while direct connectivity of the affective domain with the neurocognitive cluster was absent. The network of patients with BD, in contrast, revealed a cluster of highly interconnected psychosocial nodes but was guided by neurocognitive functions. The nodes related to the affective domain in MDD are less connected and placed in the periphery of the networks, whereas in BD they are more connected with psychosocial and neurocognitive nodes. Noteworthy is that, from T0 to T1 the "Betweenness" centrality measure was lower in both disorders which means that fewer "shortest paths" between nodes pass through the affective domain. Moreover, fewer edges were connected directly with the nodes in this domain. In MDD patients, pharmacological treatment primarily affected executive functions which seem to improve with treatment. In contrast, in patients with BD, treatment resulted in improvement of overall connectivity and centrality of the affective domain, which seems then to affect and direct the overall network. Though different network structures were observed for MDD and BD patients, data suggest that treatment should include tailored cognitive therapy, because improvement in this central domain appeared to be fundamental for better outcomes in other domains. In sum, the advantage of network analysis is that it helps to predict the trajectory of future phenotype related disease manifestations. In turn, this allows new insights in how to balance therapeutic interventions, involving different fields of function and combining pharmacological and non-pharmacological treatment modalities.
2023
- Prey populations with different predation histories show differences in behavioral and transcriptional effects under acute predation threat
[Articolo su rivista]
Rivi, V.; Batabyal, A.; Benatti, C.; Tascedda, F.; Blom, J. M. C.; Lukowiak, K.
abstract
Predator detection induces both behavioral and physiological responses in prey organisms. Our model organism, the pond snail Lymnaea stagnalis, shows multiple defensive behaviors in response to predator cues. In this study, we investigated and compared the transcriptional effects induced by the exposure to a predator scent (i.e., crayfish effluent - CE) in a strain of lab-inbred snails (i.e., W snails), which have been raised and maintained under standardized laboratory conditions for generations and a strain of freshly collected snails (i.e., Margo snails), which live in a crayfish-free pond. Neither the W- strain nor the Margo Lake snails used in this study have actually experienced crayfish. However, the W strain innately recognizes crayfish as a threat. We found that, following the exposure to CE, both strains showed significantly higher mRNA levels of serotonin-related genes. This is important, as the serotonergic system modulates predator detection and vigilance behaviors in pond snails. However, the expression levels of CREB1 and HSP70 were only upregulated in CE-exposed W snails but not in Margo ones. As CREB1 plays a key role in learning and memory formation, whereas HSP70 is involved in stress response, we investigated whether these differences in CREB1 and HSP70 mRNA levels would reflect differences in predator-induced learning (e.g., configural learning). We found that only W snails formed configural learning memory, whereas Margo snails did not. Thus, while both the strains molecularly respond to the CE by upregulating the serotoninergic system, only W snails behaviorally recognize CE as a threat and, therefore, form configural learning.
2023
- Public preferences for digital health data sharing: Discrete choice experiment study in 12 european countries
[Articolo su rivista]
Biasiotto, R.; Johansson, J. V.; Alemu, M. B.; Romano, V.; Bentzen, H. B.; Kaye, J.; Ancillotti, M.; Blom, J. M. C.; Chassang, G.; Hallinan, D.; Jonsdottir, G. A.; Astobiza1, A. M.; Rial-Sebbag, E.; Rodriguez-Arias, D.; Shah, N.; Skovgaard, L.; Staunton, C.; Tschigg, K.; Veldwijk, J.; Mascalzoni, D.
abstract
Background: With new technologies, health data can be collected in a variety of different clinical, research, and public health contexts, and then can be used for a range of new purposes. Establishing the public s views about digital health data sharing is essential for policy makers to develop effective harmonization initiatives for digital health data governance at the European level. Objective: This study investigated public preferences for digital health data sharing. Methods: A discrete choice experiment survey was administered to a sample of European residents in 12 European countries (Austria, Denmark, France, Germany, Iceland, Ireland, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom) from August 2020 to August 2021. Respondents answered whether hypothetical situations of data sharing were acceptable for them. Each hypothetical scenario was defined by 5 attributes ("data collector," "data user," "reason for data use," "information on data sharing and consent," and "availability of review process"), which had 3 to 4 attribute levels each. A latent class model was run across the whole data set and separately for different European regions (Northern, Central, and Southern Europe). Attribute relative importance was calculated for each latent class s pooled and regional data sets. Results: A total of 5015 completed surveys were analyzed. In general, the most important attribute for respondents was the availability of information and consent during health data sharing. In the latent class model, 4 classes of preference patterns were identified. While respondents in 2 classes strongly expressed their preferences for data sharing with opposing positions, respondents in the other 2 classes preferred not to share their data, but attribute levels of the situation could have had an impact on their preferences. Respondents generally found the following to be the most acceptable: A national authority or academic research project as the data user; being informed and asked to consent; and a review process for data transfer and use, or transfer only. On the other hand, collection of their data by a technological company and data use for commercial communication were the least acceptable. There was preference heterogeneity across Europe and within European regions. Conclusions: This study showed the importance of transparency in data use and oversight of health-related data sharing for European respondents. Regional and intraregional preference heterogeneity for "data collector," "data user," "reason," "type of consent," and "review" calls for governance solutions that would grant data subjects the ability to control their digital health data being shared within different contexts. These results suggest that the use of data without consent will demand weighty and exceptional reasons. An interactive and dynamic informed consent model combined with oversight mechanisms may be a solution for policy initiatives aiming to harmonize health data use across Europe.
2023
- Role of dopamine D3 receptors, dysbindin, and their functional interaction on the expression of key
genes for neuroplasticity in the mouse brain
[Abstract in Rivista]
Rivi, Veronica; Benatti, Cristina; Blom, Johanna; Pani, Luca; Brunello, Nicoletta; Drago, Filippo; Papaleo, Francesco; Torrisi, Sebastiano; Salomone, Salvatore; Leggio Gian, Marco; Tascedda, Fabio
abstract
2023
- The Development of a Screening Tool for Childcare Professionals to Detect and Refer Infant and Toddler Maltreatment and Trauma: A Tale of Four Countries
[Articolo su rivista]
Bisagno, Elisa; Cadamuro, Alessia; Serafine, Dierickx; Dima, Bou Mosleh; Anne, Groenen; Zane, Linde-Ozola; Annija, Kandāte; Dóra, Varga-Sabján; Dorottya, Morva; Noémi, László; Monika, Rozsa; Andrea, Gruber; DE FAZIO, Giovanna Laura; Blom, Johanna Maria Catharina
abstract
Abstract: Child maltreatment is considered a pressing social question, compromising the present
and future mental and physical health of one in four children in Europe. While children younger
than three years of age are especially vulnerable, few screening instruments are available for the
detection of risk in this age group. The purpose of this research was to develop a screening tool
for childcare professionals working in public and private daycare settings to support them in the
early identification and referral of infants and toddlers exposed to emotional and physical abuse
and neglect by primary caregivers, to be used in different settings across four European countries:
Belgium, Italy, Latvia, and Hungary. Method: A stratified process was used to create the screening
tool: We started by using Living lab methodology to co-create the screening tool with its final users,
which was followed by testing the tool with a total of 120 childcare professionals from the four
participating countries. Results: During the Living Lab phase, a screening tool with three layers
was developed. The initial layer includes five “red flags” that signal particular concern and require
immediate action. The second layer is a quick screener with twelve items focused on four areas:
neglect of basic needs, delays in development, unusual behaviors, and interaction with caregivers.
The third layer is an in-depth questionnaire that aids in formalizing a thorough observation of
twenty-five items within the same four areas as the quick screener. After a one-day training session,
120 childcare professionals caring for children aged 0–3 from four countries assessed the screening
tool and their overall training experience. Childcare professionals reported great satisfaction with
the three-layered structure, which made the tool versatile, and agreed on its content, which was
considered helpful in the daycare setting for the regular evaluation of the behavior of children and
their primary caregivers, thus improving the early observation of change from the normal behavior of
the infant or toddler. Conclusion: The three-layered screening tool was reported as feasible, practical,
and with great content validity by childcare professionals working in four European countries.
2023
- The Role of Dopamine D3 Receptors, Dysbindin, and Their Functional Interaction in the Expression of Key Genes for Neuroplasticity and Neuroinflammation in the Mouse Brain
[Articolo su rivista]
Rivi, Veronica; Benatti, Cristina; Blom, Johanna; Pani, Luca; Brunello, Nicoletta; Drago, Filippo; Papaleo, Francesco; Caraci, Filippo; Geraci, Federica; Torrisi, Sebastiano Alfio; Leggio, Gian Marco; Tascedda, Fabio
abstract
2023
- The dynamic interaction between symptoms and pharmacological treatment in patients with major depressive disorder: the role of network intervention analysis
[Articolo su rivista]
Guerrera, C. S.; Platania, G. A.; Boccaccio, F. M.; Sarti, P.; Varrasi, S.; Colliva, C.; Grasso, M.; De Vivo, S.; Cavallaro, D.; Tascedda, F.; Pirrone, C.; Drago, F.; Di Nuovo, S.; Blom, J. M. C.; Caraci, F.; Castellano, S.
abstract
Introduction: The Major Depressive Disorder (MDD) is a mental health disorder that affects millions of people worldwide. It is characterized by persistent feelings of sadness, hopelessness, and a loss of interest in activities that were once enjoyable. MDD is a major public health concern and is the leading cause of disability, morbidity, institutionalization, and excess mortality, conferring high suicide risk. Pharmacological treatment with Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) is often the first choice for their efficacy and tolerability profile. However, a significant percentage of depressive individuals do not achieve remission even after an adequate trial of pharmacotherapy, a condition known as treatment-resistant depression (TRD). Methods: To better understand the complexity of clinical phenotypes in MDD we propose Network Intervention Analysis (NIA) that can help health psychology in the detection of risky behaviors, in the primary and/or secondary prevention, as well as to monitor the treatment and verify its effectiveness. The paper aims to identify the interaction and changes in network nodes and connections of 14 continuous variables with nodes identified as "Treatment" in a cohort of MDD patients recruited for their recent history of partial response to antidepressant drugs. The study analyzed the network of MDD patients at baseline and after 12 weeks of drug treatment. Results: At baseline, the network showed separate dimensions for cognitive and psychosocial-affective symptoms, with cognitive symptoms strongly affecting psychosocial functioning. The MoCA tool was identified as a potential psychometric tool for evaluating cognitive deficits and monitoring treatment response. After drug treatment, the network showed less interconnection between nodes, indicating greater stability, with antidepressants taking a central role in driving the network. Affective symptoms improved at follow-up, with the highest predictability for HDRS and BDI-II nodes being connected to the Antidepressants node. Conclusion: NIA allows us to understand not only what symptoms enhance after pharmacological treatment, but especially the role it plays within the network and with which nodes it has stronger connections.
2023
- The nexus of social alliances and diverse moral domains: a bedrock for participatory clinical research
[Articolo su rivista]
Blom, Johanna; Rivi, Veronica; Tascedda, Fabio; Pani, Luca
abstract
2023
- Trauma-informed care in childcare organisations to support children exposed to child maltreatment: Joint conclusions of four European countries
[Articolo su rivista]
Dierickx, S; Bisagno, E; Varga-Sabjan, D; Morva, D; Linde-Ozola, Z; Laszlo, N; Cadamuro, A; Mosleh, Db; Rozsa, M; De Fazio, Gl; Gruber, A; Kandate, A; Blom, Jmc; Wuyts, D
abstract
Trauma-informed care is emerging as a promising good practice to recognise, treat and prevent trauma in young children. The use of trauma-informed care in childcare organisations might have a positive impact on children who suffer from child maltreatment. The current study organised desk research and focus group discussions with professional experts in Latvia, Italy, Hungary and Belgium to assess if trauma-informed care is known, applied or taught. The joint conclusions of the desk research and the focus group discussions demonstrated that childcare professionals currently lack the knowledge, skills and attitude to engage in trauma-informed care. Even though they have ways to prevent and tackle trauma, these ways are often based on gut feeling or experience and are not formalised or explicitly addressed. This lack of conscious knowhow is an issue that possibly leads to underreporting of situations of child maltreatment and a lack of attuned responses to children suffering from child maltreatment. Overall, there were no training initiatives focused on trauma-informed care for childcare professionals, which might explain why these good practices do not reach the sector.
2023
- VORTIOXETINE ATTENUATES NEUROINFLAMMATION BY MODULATING THE NOD-LIKE RECEPTOR FAMILY PYRIN DOMAIN CONTAINING 3 INFLAMMASOME ACTIVATION IN MICROGLIA: IMPLICATIONS FOR COGNITIVE FUNCTION
[Abstract in Rivista]
Rigillo, G.; Ciani, M.; Benatti, C.; Blom, J. M. C.; Tascedda, F.; Pani, L.; Alboni, S.; Brunello, N.
abstract
Vortioxetine (VTX) is a multimodal antidepressant with an
extensive pharmacological profile that includes modulation of various neurotransmitter
systems, neuroprotective activity, and beneficial effects on cognitive
functions. Recent research has revealed a novel aspect of VTX's activity - its antiinflammatory
effects - that suggests an intriguing molecular mechanism may
underpin its therapeutic benefits. Neuroinflammation, dysfunctional neurogenesis
and neurotransmission, and dysregulation of the hypothalamus–
pituitary–adrenal (HPA) axis are all pivotal in the onset and progression of
depression. One particular immune-inflammatory pathway overactivated in
brain disorders is the NOD-like receptor family pyrin domain containing 3
(NLRP3) inflammasome, a multiprotein complex. This complex's activation is
mediated by NF-kB and reactive oxygen species (ROS) signalling pathways,
leading to caspase-1-dependent release of the proinflammatory cytokines, IL-1β
and IL-18. Mounting evidence implicates NLRP3 inflammasome in neuroinflammation-
related disorders, with its activation associated with cognitive
function impairment. Of note, microglia, the resident immune cells crucial for
brain plasticity, express high levels of the NLRP3-inflammasome components.
Our initial findings indicate that VTX exerts a region-dependent modulatoryeffect on the NLRP3-inflammasome system in a LPS-induced memory impairment
in vivo model. Furthermore, VTX's ability to modulate immune response
suggests that microglia could be a direct target of the drug.
AIM: In light of the compelling evidence surrounding the role of the NLRP3
inflammasome in cognitive dysfunctions and the recent discovery of VTX's anti-inflammatory
activity, we aimed to investigate the molecular effects induced by
VTX pre-treatment in the presence or absence of the inflammasome-inducer LPS
in a well-established in vitro model of mouse microglia: BV2 cells.
METHODS: To dissect the influence of VTX pre-treatment (24h) on the NLRP3
inflammasome signaling pathway and microglial polarization, we analyzed gene
and protein expression in BV2 cells stimulated with LPS or vehicle for 6h. We also
scrutinized the activation/translocation of NF-kB and ROS release under these
conditions. We applied one-way or two-way ANOVA followed by Tukey’s post
hoc test for statistical analysis based on the experimental design.
RESULTS: Our data demonstrate that short-term exposure to LPS significantly
induces the activation/translocation of NF-kB signaling and ROS release in BV2
cells. We observed a time-dependent transcriptional upregulation of the
inflammasome complex, IL-1β and IL-18, and microglial pro-inflammatory targets
post-LPS stimulation, alongside a downregulation of the anti-inflammatory
factors. Interestingly, a pre-treatment with VTX (10 nM) for 24h effectively
modulated the LPS-induced NF-kB translocation and ROS production compared
to control cells. Cells pre-treated with VTX exhibited lower levels of LPS-induced
NLRP3 inflammasome- and microglia pro-inflammatory-related targets. However,
VTX did not influence the expression of anti-inflammatory factors in both
unstimulated and LPS-stimulated BV2 cells.
CONCLUSIONS: Our findings reinforce the emerging evidence that supports
VTX's anti-inflammatory activity. This activity is mediated via modulation of the
inflammasome signaling pathway, which plays a pivotal role in the inflammatory
response of microglia cells.
2022
- A flavonoid, quercetin, is capable of enhancing long-term memory formation if encountered at different times in the learning, memory formation, and memory recall continuum
[Articolo su rivista]
Rivi, V.; Batabyal, A.; Benatti, C.; Blom, J. M.; Tascedda, F.; Lukowiak, K.
abstract
A major extrinsic factor influencing memory and neuro-cognitive performances across taxa is diet. Studies from vertebrates have shown the effects of a flavonoid rich diet on cognitive performance, but the mechanism underlying this action is still poorly understood. A common and abundant flavonoid present in numerous food substances is quercetin (Q). The present study provides the first support for Q-modulated enhancement of cognitive function in an invertebrate model, the pond snail Lymnaea stagnalis, after an operant conditioning procedure. We found that when snails were exposed to Q 3 h before or after a single 0.5 h training session, which typically results in memory lasting ~ 3 h, they formed a long-term memory (LTM) lasting for at least 24 h. Additionally, we assessed the effects of the combined presentation of a single reinforcing stimulus (at 24 h post-training or 24 h before training) and Q-exposure on both LTM formation and reconsolidation. That is, when applied within 3 h of critical periods of memory, Q regulates four different phases: (1) acquisition (i.e., a learning event), (2) consolidation processes after acquisition, (3) memory recall, and (4) memory reconsolidation. In all these phases Q-exposure enhanced LTM persistence.
2022
- Aspirin reverts lipopolysaccharide-induced learning and memory impairment: first evidence from an invertebrate model system
[Articolo su rivista]
Rivi, V.; Batabyal, A.; Benatti, C.; Tascedda, F.; Blom, J. M. C.; Lukowiak, K.
abstract
By employing a reductionistic (but not simplistic) approach using an established invertebrate model system, the pond snail Lymnaea stagnalis, we investigated whether (1) lipopolysaccharide (LPS)-induced inflammation would cause a sickness state and impair cognitive function, and-if so-(2) would aspirin (acetylsalicylic acid-ASA) restore the impaired cognition. To test our hypotheses, we first determined if the injection of 25 mg (6.25 μg/mL) of Escherichia coli-derived LPS serotype O127:B8 altered homeostatic behavior, aerial respiration, and then determined if LPS altered memory formation when this behavior was operantly conditioned. Next, we determined if ASA altered the LPS-induced changes in both aerial respiration and cognitive functions. LPS induced a sickness state that increased aerial respiration and altered the ability of snails to form or recall long-term memory. ASA reverted the LPS-induced sickness state and thus allowed long-term memory both to be formed and recalled. We confirmed our hypotheses and provided the first evidence in an invertebrate model system that an injection of LPS results in a sickness state that obstructs learning and memory, and this impairment can be prevented by a non-steroidal anti-inflammatory.
2022
- Comprehensive Pain Management Using Opioids for Children and Adolescents: Still a Wild Goose to Chase?
[Articolo su rivista]
Blom, J. M. C.; Benatti, C.
abstract
2022
- Deciphering the central immunomodulatory effects of a vortioxetine pretreatment on the LPS-induced inflammatory cascade
[Abstract in Atti di Convegno]
Ciani, M.; Toscano, Y.; Benatti, C.; Blom, J. M. C.; Tascedda, F.; Alboni, S.; Brunello, N.
abstract
2022
- Editorial: Digital biomarkers in testing the safety and efficacy of new drugs in mental health: A collaborative effort of patients, clinicians, researchers, and regulators
[Articolo su rivista]
Blom, Johanna Maria Catharina; Benatti, Cristina; Mascalzoni, Deborah; Tascedda, Fabio; Pani, Luca
abstract
2022
- Fluoride affects memory by altering the transcriptional activity in the central nervous system of Lymnaea stagnalis
[Articolo su rivista]
Rivi, V.; Batabyal, A.; Wiley, B.; Benatti, C.; Tascedda, F.; Blom, J. M. C.; Lukowiak, K.
abstract
Fluoride (F-), has been found to affect learning and memory in several species. In this study, we exposed an F--naïve, inbred strain of Lymnaea stagnalis to a concentration of F- similar to that naturally occurring in wild ponds. We found that the exposure to F- before the configural learning procedure obstructs the memory formation and blocks the configural learning-induced upregulation of CREB1, GRIN1, and HSP70 in snails' central ring ganglia. Along with altering the mRNA levels of these key genes for memory formation, a single acute F- exposure also upregulates Cytochrome c Oxidase, a major regulatory enzyme of the electron transport chain, which plays direct or indirect roles in reactive oxygen species production. As the central nervous system is sensitive to oxidative stress and consistent with previous studies from mammals, our results suggest a potential role of oxidative stress in memory impairment. To our knowledge, this is the first study investigating the neuronal mechanism of memory impairment in an invertebrate species that is exposed to natural F- levels.
2022
- Identification and characterization of the kynurenine pathway in the pond snail Lymnaea stagnalis
[Articolo su rivista]
Benatti, Cristina; Rivi, Veronica; Alboni, Silvia; Grilli, Andrea; Castellano, Sara; Pani, Luca; Brunello, Nicoletta; Blom, Johanna Maria Catharina; Bicciato, Silvio; Tascedda, Fabio
abstract
2022
- Identifying child maltreatment in the 0-3 age group: A screening protocol for childcare professionals developed within the ECLIPS project.
[Abstract in Atti di Convegno]
Blom, J. M. C.; Benassi, Erika
abstract
2022
- Nature versus nurture in heat stress induced learning between inbred and outbred populations of Lymnaea stagnalis
[Articolo su rivista]
Rivi, V.; Batabyal, A.; Benatti, C.; Blom, J. M.; Lukowiak, K.
abstract
Changing environmental conditions often lead to microevolution of traits that are adaptive under the current selection pressure. Currently, one of the major selection pressures is the rise in temperatures globally that has a severe impact on the behavioral ecology of animals. However, the role of thermal stress on neuronal plasticity and memory formation is not well understood. Thermal tolerance and sensitivity to heat stress show variation across populations of the same species experiencing different thermal regimes. We used two populations of the pond snail Lymnaea stagnalis: one lab-bred W-snails and the other wild Delta snails to test heat shock induced learning and memory formation for the Garcia effect learning paradigm. In Garcia effect, a single pairing of a heat stressor (30 °C for 1h) with a novel taste results in a taste-specific negative hedonic shift lasting 24h as long-term memory (LTM) in lab bred W-snails. In this study we used a repeated heat stress procedure to test for increased or decreased sensitivity to the heat before testing for the Garcia effect. We found that lab-bred W-snails show increased sensitivity to heat stress after repeated heat exposure for 7days, leading to enhanced LTM for Garcia effect with only 15min of heat exposure instead of standard 1h. Surprisingly, the freshly collected wild snails do not show Garcia effect. Additionally, F1 generation of wild snails raised and maintained under laboratory conditions still retain their heat stress tolerance similar to their parents and do not show a Garcia effect under standard learning paradigm or even after repeated heat stressor. Thus, we found a differential effect of heat stress on memory formation in wild and lab bred snails. Most interestingly we also show that local environmental (temperature) conditions for one generation is not enough to alter thermal sensitivity in a wild population of L. stagnalis.
2022
- Recommendations for the surveillance of mental health problems in childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group
[Articolo su rivista]
Marchak, J. G.; Christen, S.; Mulder, R. L.; Baust, K.; Blom, J. M. C.; Brinkman, T. M.; Elens, I.; Harju, E.; Kadan-Lottick, N. S.; Khor, J. W. T.; Lemiere, J.; Recklitis, C. J.; Wakefield, C. E.; Wiener, L.; Constine, L. S.; Hudson, M. M.; Kremer, L. C. M.; Skinner, R.; Vetsch, J.; Lee, J. L.; Michel, G.
abstract
Survivors of childhood, adolescent, and young adult (diagnosed when <25 years of age) cancer are at risk of mental health problems. The aim of this clinical practice guideline is to harmonise international recommendations for mental health surveillance in survivors of childhood, adolescent, and young adult cancer. This guideline was developed by a multidisciplinary panel of experts under the sponsorship of the International Guideline Harmonization Group. We evaluated concordance among existing survivorship clinical practice guidelines and conducted a systematic review following evidence-based methods. Of 7249 studies identified, 76 articles from 12 countries met the inclusion criteria. Recommendations were formulated on the basis of identified evidence in combination with clinical considerations. This international clinical practice guideline strongly recommends mental health surveillance for all survivors of childhood, adolescent, and young adult cancers at every follow-up visit and prompt referral to mental health specialists when problems are identified. Overall, the recommendations reflect the necessity of mental health surveillance as part of comprehensive survivor-focused health care.
2022
- The Use of Psychotropic Medication in Pediatric Oncology for Acute Psychological and Psychiatric Problems: Balancing Risks and Benefits
[Articolo su rivista]
Blom, Johanna M C; Barisone, Elena; Bertolotti, Marina; Caprino, Daniela; Cellini, Monica; Clerici, Carlo Alfredo; Colliva, Chiara; Favara-Scacco, Cinzia; Di Giuseppe, Silvia; Jankovic, Momcilo; Pancaldi, Alessia; Pani, Luca; Poggi, Geraldina; Rivi, Veronica; Tascedda, Fabio; Torta, Riccardo; Scarponi, Dorella
abstract
Severe acute behavioral and emotional problems represent one of the most serious treatment-related adverse effects for children and adolescents who have cancer. The critical and severe nature of these symptoms often makes necessary the use of psychotropic drugs. A working group composed of experts in multiple disciplines had the task of creating an agreement regarding a management plan for severe acute behavioral and emotional problems (SABEPs) in children and adolescents treated for cancer. To obtain global information on the use of psychotropic drugs in pediatric oncology, the working group first developed and mailed a 15-item questionnaire to many Italian pediatric oncology centers. Overall, an evident lack of knowledge and education regarding the use of psychotropic medications for the treatment of SABEPs was found. Thus, by referring to an adapted version of the Delphi method of consensus and standard methods for the elaboration of clinical questions (PICOs), the working group elaborated evidence-based recommendations for psychotropic drugs in the pediatric oncology setting. Furthermore, based on a thorough multivariate analysis of needs and difficulties, a comprehensive management flow was developed to optimize therapeutic interventions, which allows more accurate and efficient matching of the acute needs of patients while guiding treatment options.
2022
- Too Hot to Eat: Wild and Lab-Bred Lymnaea stagnalis Differ in Feeding Response Following Repeated Heat Exposure
[Articolo su rivista]
Rivi, V.; Batabyal, A.; Benatti, C.; Tascedda, F.; Blom, J. M.; Lukowiak, K.
abstract
AbstractAcute extreme heat events are increasing in frequency and intensity. Understanding their effects on ectothermic organisms' homeostasis is both important and urgent. In this study we found that the exposure to an acute heat shock (30 °C for 1 hour) repeated for a seven-day period severely suppressed the feeding behavior of laboratory-inbred (W-strain) Lymnaea stagnalis, whereas the first-generation offspring of freshly collected wild (F1 D-strain) snails raised and maintained under similar laboratory conditions did not show any alterations. The W-strain snails might have inadvertently been selected against heat tolerance since they were first brought into the laboratory many (∼70) years ago. We also posit that the F1 D-strain snails do not perceive the heat shock as a sufficient stressor to alter their feeding response because their parental populations in wild environments have repeatedly experienced temperature fluctuations, thus becoming more tolerant and resilient to heat. The different responses exhibited by two strains of the same species highlight the importance of selecting the most appropriate strain for addressing questions about the impacts of global warming on organisms' physiology and behavior.
2021
- Digital Phenotyping and Dynamic Monitoring of Adolescents Treated for Cancer to Guide Intervention: Embracing a New Era
[Articolo su rivista]
Blom, J. M. C.; Colliva, C.; Benatti, C.; Tascedda, F.; Pani, L.
abstract
2021
- How to humanise the COVID-19 intensive care units
[Articolo su rivista]
Rivi, V.; Melegari, G.; Blom, J. M. C.
abstract
2021
- Long term memory of configural learning is enhanced via CREB upregulation by the flavonoid Quercetin in Lymnaea stagnalis
[Articolo su rivista]
Batabyal, Anuradha; Rivi, Veronica; Benatti, Cristina; Blom, Johanna M. C.; Lukowiak, Ken
abstract
2021
- To eat or not to eat: a Garcia effect in pond snails (Lymnaea stagnalis)
[Articolo su rivista]
Rivi, Veronica; Batabyal, Anuradha; Juego, Karla; Kakadiya, Mili; Benatti, Cristina; Blom, Johanna M C; Lukowiak, Ken
abstract
Taste aversion learning is universal. In animals, a single presentation of a novel food substance followed hours later by visceral illness causes animals to avoid that taste. This is known as bait-shyness or the Garcia effect. Humans demonstrate this by avoiding a certain food following the development of nausea after ingesting that food ('Sauce Bearnaise effect'). Here, we show that the pond snail Lymnaea stagnalis is capable of the Garcia effect. A single 'pairing' of a novel taste, a carrot slurry followed hours later by a heat shock stressor (HS) is sufficient to suppress feeding response elicited by carrot for at least 24 h. Other food tastes are not suppressed. If snails had previously been exposed to carrot as their food source, the Garcia-like effect does not occur when carrot is 'paired' with the HS. The HS up-regulates two heat shock proteins (HSPs), HSP70 and HSP40. Blocking the up-regulation of the HSPs by a flavonoid, quercetin, before the heat shock, prevented the Garcia effect in the snails. Finally, we found that snails exhibit Garcia effect following a period of food deprivation but the long-term memory (LTM) phenotype can be observed only if the animals are tested in a food satiated state.
2021
- Vortioxetine Prevents Lipopolysaccharide-Induced Memory Impairment Without Inhibiting the Initial Inflammatory Cascade
[Articolo su rivista]
Alboni, S.; Benatti, C.; Colliva, C.; Radighieri, G.; Blom, J. M. C.; Brunello, N.; Tascedda, F.
abstract
Vortioxetine is a novel multimodal antidepressant that modulates a wide range of neurotransmitters throughout the brain. Preclinical and clinical studies have shown that vortioxetine exerts positive effects on different cognitive domains and neuroprotective effects. Considering the key role of microglial cells in brain plasticity and cognition, we aimed at investigating the effects of pretreatment with vortioxetine in modulating behavioral and molecular effects induced by an immune challenge: peripheral injection of lipopolysaccharide (LPS). To this purpose, C57BL/6J male mice were first exposed to a 28-day standard diet or vortioxetine-enriched diet, which was followed by an acute immune challenge with LPS. Sickness symptoms and depressive-like behaviors (anhedonia and memory impairment) were tested 6 and 24 h after exposure to LPS, respectively. Moreover, the expressions of markers of immune activation and M1/M2 markers of microglia polarization were measured in the dorsal and ventral parts of the hippocampus. The pretreatment with vortioxetine did not affect both LPS-induced sickness behavior and anhedonia but prevented the deficit in the recognition memory induced by the immune challenge. At the transcriptional level, chronic exposure to vortioxetine did not prevent LPS-induced upregulation of proinflammatory cytokines 6 h after the immune challenge but rather seemed to potentiate the immune response to the challenge also by affecting the levels of expression of markers of microglia M1 phenotype, like cluster of differentiation (CD)14 and CD86, in an area-dependent manner. However, at the same time point, LPS injection significantly increased the expression of the M2 polarization inducer, interleukin 4, only in the hippocampus of animals chronically exposed to vortioxetine. These results demonstrate that a chronic administration of vortioxetine specifically prevents LPS-induced memory impairment, without affecting acute sickness behavior and anhedonia, and suggest that hippocampal microglia may represent a cellular target of this novel antidepressant medication. Moreover, we provide a useful model to further explore the molecular mechanisms specifically underlying cognitive impairments following an immune challenge.
2021
- What can we teach Lymnaea and what can
Lymnaea teach us?
[Articolo su rivista]
Rivi, Veronica; Benatti, Cristina; Lukowiak, Ken; Colliva, Chiara; Alboni, Silvia; Tascedda, Fabio; Blom, Johanna M. C.
abstract
2020
- Biological and neuropsychological markers of cognitive dysfunction in unipolar vs bipolar Depression: What evidence do we have?
[Articolo su rivista]
Platania, G. A.; Varrasi, S.; Castellano, S.; Godos, J.; Pirrone, C.; Petralia, M. C.; Cantarella, R. A.; Tascedda, F.; Guerrera, C. S.; Buono, S.; Caraci, F.; Blom, J. M. C.
abstract
Cognition is a critical aspect of psychopathology. The aim of this review is to evaluate and discuss evidence on the biological and neuropsychological markers of cognitive dysfunction in unipolar and bipolar Depression to improve the differential diagnosis and develop plans of personalized pharmacological treatment. The different use of biological and neuropsychological markers is reviewed and their use to support the clinical process and differential diagnosis is critically examined. While biological markers can help to reduce the risk of misdiagnosis, neuropsychological markers can be assessed more readily and with a less invasive methodology. To this end, additional research on the thresholds differentiating the cognitive dysfunction in unipolar and bipolar Depression should be conducted on specific psychometric tools proposed in this review. Most importantly future effort should be directed towards the validation of both types of markers specifically for these two populations. Finally this review contributes to the field by focusing on the clinical need of a precise differential diagnosis that, when put in a translational framework, should combine an integration of research and clinical practice allowing for a better understanding of mental health and for evidence-based clinical practice.
2020
- Lymnaea stagnalis as model for translational neuroscience research: from pond to bench
[Articolo su rivista]
Rivi, Veronica; Benatti, C; Colliva, C; Radighieri, G; Brunello, N; Tascedda, F; Blom, Johanna
abstract
The purpose of this review is to illustrate how a reductionistic, but sophisticated, approach based on the use of a simple model system such as the pond snail Lymnaea stagnalis (L. stagnalis), might be useful to address fundamental questions in learning and memory. L. stagnalis, as a model, provides an interesting platform to investigate the dialog between the synapse and the nucleus and vice versa during memory and learning. More importantly, the "molecular actors" of the memory dialogue are well-conserved both across phylogenetic groups and learning paradigms, involving single- or multi-trials, aversion or reward, operant or classical conditioning. At the same time, this model could help to study how, where and when the memory dialog is impaired in stressful conditions and during aging and neurodegeneration in humans and thus offers new insights and targets in order to develop innovative therapies and technology for the treatment of a range of neurological and neurodegenerative disorders.
2020
- Mind the Mother When Considering Breastfeeding
[Articolo su rivista]
Rivi, Veronica; Petrilli, Greta; Blom, Johanna M. C.
abstract
2020
- P.304 Executive functioning and genetic variation in pediatric patients with cancer
[Abstract in Rivista]
Colliva, C.; Dalla Porta, M. F.; Ferrari, M.; Benatti, C.; Cellini, M.; Brunello, N.; Blom, J. M.
abstract
2020
- Psychosocial assessment of families caring for a child with acute lymphoblastic leukemia, epilepsy or asthma: Psychosocial risk as network of interacting symptoms
[Articolo su rivista]
Colliva, C.; Cellini, M.; Porta, F. D.; Ferrari, M.; Bergamini, B. M.; Guerra, A.; Di Giuseppe, S.; Pinto, A.; Capasso, R.; Caprino, D.; Ferrari, M.; Benatti, C.; Tascedda, F.; Blom, J. M. C.
abstract
The purpose of this study is to assess psychosocial risk across several pediatric medical conditions and test the hypothesis that different severe or chronic pediatric illnesses are characterized by disease specific enhanced psychosocial risk and that risk is driven by disease specific connectivity and interdependencies among various domains of psychosocial function using the Psychosocial Assessment Tool (PAT). In a multicenter prospective cohort study of 195 patients, aged 5-12, 90 diagnosed with acute lymphoblastic leukemia (ALL), 42 with epilepsy and 63 with asthma, parents completed the PAT2.0 or the PAT2.0 generic version. Multivariate analysis was performed with disease as factor and age as covariate. Graph theory and network analysis was employed to study the connectivity and interdependencies among subscales of the PAT while data-driven cluster analysis was used to test whether common patterns of risk exist among the various diseases. Using a network modelling approach analysis, we observed unique patterns of interconnected domains of psychosocial factors. Each pathology was characterized by different interdependencies among the most central and most connected domains. Furthermore, data-driven cluster analysis resulted in two clusters: patients with ALL (89%) mostly belonged to cluster 1, while patients with epilepsy and asthma belonged primarily to cluster 2 (83% and 82% respectively). In sum, implementing a network approach improves our comprehension concerning the character of the problems central to the development of psychosocial difficulties. Therapy directed at problems related to the most central domain(s) constitutes the more rational one because such an approach will inevitably carry over to other domains that depend on the more central function.
2020
- Redefining operant conditioning of escape behaviour in lymnaea stagnalis
[Articolo su rivista]
Benatti, C.; Rivi, V.; Colliva, C.; Radighieri, G.; Tascedda, F.; Blom, J. M. C.
abstract
The escape behaviour is one of the many behavioural responses that can be operantly conditioned in a stimulus-dependent manner in both vertebrates and invertebrates. By exposing the pond snail Lymnaea stagnalis repeatedly to a negative reinforcement its natural tendency to explore its surroundings can be operantly conditioned in both adult and aged snails. When adult snails were trained with 100 mM of KCl their number of escapes was significantly decreased and the latency to first escape was significantly increased. Our behavioural protocol allowed us to investigate memory acquisition, consolidation, and retrieval in pre-and post-training sessions over different days. From the 3rd day of training the learned response was strengthened: the number of the escapes in the post-test session remained significantly reduced even when animals were presented with distilled water. Moreover, adult snails exposed to the negative reinforcement for at least 4 days started to escape significantly less than the control group also in the pre-test session. This effect became more pronounced in the following days and was accompanied by a significant increase in the latency to first escape at the beginning of the pre-test on day 6 and 7. Aged snails, instead, showed selective deficiencies when operantly conditioned: memory retention appeared only after 7 days, while memory retrieval could not be induced. This redefined paradigm can help unravelling a variety of sophisticated cognitive phenomena in L. stagnalis and could be employed also to study the basis of memory impairment occurring during neuro-aging.
2019
- Executive functioning in children with epilepsy: Genes matter
[Articolo su rivista]
Colliva, Chiara; Ferrari, Marta; Benatti, Cristina; Guerra, Azzurra; Tascedda, Fabio; Blom, Johanna Maria Catharina
abstract
Pediatric epilepsy has emerged as a chronic medical disease with a characteristic behavioral and cognitive phenotype, which includes compromised executive functioning (EF) and attention-related deficits. However, considerable interindividual variability exists; children often display very different or even opposite outcomes, and some children are more likely than others to develop neurocognitive problems in the face of similar individual and disease-related problems. The factors responsible for this interindividual variability are still largely unknown, but we do know that some genetic factors render the developing brain more susceptible to damage or traumatic experiences than others. Dopamine availability has a neuromodulatory function in the prefrontal cortex (PFC) and especially affects EF. Dopamine availability relates to polymorphisms in the gene encoding catechol-O-methyltransferase (COMT Val158Met), which in turn is affected by the methylation state of its promoter. Allelic variation of the methylenetetrahydrofolate reductase (MTHFR C677T) gene, alters methylation and may influence the methylation state of the COMT promoter. Given this, we tested the hypothesis that these polymorphisms interact in children with epilepsy, and that variability in allelic expression is associated with variability in cognitive phenotype. Executive function was tested directly and indirectly (parent-rated) in 42 children between 5 and 12 years of age. The MTHFR T allele carriers performed worse than MTHFR homozygous CC carriers on indirect EF, and a significant decline was observed when T allele carriers had at least one met allele of the COMT gene, especially on Working Memory. Direct EF was significantly compromised in COMT Val/Val carriers where reduced dopamine availability seems to confer a higher risk in a test that requests a high degree of executive attention and planning. This finding suggests that in children with epilepsy, genes that influence methylation and dopamine availability affect PFC-related EF. Therefore, we should consider genetic vulnerability as a polygenic risk, which might predispose for a particular phenotype and include specific genetic signatures as part of each patient's behavioral and cognitive profile from the moment that we start to take care of the child.
2019
- Modulation of neuroplasticity-related targets following stress-induced acute escape deficit
[Articolo su rivista]
Benatti, C.; Radighieri, Giulia; Alboni, S.; Blom, J. M. C.; Brunello, N.; Tascedda, F.
abstract
Understanding resilience is a major challenge to improve current pharmacological therapies aimed at complementing psychological-based approaches of stress-related disorders. In particular, resilience is a multi-factorial construct where the complex network of molecular events that drive the process still needs to be resolved. Here, we exploit the acute escape deficit model, an animal model based on exposure to acute unavoidable stress followed by an escape test, to define vulnerable and resilient phenotypes in rats. Hippocampus and prefrontal cortex (PFC), two of the brain areas most involved in the stress response, were analysed for gene expression at two different time points (3 and 24 h) after the escape test. Total Brain-Derived Neurotrophic Factor (BDNF) was highly responsive in the PFC at 24-h after the escape test, while expression of BDNF transcript IV increased in the hippocampus of resistant animals 3 h post-test. Expression of memory enhancers like Neuronal PAS Domain Protein 4 (Npas4) and Activity-regulated cytoskeleton-associated protein (Arc) decreased in a time- and region-dependent fashion in both behavioural phenotypes. Also, the memory inhibitor Protein Phosphatase 1 (Ppp1ca) was increased in the hippocampus of resilient rats at 3 h post-test. Given the importance of neurotrophic factors and synaptic plasticity-related genes for the development of appropriate coping strategies, our data contribute to an additional step forward in the comprehension of the psychobiology of stress and resiliency.
2019
- P.1.04 Expression of histone variants H3.3 and H2a.z in the rat brain: Physiopathological and pharmacological implications
[Abstract in Rivista]
Radighieri, G.; Benatti, C.; Zoli, M.; Blom, J. M. C.; Brunello, N.; Tascedda, F.
abstract
In the overall context of epigenetic modifications in charge of managing genome plasticity and dynamics [1, 2], the role of nucleosomal loading of histone variants is becoming increasingly captivating. Two replication-independent isoforms of histones H3 and H2A, namely H3.3 and H2A.Z, have caught attention because of their involvement in neuronal plasticity processes, cognitive functions and behavioral outcomes. In fact, their incorporation/eviction in nucleosomes and their turnover in neurons influence chromatin accessibility and therefore transcription. H3.3 enrichment at gene bodies and promoters of genes involved in synaptic plasticity was proved to be positively correlated with their expression, while learning-induced H2A.Z eviction in specific genes promotes gene transcription, intervening in memory consolidation processes. H3.3 is encoded by H3f3a and H3f3b independent genes, generating identical proteins, namely H3.3A and H3.3B. Notably, H3f3b gene, but not H3f3a, was proved responsive to neuronal activating stimuli as well as environmental triggers and stressful procedures [3]. H2A.Z hypervariants H2A.Z.1 and H2A.Z.2, encoded respectively by H2afz and H2afv genes, regulate both basal and stimulus-induced neuronal gene expression of independent gene sets [4]. Starting from this evidence, the purpose of this study was to characterize basal expression levels of all genes encoding for the histones variants above mentioned in rodent hippocampus and prefrontal cortex (PFC), two brain regions closely related to brain plasticity, cognition and behavior. Adult male rats (n=7) were sacrificed, their brains removed and dissected. Total RNA extraction was performed, followed by total RNA reverse transcription and Real Time PCR, where specific forward and reverse primer were used for each gene encoding for H3.3 (H3f3a and H3f3b), H2A.Z (H2afz and H2afv) and endogenous control GAPDH. Statistical analysis was performed by means of one-way ANOVA; p<0.05 was considered as a threshold for statistically significant difference. Molecular analyses revealed that, for both hippocampus and PFC, H3f3a mRNA was more expressed at the steady-state compared to H3f3b (p<0.001), as happens for H2afz mRNA, which displays higher levels than H2afv (p<0.001). Moreover, comparing hippocampal and PFC mRNA levels for each variant, H3f3a and H3f3b expression was increased in the hippocampus with respect to the prefrontal cortex (p<0.001), and a comparable outcome was showed for H2afv (p<0.001) but not for H2afz (p>0.05). Our results suggest that 1) differential basal expression levels of genes encoding for H3.3 and H2A.Z may underlie unique gene responsiveness following different stimuli, as previously hypothesized by others [3,4], and this may be crucial in highly-responsive, pathological- and environment-related tissues like hippocampus and PFC; 2) striking lower steady-state expression of H3f3b and H2afv genes might imply a major sensitivity to neuronal inputs compared to their correspondent counterparts; 3) higher expression levels in the hippocampus with respect to the PFC might underpin brain-region specific expression and function for histone variants and their isoforms. Together, these data clear the way for further studies meant at investigating stimulus-dependent regulation of H3.3 and H2A.Z gene isoforms expression and their putative involvement in the physiopathology of brain and its diseases [5]. References [1] Rigillo, G., Vilella, A., Benatti, C., Schaeffer, L., Brunello, N., Blom, J.M.C., Zoli, M., Tascedda, F., 2018. LPS-induced histone H3 phospho(Ser10)-acetylation(Lys14) regulates neuronal and microglial neuroinflammatory response. Brain Behav Immun. https://doi.org/10.1016/j.bbi.2018.09.019. [2] Ottaviani, E., Accorsi, A., Rigillo, G., Malagoli, D., Blom, J.M., Tascedda, F., 2013. Epigenetic modification in neurons of the mollusc Pomacea canaliculata after immune challe
2019
- The many faces of mitochondrial dysfunction in depression: From pathology to treatment
[Articolo su rivista]
Caruso, G.; Benatti, C.; Blom, J. M. C.; Caraci, F.; Tascedda, F.
abstract
Introduction
The last years of neurobiological research have transformed the way we consider mental illnesses. We have gone from a deterministic genetic view to a broader vision that includes the involvement of non-cerebral systems. This is especially true for major depression (MD). Historically, MD has been perceived as a multifactorial disorder correlated to various neurobiological changes like neurotransmitter deficits, endocrine disturbances, impaired plasticity, and neural adaptation (Benatti et al., 2016). Indeed, the development and progression of depressive disorders has been conceived as the disruption of body allostasis, defined as the process of achieving stability of physiological and mental processes through dynamic change (Wang et al., 2019). The main player in the “allostatic game” is the brain, an organ designed to integrate signals from the periphery that anticipate fluctuations, changes, and needs and coordinates allostatic mediators in order to develop successful coping mechanisms that ultimately lead to an adaptative strategy and resilience (de Kloet et al., 2005).
The establishment and maintenance of these mechanisms requires large amounts of energy from the organism. Without energy, or in a partial lack of energy, the biological mechanisms necessary to respond appropriately to stimuli may not occur or be established incorrectly or abnormally.
Human and animal studies suggest an intriguing link between our body’s ability to produce energy and the brain’s ability to correctly perform the complex cellular and molecular processes involved in allostatic processes.
In eukaryotic cells, mitochondria are the powerhouse that produces and distributes energy to all other components. Functional or quantitative alterations of the ability of mitochondria to adequately supply energy can have important repercussions primarily on cellular processes and cascades of serial events (Herst et al., 2017) as well as on the correct functioning of the organism including mechanisms of brain plasticity, mood, and behavior in general (Allen et al., 2018). In this framework, it is particularly intriguing to think of the mitochondria as an active regulator of many of the biological phenomena involved in depression and in the efficacy of or resistance to the most widely used pharmacological treatments.
Once the energetic equilibrium is compromised, the body becomes more “vulnerable.” This is especially true for stress-related disorders, such as depression. In fact, depression is often associated with energetic imbalance leading to profound effects on the disease (Zuccoli et al., 2017). The driving questions then are as follows: What happens to the brain in the presence of an energetic imbalance? Does depression or depression-related symptoms impact mitochondrial energetic efficiency? Is antidepressant efficacy mediated by mitochondrial functionality?
2018
- LPS-induced histone H3 phospho(Ser10)-acetylation(Lys14) regulates neuronal and microglial neuroinflammatory response
[Articolo su rivista]
Rigillo, Giovanna; Vilella, Antonietta; Benatti, Cristina; Schaeffer, Laurent; Brunello, Nicoletta; Blom, Johanna M. C.; Zoli, Michele; Tascedda, Fabio
abstract
Epigenetic modifications of DNA and histone proteins are emerging as fundamental mechanisms by which neural cells adapt their transcriptional response to environmental cues, such as, immune stimuli or stress. In particular, histone H3 phospho(Ser10)-acetylation(Lys14) (H3S10phK14ac) has been linked to activation of specific gene expression. The purpose of this study was to investigate the role of H3S10phK14ac in a neuroinflammatory condition. Adult male rats received a intraperitoneal injection of lipopolysaccharide (LPS) (830 μg/Kg/i.p., n = 6) or vehicle (saline 1 mL/kg/i.p., n = 6) and were sacrificed 2 or 6 h later. We showed marked region- and time-specific increases in H3S10phK14ac in the hypothalamus and hippocampus, two principal target regions of LPS. These changes were accompanied by a marked transcriptional activation of interleukin (IL) 1β, IL-6, Tumour Necrosis Factor (TNF) α, the inducible nitric oxide synthase (iNOS) and the immediate early gene c-Fos. By means of chromatin immunoprecipitation, we demonstrated an increased region- and time-specific association of H3S10phK14ac with the promoters of IL-6, c-Fos and iNOS genes, suggesting that part of the LPS-induced transcriptional activation of these genes is regulated by H3S10phK14ac. Finally, by means of multiple immunofluorescence approach, we showed that increased H3S10phK14ac is cell type-specific, being neurons and reactive microglia, the principal histological types involved in this response. Present data point to H3S10phK14ac as a principal epigenetic regulator of neural cell response to systemic LPS and underline the importance of distinct time-, region- and cell-specific epigenetic mechanisms that regulate gene transcription to understand the mechanistic complexity of neuroinflammatory response to immune challenges.
2018
- Molecular changes associated with escitalopram response in a stress-based model of depression
[Articolo su rivista]
Benatti, Cristina; Alboni, Silvia; Blom, Johanna Maria Catharina; Mendlewicz, Julien; Tascedda, Fabio; Brunello, Nicoletta
abstract
Converging evidence points at hypothalamus-pituitary-adrenal (HPA) axis hyperactivity and neuroinflammation as important factors involved in the etiopathogenesis of major depressive disorder (MDD) and in therapeutic efficacy of antidepressants. In this study, we examined the molecular effects associated with a response to a week-long treatment with escitalopram in the chronic escape deficit (CED) model, a validated model of depression based on the induction of an escape deficit after exposure of rats to an unavoidable stress. We confirmed our previous result that a treatment with escitalopram (10 mg/kg) was effective after 7 days in reverting the stress-induced escape deficit in approximately 50% of the animals, separating responders from non-responders. Expression of markers of HPA axis functionality as well as several inflammatory mediators were evaluated in the hypothalamus, a key structure integrating signals from the neuro, immune, endocrine systems. In the hypothalamus of responder animals we observed a decrease in the expression of CRH and its receptors and an increase in GR protein in total and nuclear extracts; this effect was accompanied by a significant decrease in circulating corticosterone in the same cohort. Hypothalamic IL-1β and TNFα expression were increased in stressed animals, while CXCL2, IL-6, and ADAM17 mRNA levels were decreased in escitalopram treated rats regardless of the treatment response. These data suggest that efficacy of a one week treatment with escitalopram may be partially mediated by a decrease HPA axis activity, while in the hypothalamus the drug-induced effects on the expression of immune modulators did not correlate with the behavioural outcome.
2017
- Immune-Neuroendocrine Interactions: Evolution, Ecology, and Susceptibility to Illness
[Articolo su rivista]
Blom, Johanna M. C.; Ottaviani, Enzo
abstract
The integration between immune and neuroendocrine systems is crucial for maintaining homeostasis from invertebrates to humans. In the first, the phagocytic cell, i.e., the immunocyte, is the main actor, while in the latter, the principle player is the lymphocyte. Immunocytes are characterized by the presence of pro-opiomelanocortin (POMC) peptides, CRH, and other molecules that display a significant similarity to their mammalian counterparts regarding their functions, as both are mainly involved in fundamental functions such as immune (chemotaxis, phagocytosis, cytotoxicity, etc.) and neuroendocrine (stress) responses. Furthermore, the immune-neuroendocrine system provides vital answers to ecological and immunological demands in terms of economy and efficiency. Finally, susceptibility to disease emerges as the result of a continuous dynamic interaction between the world within and the world outside. New fields such as ecological immunology study the susceptibility to pathogens in an evolutionary perspective while the field of neuro-endocrine-immunology studies the susceptibility from a more immediate perspective.
2017
- Transcriptional effect of serotonin in the ganglia of Lymnaea stagnalis
[Articolo su rivista]
Benatti, Cristina; Colliva, Chiara; Blom, Johanna Maria Catharina; Ottaviani, Enzo; Tascedda, Fabio
abstract
The serotonin system (5HT) is highly conserved in both vertebrates and invertebrates, and numerous evidence supports a biological link between 5HT and numerous animal function. In the present paper we evaluated the transcriptional effects of a serotonergic stimulation on selected targets involved in 5HT signalling and neurotransmission in the central nervous system of the great pond snail Lymnaea stagnalis. Adult snails were treated acutely (6 h) or chronically (48 h) with either 5-hydroxytrypthophan (5-HTP 1mM), the immediate precursor of serotonin, fluoxetine (FLX 1μM), a selective serotonin reuptake inhibitor, or a combination of two. The central ring ganglia were dissected and used for q-PCR gene expression analysis. Transcription was strongly induced following a chronic, but not an acute, exposure to 5-HTP in the ganglia of Lymnaea. In particular, LymCREB1 and LymP2X mRNA levels were decreased following a 6 h exposure and increased in snails receiving 5-hydroxytryptophan for 48 h. Interestingly, this effect was reduced when snails were exposed chronically to both 5-HTP and FLX, suggesting a role for SERT in mediating the effect of 5-hydroxytryptophan. These data suggest that L. stagnalis is suited to unravel the complexity of the serotonin signaling pathway.
2016
- Disease-induced neuroinflammation and depression
[Articolo su rivista]
Benatti, Cristina; Blom, Johanna Maria Catharina; Rigillo, Giovanna; Alboni, Silvia; Zizzi, Francesca; Torta, Riccardo; Brunello, Nicoletta; Tascedda, Fabio
abstract
Progression of major depression, a multifactorial disorder with a neuroinflammatory signature, seems to be associated with the disruption of body allostasis. High rates of comorbidity between depression and specific medical disorders, such as, stroke, chronic pain conditions, diabetes mellitus, and human immunodeficiency virus (HIV) infection, have been extensively reported. In this review, we discuss how these medical disorders may predispose an individual to develop depression by examining the impact of these disorders on some hallmarks of neuroinflammation known to be impaired in depressed patients: altered permeability of the blood brain barrier, immune cells infiltration, activated microglia, increased cytokines production, and the role of inflammasomes. In all four pathologies, blood brain barrier integrity was altered, allowing the infiltration of peripheral factors, known to activate resident microglia. Evidence indicated morphological changes in the glial population, increased levels of circulating pro-inflammatory cytokines or increased production of these mediators within the brain, all fundamental in neuroinflammation, for the four medical disorders considered. Moreover, activity of the kynurenine pathway appeared to be enhanced. With respect to the inflammasome NLRP3, a new target whose role in neuroinflammation is emerging as being important, accumulating data suggest its involvement in the pathogenesis of brain injury following stroke, chronic pain conditions, diabetes mellitus or in HIV associated immune impairment. Finally, data gathered over the last 10 years, indicate and confirm that depression, stroke, chronic pain, diabetes, and HIV infection share a combination of underlying molecular, cellular and network mechanisms leading to a general increase in the neuroinflammatory burden for the individual.
2016
- Use of Psychotropic Drugs for Acute Psychiatric and Behavioral Problems in Paediatric Oncology: A Multi-Center Study
[Abstract in Atti di Convegno]
Blom, Johanna Maria Catharina; Bertolotti, M; Barisone, E; Di Giuseppe, S; Scarponi, D; Vignola, V; Migliozzi, C; Pancaldi, Alessia; Cellini, M; Tascedda, Fabio
abstract
Background/Objectives: : Children and adolescents diagnosed with cancer are forced in the most unexpected way to cope with an extraordinary, highly unlikely event. Such an experience can be extremely disruptive. When symptoms become pathological and impair a child's development and functioning, early intervention is warranted. Given that severe childhood and adolescent adversities may negatively impact adult mental health, our aim was to critically examine, the advantages and disadvantages of acute symptom management and (short-term) psychopharmacological interventions in these severely ill patients.
Design/Methods: Twenty-one patients (1-18 years old) diagnosed with cancer were enrolled in five centers. Categorical variables were analyzed with descriptive statistics and open-ended questions were examined qualitatively. Because of the importance of developmental phase, patients were divided in three age groups: 1) aged 1-6: 2) >6-11; and 3) >11-18. Variables included age, gender, the type of cancer, treatment protocol, oncologic treatment complications, the use of corticosteroids, methotrexate and vincristine, first onset of psychiatric symptoms, treatment approach to symptoms, and the possible presence of side effects due to psychotropic drugs.
Results: The development of psychiatric problems differed according to tumour type and treatment protocol. Also, age was an important factor: younger children (< 6 years) and adolescents (>12) were more vulnerable, especially when the CNS was directly or indirect involved. Finally, the necessity to use psychotropic drugs was related to treatment phase (the first six months of treatment), and to treatments involving corticosteroids.
Conclusion: Psychotropic drug use in children is still extremely controversial, and seems like a catch-22, in which a true solution or desired outcome is almost impossible. However, efficient and prompt management of mainly acute behavioral or psychiatric symptoms during treatment might help improve quality of life as well as psychological, functional, and medical outcomes for a child or adolescent who is trying to handle their cancer.
2015
- Molluscs as models for translational medicine
[Articolo su rivista]
Tascedda, Fabio; Malagoli, Davide; Accorsi, Alice; Rigillo, Giovanna; Blom, Johanna Maria Catharina; Ottaviani, Enzo
abstract
This paper describes the advantages of adopting a molluscan model for studying the biological basis of some central nervous system pathologies affecting humans. In particular, we will focus on the freshwater snail Lymnaea stagnalis, which is already the subject of electrophysiological studies related to learning and memory, as well as ecotoxicological studies. The genome of L. stagnalis has been sequenced and annotated but the gene characterization has not yet been performed. We consider the characterization of the gene networks that play crucial roles in development and functioning of the central nervous system in L. stagnalis, an important scientific development that comparative biologists should pursue. This important effort would add a new experimental model to the limited number of invertebrates already used in studies of translational medicine, the discipline that seeks to improve human health by taking advantage of knowledge collected at the molecular and cellular levels in non-human organisms.
2015
- RESILIENCY OF CHILDREN AND ADOLESCENTS DURING TREATMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA: THE USE OF 5-HTT AND BDNF POLYMORPHISMS AS BIOMARKERS
[Abstract in Rivista]
Blom, Johanna Maria Catharina; Pomicino, L; Migliozzi, C; Montanari, L; Rigillo, Giovanna; Zanazzo, G; Cellini, M; Benatti, Cristina; Tascedda, Fabio
abstract
Background/Objectives: Why are some children more likely than others to develop resilience in the face of similar levels of trauma exposure as compared to others who do not. It is increasingly clear that there are critical roles for predisposing genetic and environmental influences in differentially mediating psychological risk. Resilience differs from traditional concepts of risk and protection in its focus on individual variations in response to comparable experiences. Here, we tested the hypothesis that anxiety and depression as well as neural repair and plasticity related polymorphisms may partly account for the difference in resilience observed during treatment for acute lymphoblastic leukemia (ALL).
Design/Methods: Forty-five patients (1-18 yrs old) diagnosed with ALL were enrolled in two centers (protocol AIEOP-BFM-2009) and genotyped for 5HTT and BDNF (val66met). Patients and their family were subjected to a short screening battery, psychosocial testing (PAT2.1) and a specific assessment of their resiliency during treatment. The resiliency scale was composed of three subscales: Sense of Mastery (MAS), Sense of Relatedness (REL), and Emotional Reactivity (REA).
Results: Patients with the SL allele of 5HTTLPR had a more compromised score in some areas of resiliency than patients with the LL allele; the presence of the S allele most affected emotional reactivity REA and sense of mastery MAS. Furthermore, age was an important factor, as younger children displayed a reduced trust and tolerance versus their surroundings. This then contributed importantly to an overall reduction in their overall resiliency. Also, resiliency was reduced one year into therapy while vulnerability was significantly enhanced.
Conclusion: Genes regulating susceptibility to stress, such as 5HTTLPR and BDNF, may help to predict susceptibility towards the development of resiliency in children and adolescents treated for cancer, and may play a critical role as a predisposing factor in differentially dealing efficiently with the emotional risks related to cancer and its treatment.
2014
- Behavioural and transcriptional effects of escitalopram in the chronic escape deficit model of depression
[Articolo su rivista]
Benatti, Cristina; Alboni, Silvia; Blom, Johanna Maria Catharina; Gandolfi, Francesco; Mendlewicz, Julien; Brunello, Nicoletta; Tascedda, Fabio
abstract
The study of depression is facing major challenges: first, the need to develop new drugs with a faster onset of action and second, fulfilling the unmet needs of treatment resistant patients with more effective compounds. The chronic escape deficit (CED) is a valid and useful model of depression and is based on the induction of an escape deficit after exposure of rats to an unavoidable stress. This behavioural model provides a method for evaluating the capacity of a treatment to revert the escape deficit. The majority of antidepressant drugs need to be administered for at least 3-4 weeks in order to revert the escape deficit. A 7-day treatment with escitalopram reverted the stress-induced escape deficit in approximately 50% of the animals. Escitalopram treatment decreased anxiety-related behaviours in stressed animals, by increasing the time spent in the central part of the arena with respect to saline treated stressed animals, without affecting exploratory related behaviours. Gene expression profiling was carried out in the hippocampus to identify new targets associated with the effects of stress or with the different response to escitalopram. By combining a well-validated animal model with gene expression analysis we demonstrated that the CED model may represent a perfect tool for studying treatment-resistant depression.
2014
- Interleukin 18 activates MAPKs and STAT3 but not NF-κB in hippocampal HT-22 cells
[Articolo su rivista]
Alboni, Silvia; Montanari, C; Benatti, Cristina; Sanchez Alavez, M; Rigillo, Giovanna; Blom, Johanna Maria Catharina; Brunello, Nicoletta; Conti, B; Pariante, Mc; Tascedda, Fabio
abstract
Interleukin (IL)-18 is a cytokine previously demonstrated to participate in neuroinflammatory processes. Since the components of the IL-18 receptor complex are expressed in neurons throughout the brain, IL-18 is also believed to directly influence neuronal function. Here we tested this hypothesis on mouse hippocampal neurons by measuring the effects of IL-18 on three pathways previously shown to be regulated by this cytokine in non-neuronal cells: the MAPK pathways, p38 and ERK1/2 MAPKs, STAT3 and NF-κB. Experiments were carried out in vitro using the immortalized hippocampal neuronal line HT-22 or in vivo following i.c.v. injection with recombinant mouse IL-18. We showed that IL-18 did not activate NF-κB in HT-22 cells whereas it induced a rapid (within 15min) activation of the MAPK pathways. Moreover, we demonstrated that IL-18 treatment enhanced P-STAT3 (Tyr705)/STAT3 ratio in the nucleus of HT-22 cells after 30-60min of exposure. A similar increase in P-STAT3 (Tyr705)/STAT3 ratio was observed in the whole hippocampus one hour after i.c.v. injection. These data demonstrate that IL-18 can act directly on neuronal cells affecting the STAT3 pathway; therefore, possibly regulating the expression of specific genes within the hippocampus. This effect may help to explain some of the IL-18-induced effects on synaptic plasticity and functionality within the hippocampal system.
2013
- Epigenetic modification in neurons of the mollusc Pomacea canaliculata after immune challenge
[Articolo su rivista]
Ottaviani, Enzo; Accorsi, Alice; Rigillo, Giovanna; Malagoli, Davide; Joan M. C., Blom; Tascedda, Fabio
abstract
In human and rodents, the transcriptional response of neurons to stress is related to epigenetic modifications of both DNA and histone proteins. To assess the suitability of simple invertebrate models in studying the basic mechanisms of stress-related epigenetic modifications, we analyzed epigenetic modifications in neurons of the freshwater snail Pomacea canaliculata after the injection of Escherichia coli-derived lipopolysaccharide (LPS). The phospho-acetylation of histone H3, together with the induction of stress-related factors, c-Fos and HSP70, were evaluated in large and small neurons of the pedal ganglia of sham- and LPS-injected snails. Immunocytochemical investigations showed that after LPS injection, the immunopositivity towards phospho (Ser10)-acetyl (Lys14)-histone H3 and c-Fos increases in the nuclei of small gangliar neurons. Western blot analysis confirmed a significant increase of phospho (Ser10)-acetyl (Lys14)-histone H3 in nuclear extracts from 2h LPS-injected animals. c-Fos protein levels were significantly augmented 6h after LPS injection. Immunocytochemistry and western blot indicated that no changes occurred in HSP70 distribution and protein levels. To our knowledge this is the first demonstration of epigenetic changes in molluscan neurons after an immune challenge and indicate the gastropod P. canaliculata as a suitable model for evolutionary and translational studies on stress-related epigenetic modifications.
2013
- The injection of LPS induces epigenetic changes in Pomacea canaliculata neurons. XIII Meeting of the Italian Association of Developmental and Comparative Immunology, Palermo, Inv. Surv. J., 10: 16, 2013
[Abstract in Rivista]
Accorsi, Alice; Rigillo, Giovanna; Malagoli, Davide; Blom, Johanna Maria Catharina; Tascedda, Fabio; Ottaviani, Enzo
abstract
The injection of LPS induces epigenetic changes in Pomacea canaliculata neurons
2012
- Transcriptional profiles underlying vulnerability and resilience in rats exposed to an acute unavoidable stress
[Articolo su rivista]
Benatti, Cristina; Valensisi, Cristina; Blom, Johanna Maria Catharina; Alboni, Silvia; Montanari, Claudia; Ferrari, Francesco; Tagliafico, Enrico; Julien, Mendlewicz; Brunello, Nicoletta; Tascedda, Fabio
abstract
A complex interplay between gene and environment influences the vulnerability or the resilience to stressful events. In the acute escape deficit (AED) paradigm, rats exposed to an acute unavoidable stress (AUS) develop impaired reactivity to noxious stimuli. Here we assessed the behavioral and molecular changes in rats exposed to AUS. A genome-wide microarray experiment generated a comprehensive picture of changes in gene expression in the hippocampus and the frontal cortex of animals exposed or not to AUS. Exposure to AUS resulted in two distinct groups of rats with opposite behavioral profiles: one developing an AED, called “stress vulnerable,” and one that did not develop an AED, called “stress resilient.” Genome-wide profiling revealed a low percentage of overlapping mechanisms in the two areas, suggesting that, in the presence of stress, resilience or vulnerability to AUS is sustained by specific changes in gene expression that can either buffer or promote the behavioral and molecular adverse consequences of stress. Specifically, we observed in the frontal cortex a downregulation of the transcript coding for interferon-β and leukemia inhibitory factor in resilient rats and an upregulation of neuroendocrine related genes, growth hormone and prolactin, in vulnerable rats. In the hippocampus, the muscarinic M2 receptor was downregulated in vulnerable but upregulated in resilient rats. Our findings demonstrate that opposite behavioral responses did not correspond to opposite regulatory changes of the same genes, but resilience rather than vulnerability to stress was associated with specific changes, with little overlap, in the expression of patterns of genes.
2011
- Central effects of a local inflammation in three commonly used mouse strains with a different anxious phenotype
[Articolo su rivista]
Benatti, Cristina; Alboni, Silvia; Montanari, Claudia; Caggia, Federica; Tascedda, Fabio; Brunello, Nicoletta; Blom, Johanna Maria Catharina
abstract
As in humans, genetic background in rodents may influence a peculiar set of behavioural traits such as sensitivity to pain and stressors or anxiety-related behaviours. Therefore, we tested the hypothesis that mice with different genetic backgrounds [outbred (CD1), inbred (C57BL/6J) and hybrid (B6C3F1) adult male mice] display altered reactivity to pain, stress and anxiety related behaviours. We demonstrated that B6C3F1 mice displayed the more anxious phenotype with respect to C57BL/6J or CD1 animals, with the latter being the less anxious strain when tested in an open field and on an elevated plus maze. No difference was observed across strains in thermal sensitivity to a radiant heat source. Mice were then treated with a sub-plantar injection of the inflammatory agent Complete Freund's Adjuvant (CFA), 24h later they were hyperalgesic with respect to saline exposed animals, irrespective of strain. We then measured intra-strain differences and CFA-induced inter-strain effects on the expression of various genes with a recognized role in pain and anxiety: BDNF, IL-6, IL-1β, IL-18 and NMDA receptor subunits in the mouse thalamus, hippocampus and hypothalamus. The more anxious phenotype observed in B6C3F1 hybrid mice displayed lower levels of BDNF mRNA in the hippocampus and hypothalamus when compared to outbred CD1 and C57BL/6J inbred mice. CFA led to a general decrease in central gene expression of the evaluated targets especially in CD1 mice, while BDNF hypothalamic downregulation stands out as a common effect of CFA in all three strains evaluated
2011
- Constitutive and LPS-regulated expression of interleukin-18 receptor beta variants in the mouse brain
[Articolo su rivista]
Alboni, Silvia; Montanari, Claudia; Benatti, Cristina; Blom, Johanna Maria Catharina; Simone, Ml; Brunello, Nicoletta; Caggia, Federica; Guidotti, G; Marcondes, Mc; Sanchez Alavez, M; Conti, B; Tascedda, Fabio
abstract
Interleukin (IL)-18 is a pro-inflammatory cytokine that is proposed to be involved in physiological as well as pathological conditions in the adult brain. IL-18 acts through a heterodimer receptor comprised of a subunit alpha (IL-18Rα) required for binding, and a subunit beta (IL-18Rβ) necessary for activation of signal transduction. We recently demonstrated that the canonical alpha binding chain, and its putative decoy isoform, are expressed in the mouse central nervous system (CNS) suggesting that IL-18 may act on the brain by directly binding its receptor. Considering that the co-expression of the beta chain seems to be required to generate a functional receptor and, a short variant of this chain has been described in rat and human brain, in this study we have extended our investigation to IL-18Rβ in mouse. Using a multi-methodological approach we found that: (1) a short splice variant of IL-18Rβ was expressed in the CNS even if at lower levels compared to the full-length IL-18Rβ variants, (2) the canonical IL-18Rβ is expressed in the CNS particularly in areas and nuclei belonging to the limbic system as previously observed for IL-18Rα and finally (3) we have also demonstrated that both IL-18Rβ isoforms are up-regulated in different brain areas three hours after a single lipopolysaccharide (LPS) injection suggesting that IL-18Rβ in the CNS might be involved in mediating the endocrine and behavioral effects of LPS. Our data highlight the considerable complexity of the IL-18 regulation activity in the mouse brain and further support an important central role for IL-18.
2011
- Stress induces altered CRE/CREB pathway activity and BDNF expression in the hippocampus of glucocorticoid receptor-impaired mice
[Articolo su rivista]
Alboni, Silvia; Tascedda, Fabio; Corsini, Daniela; Benatti, Cristina; Caggia, Federica; Capone, Giacomo; Barden, N; Blom, Johanna Maria Catharina; Brunello, Nicoletta
abstract
The gene coding for the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) is a stress-responsive gene. Changes in its expression may underlie some of the pathological effects of stress-related disorders like depression. Data on the stress-induced regulation of the expression of BDNF in pathological conditions are rare because often research is conducted using healthy animals. In our experiments, we used transgenic mice with glucocorticoid receptor impaired (GR-i) expression in the hypothalamus created as a tool to study the neuroendocrine changes occurring in stress-related disorders. First, under basal condition, GR-i mice displayed lower levels of BDNF exons IX and IV and decreased CRE(BDNF) binding activity with respect to wild-type (WT) mice in the hippocampus. Then, we exposed GR-i and WT mice to an acute restraint stress (ARS) to test the hypothesis that GR-i mice display: 1] different ARS induced expression of BDNF, and 2] altered activation of signaling pathways implicated in regulating BDNF gene expression in the hippocampus with respect to WT mice. Results indicate that ARS enhanced BDNF mRNA expression mainly in the CA3 hippocampal sub-region of GR-i mice in the presence of enhanced levels of pro-BDNF protein, while no effect was observed in WT mice. Moreover, ARS reduced CREB signaling and binding to the BDNF promoter in GR-i mice but enhanced signaling and binding, possibly through ERK1/2 activation, in WT mice. Thus, life-long central GR dysfunction resulted in an altered sensitivity at the transcriptional level that may underlie an impaired response to an acute psycho-physical stress.
2010
- CONDIZIONI MEDICHE CHE POSSONO DETERMINARE DISABILITA' INTELLETTIVA
[Capitolo/Saggio]
Blom, Johanna Maria Catharina; Ciotti, F; Lassi, S.
abstract
Il ritardo mentale o disabilità intellettiva è secondario o associato a molte differenti patologie croniche che si manifestano principalmente durante lo sviluppo.
Negli ultimi anni si è assistito a un crescente interesse nei confronti delle conseguenze neurocognitive derivanti da condizioni mediche o da terapie ad esse conseguenti, che coinvolgono, direttamente o indirettamente, il Sistema Nervoso Centrale (SNC). Gli effetti di condizioni mediche, come la Leucemia Linfoblastica Acuta (LLA), l’asma o il diabete non sono né trasparenti né diretti. Le conseguenze sul versante neurocognitivo e neurocomportamentale sono il risultato non solo della condizione medica ma anche dell’interazione di quest’ultima e delle terapie ad essa necessarie con lo sviluppo, il tempo e le capacità di resilience.
Le attuali ricerche suggeriscono che i profili neurocognitivi e i fenotipi comportamentali risultanti da una determinata condizione medica debbano essere considerati come la risultate di un algoritmo che esprime il rischio biologico, associato alle condizioni mediche, moderate dallo sviluppo del bambino, dall’età e dal periodo di insorgenza della malattia e, non ultima, dalla capacità di resilience del bambino, della famiglia, della scuola e della società in generale.
In presenza di un danno al SNC la domanda che ci dobbiamo porre è: alla base del declino vi è un processo di natura biologica, psicologica o entrambi? E, più specificamente: la patologia o il trattamento hanno deteriorato un processo psicologico elementare (memoria, attenzione, funzioni esecutive), che svolge un ruolo critico nello sviluppo futuro del soggetto.
2010
- Il concetto di qualità di vita nelle diverse età
[Capitolo/Saggio]
Bertelli, M; Blom, Johanna Maria Catharina; Manzotti, S; Verri, A.
abstract
L’attenzione e l’interesse nel proteggere i diritti, la salute e il benessere delle persone, adolescenti e bambini e del loro sviluppo è cresciuta in modo esponenziale nell’ultimo decennio. La trasformazione sociale che hanno subito l’infanzia e l’adolescenza nella società moderna riflette, e nello stesso tempo ritrae, il passaggio da una concezione che vede i genitori con piena e illimitata giurisdizione nei confronti dei loro figli, ad una visione nella quale il benessere dei minori e di persone con disabilita intellettiva è concepito sempre più come una distinta e indipendente responsabilità sociale per la quale sono richiesti investimenti nell’ambito dell’educazione, della salute e di altre istituzioni. Contemporaneamente, si è assistito ad una sempre più crescente mole di evidenze che il loro benessere e sviluppo è influenzato sia dalla famiglia che dalle istituzioni sociali, dalle norme e dai valori culturali prodotti dalla società stessa.
Questa prospettiva vede la persona e il suo sviluppo come condizionata da ciascuna delle istituzioni presenti, la scuola, i servizi sociali e il sistema sanitario, i quali giocano un ruolo estremamente importante nel preparare l’individuo ad affrontare la società moderna e a diventare adulti, preparandoli alla vita che si fa strada in un mondo sempre più complesso.
Considerando le numerose evidenze che vedono il benessere e la qualità di vita come un costrutto complesso e molto particolare, emerge la necessità di avere una concezione di salute comprensiva e integrata che rifletta le dinamiche (che influenzano la persona nell’arco della vita) proprie della natura dell’età dello sviluppo. Questo concetto dovrebbe essere basato sulle migliori evidenze scientifiche e fornire le basi sia per misurare sia per migliorare la qualità di vita e la salute delle persone con DI. Il riconoscimento che la salute ed il benessere sono il risultato di un’interazione tra fattori biologici psicologici socioculturali e fisici richiede che la qualità di vita venga promossa usando il legame tra i persone con DI, la famiglia e la comunità.
Di conseguenza la QdV viene vista come una risorsa di ogni giorno non come un oggetto di vita. Questa definizione vede la QdV come una risorsa positiva che dà all’individuo la possibilità di interagire con il proprio ambiente e di rispondere alle necessità e ai cambiamenti della vita in modo suo. Inoltre, questa prospettiva incorpora la concezione di sviluppo e in particolare di uno dei principi fondamentali: l’ottimizzazione e il mantenimento del funzionamento nel corso del tempo.
2010
- Perinatal psychopathology: characterisation of a selected italian women sample
[Abstract in Rivista]
Petrilli, Greta; G., Rizzi; R., Anniverno; C., Mencacci; Blom, Johanna Maria Catharina
abstract
Psychopathology during pregnancy and postpartum period is a clinical-medical affair, as well as a social
one.
For many woman, pregnancy and postpartum may constitute a trigger, moreover if a woman is, or have
been in her life, already affected by a manifest psychopathology or an asymptomatic one.
Primary-preventive approach should be considered in preconception planning with all women in
childbearing age who have or are at risk for psychopathology and psychiatric illness. For them, preventive
and healing standardized and evidence-based programs are needed, in particular with respect of
pharmacological treatment in a so critical period; even if is not proved that any specific psychotropic drug
is completely safe, due to the fact that all psychotropic medication cross the placenta barrier, there are
guidelines to follow. It's as well important to highlight that even if lots have to be studied, evidence
suggests that untreated depression, rather than treatment with antidepressant during pregnancy, results
in adverse outcomes.
Resources, resilence, copying abilities assessment, risk and protective factors evaluation, together with
pharmacological treatment costs-benefits balance, are the first steps for a personalized and effective
healing program.
from a study on a high risk and selected sample recruited from PsicheDonna Center-Milan-Italy
(Macedonio-Melloni, Fatebenefratelli Hospital) will be discussed.
This center is specialized in women's lifecycle mood disorders; the characterization of this peculiar
sample will be presented, with respect to: - diagnosis -risk and protective factors configuration -
assessment tools - pharmacological treatment planning - clinical healing activities adopted - intervention
and preventive model developed.
2009
- Early neonatal inflammation affects adult pain reactivity and anxiety related traits in mice: genetic background counts
[Articolo su rivista]
Benatti, Cristina; Alboni, Silvia; Capone, Giacomo; Corsini, Daniela; Caggia, Federica; Brunello, Nicoletta; Tascedda, Fabio; Blom, Johanna Maria Catharina
abstract
Protracted or recurrent pain and inflammation in the early neonatal period may cause long-lasting changes in central neural function. However, more research is necessary to better characterize the long-term behavioral sequelae of such exposure in the neonatal period. Objectives: (1) to study whether timing of postnatal exposure to persistent inflammation alters responsiveness to thermal pain in the adult animal; (2) to assess whether animals experiencing early postnatal chronic inflammation display altered anxiety related behavior; (3) to study the importance of genetic background. Newborn mice (outbred strain, CD1 and F1 hybrid strain, B6C3F1) received an injection of Complete Freund's Adjuvant (CFA) or saline on either postnatal day 1 or 14 (PND1; PND14) into the left hind paw. Pain to radiant heat and anxiety were examined in 12-week-old adult animals. Adult baseline PWL was significantly decreased in CD1 mice exposed to CFA on PND 1 and 14 as compared to their saline treated counterparts. B6C3F1 mice exposed to CFA on PND14 showed markedly reduced baseline PWL compared to the PND14 saline group. Persistent inflammation experienced by B6C3F1 mice on PND1 failed to affect baseline adult thermal responsiveness. Adult mice, CD1 and B6C3F1, displayed low anxiety traits only if they had been exposed to persistent inflammation on PND1 and not on PND14. Our research suggests a role for genetic background in modulating long-term behavioral consequences of neonatal persistent inflammation: the data support the hypothesis that pain experienced very early in life differentially affects adult behavioral and emotional responsiveness in outbred (CD1) and hybrid mice (B6C3F1).
2009
- Gene expression profile of the hippocampus of a behavioural model of depression
[Abstract in Rivista]
Valensisi, Cristina; Caggia, Federica; Alboni, Silvia; Benatti, Cristina; Ferrari, F; Mendlewicz, J; Blom, Johanna Maria Catharina; Brunello, Nicoletta; Tascedda, Fabio
abstract
Although the neurobiological basis of depression has not been fully elucidated, numerous studies have emphasized that in the etiology of depression stress may be the most significant cause, together with genetic vulnerability. Stress induces a coordinated and complex response that is adaptive and integral to survival. The brain's ability to adapt and change over time is refered to neuroplasticity and long-term plasticity in the brain requires changes in gene expression. However, exposure to intense or chronic stressors leads to an increased risk for the development of stress-related disorders including major depression. Numerous studies demonstrate that neuronal atrophy and loss of plasticity occur in hippocampus in response to stress and depression. Therefore, the hippocampal region may play a central role in depressive illness. Likewise changes in gene expression underlying the plasticity of hippocampal structures appear to be relevant in undenstanding the molecular and cellular mechanisms involved in the etiology as well as the treatment of depression, and the mechanisms leading vulnerability or resilience to stress. In fact, humans display a remarkable heterogeneity in their responses to stress and adversity. Although we are beginning to understand how maladaptive neurobiological changes may contribute to depression, relatively little is known about the molecular mechanisms that may underlie stress resilience. Here we set out to investigate the changes in the gene expression profile underlying the effects of stress on the hippocampus using a behavioural paradigm of depression, the chronic escape deficit model [1], which is based on the modified reactivity of rats to external stimuli, the escape deficit, induced by exposure to intense and unavoidable stress. The chronic escape deficit model starts as an acute escape deficit which can be indefinitely sustained by repeated administration of mild stressors. This approach has proved to be a valid and useful model of depression because it consider depressive symptoms like behavioural despair. We performed gene expression profiling in the rat hippocampus, using GeneChip Rat Exon Array (Affymetrix). Using this new platform we carried out analyses of gene expression on three different levels: gene, transcript and exon level analyses. The behavioural results showed that exposure to intense and unavoidable stressful procedure induced escape deficit only in 60% of them. Whereas the animals remaining display a behaviour apparently identical to control animals which did not undergo the stressful procedure. Comparing gene expression profiles and performing functional analysis on differently expressed genes we have indicated multiple pathways that may be involved in the underlying mechanisms of stress condition associated with escape deficit. Moreover we identified possible cellular functions and biological processes that could represent targets that may contribute to mediate the effects of stress on the hippocampal plasticity. Such as, gene expression profiling of stress-vulnerable and stress-resilient animals revealed distinct transcriptional profiles, suggesting that resilient behaviour represents an active neurobiological process and not simply the absence of vulnerability.
2009
- Mapping of the full length and the truncated interleukin-18 receptor alpha in the mouse brain
[Articolo su rivista]
Alboni, Silvia; Cervia, D; Ross, B; Montanari, Claudia; Gonzalez, As; Sanchez Alavez, M; Marcondes, Mc; De Vries, D; Sugama, S; Brunello, Nicoletta; Blom, Johanna Maria Catharina; Tascedda, Fabio; Conti, B.
abstract
The cytokine IL-18 acts on the CNS both in physiological and pathological conditions. Its action occurs through the heterodimeric receptor IL-18Rα β. To better understand IL-18 central effects, we investigated in the mouse brain the distribution of two IL-18Rα transcripts, a full length and an isoform lacking the intracellular domain hypothesized to be a decoy receptor. Both isoforms were expressed in neurons throughout the brain primarily with overlapping distribution but also with some unique pattern. These data suggest that IL-18 may modulate neuronal functions and that its action may be regulated through expression of a decoy receptor.
2009
- Psychopathology during pregnancy and postpartum: characterization of a selected high risk Italian sample
[Abstract in Rivista]
Petrilli, Greta; Anniverno, R; Mencacci, C; Blom, Johanna Maria Catharina
abstract
Psychological distress is common during pregnancy but the field
of perinatal-psychology and related research as well as health
services have focused their attention essentially on the post-partunl
period.
New data suggest that stress and psychopathology during pregnancy
may be associated with significant risks for the mother and
the baby and may lead to detrimental effects for both. Maternal
psychopathology is related to reduced quality of life, higher rate
of risk behaviors, postpartunl psychopathology, and to a decline
in the quality of dyadic relationship. Antenatal stress and psychological
disease and their underlying neuroendocrine changes
are associated with poor pregnancy and birth outcomes. Maternal
stress and psychopathology together with fetal vulnerability and
other ~ediating factors, such as pharmachological treatment, may
determme long-term consequences by altering developmental processes,
affecting the structural development of certain brain areas
circuits, and systems, as well as brain functioning. '
~fter h~ving studied a sample obtained from the general population,
thIS study focused on a selected and high risk sample
of women diagnosed with psychopathology and recruited from a
center specialized in Women's lifecycle mood disorders (psicheDonna
Center-Milan).
General aim: The general aim of this study was threefold:
- to study different manifestations ofpsychological illness as well
as to detect risk and protective factors in this selected sample
of pregnant and postpartunl women
- to analyze the characteristics of these women in order to
understand the mechanisms underlying the interaction between
protective and risk factors which may predict the course of psychopathological
manifestations across pregnancy and beyond.
- to analyze, in follow-up, the choice and efficacy of pharmacological
and-or psychotherapy treatment of these women.
Methods: A sample of91 pregnant and postpartunl women was
enrolled from the Center. Women were subjected to a test battery
in order to evaluate:
- ~ndex ofpregnancy specific-related anxiety (PRAQ-R, Huizink)
- mdex of State Anxiety and of Trait Anxiety, as defined by
Spielberger (STAI-Y, Spielberger)
- ananmestic data and risk and protection factors (scale constructed
ad hoc and PDPI, Tatano Beck) - index of depressionlpostpartunl
depression (EPDS, Cox).
Conclusions and Considerations: Differences were found
between ~is sample and the one from the general population,
not only m test scores but overall in the role played by risk
and protection factors. The presence of pregnancy-related specific
anxiety (detected by PRAQ-R) was found more in the general population: a working hypothesis as to the underlying cause was
developed.
Women recruited from the Center are characterized by a peculiar
configuration of risk and protection factors, where a previous
history of psychopathology seems to play a prominent role in
defining the sample.
This type of evidence indicates a possible new key point
with respect to intervention and prevention, that is, the previous
history of psychopathology. Consequently we need to consider the
necessity of different approaches in the use of screening tools, and
in the development of preventive measures and healing programs,
and tailor all activities and interventions to the patient in order to
be effective. This has lead to new evidence-based perspectives for
intervention.
2008
- Impaired stress-induced regulation of brain derived neurotrophic factor expression in hippocampus of glucocorticoid receptor impaired mice: Model of depression
[Abstract in Rivista]
Alboni, Silvia; Corsini, Daniela; Caggia, Federica; Benatti, Cristina; Capone, Giacomo; Barden, N; Blom, Johanna Maria Catharina; Tascedda, Fabio; Brunello, Nicoletta
abstract
Objective: The gene codifying for the neurotrophin Brain Derived Nurotrophic
Factor (BDNF) is a stress-responsive gene and alteration in its expression may
be important in producing some of the pathophysiological effects of stress in
the hippocampus as seen in stress-related pathologies like depression. While the
effects of stress procedures on the regulation of BDNF expression was widely
investigated in hippocampus of healthy control animals, the stress-induced effects
on BDNF hippocampal expression in “pathological” condition are still lacking.
In order to deepen our knowledge in the understanding of the effects of an acute
stressful procedure on molecular targets of synaptic plasticity we used transgenic
mice with impaired glucocorticoid receptor (GR-i) expression that represent an
animal model of depression. The hypothesis was tested that a single period of
restraint stress (6 hours) affects BDNF mRNA expression in the hippocampus
of GR-i mice differently than in wild-type (WT) mice.
Methods: Using real time RT-PCR we evaluated the effects of a 6 hours acute
stress on the levels of BDNF coding exon VIII and the activity regulated BDNF
exon IV mRNA. In the WT and in the GR-i animals, the hippocampal levels of
the two BDNF exons, immediately after the stress ended, were significantly lower
in stressed animals with the respect to respective control unstressed animals.
However, for the BDNF exon IV mRNA the reduction is most pronounced inWT animals and two-way ANOVA followed by Bonferroni posttest revealed a
significant interaction between stress response and genotype at the level of BDNF
exon IV mRNA expression.
Results: The BDNF gene is a very complex gene regulated by a wide array of
stimuli and signalling pathways. An electophoresis mobility shift assay (EMSA)
was used to study DNA-binding activity of two transcription factors with an
important role in controlling synaptic plasticity most likely trough an involvement
BDNF: the cAMP responsive element binding (CREB) protein and the nuclear
factor kB (Nf-kB). Taken together, our results show a different binding activity
of these transcription factors in GR-i mice with respect to WT mice following
acute stressful conditions.
Conclusion: The identification of the molecular mechanisms activated by
stress in GR-i mice model of depression may contribute to the development
of new strategies that reducing neuron vulnerability to stress and prevent
neurophatologocal alteration in the hippocampus.
2008
- Molecular effects of subchronic andchronic treatment with escitalopram inthe rat central nervous system
[Abstract in Rivista]
Benatti, Cristina; Alboni, Silvia; Capone, Giacomo; Corsini, Daniela; Caggia, Federica; Blom, Johanna Maria Catharina; Tascedda, Fabio; Brunello, Nicoletta
abstract
A clear understanding of the mechanisms behind depressionand its treatment is a critical issue for amelioratethe effectiveness of existing antidepressants. Acutely,antidepressant drugs increase synaptic concentrations ofmonoamines, but clinical efficacy requires several weeksof continuous treatment, proposing a key role for timedependentneural adaptations, perhaps induced by acutesynaptic actions, in their therapeutic efficacy.Escitalopram is the S(+) enantiomer of citalopram, oneof the most widely prescribed serotonin selective reuptakeinhibitor (SSRIs) antidepressants. In the chronic mildstress model of depression sucrose intake was alreadynormalized after one week of treatment.We evaluated the effects of a subchronic or a chronictreatment with escitalopram on expression levels of someof the main targets of antidepressant drugs such as theneurotrophin Brain Derived Neurotrophic Factor (BDNF),the transcription factors cAMP Response Element Binding(CREB) [1] Protein and Calcium Responsive Factor(CaRF).Sprague-Dawley rats were treated for 7 days (subchronic)or 21 days (chronic) with either escitalopram(10 mg/kg die i.p) or saline (1 mL/kg die); BDNF, CREBand CaRF mRNAs were evaluated using RNAse ProtectionAssay in hippocampus and prefrontal cortex.No difference was observed on BDNF, CREB andCaRF expression in the hippocampus of rats treatedsubchronically with escitalopram with respect to the grouptreated with saline. In contrast a significant inductionof BDNF mRNA was observed in prefrontal cortexof escitalopram-treated animals with respect to salinetreated ones. CaRF expression patterns were similar.Escitalopram for 7 days caused a significant induction ofCaRF mRNA with respect to the group treated with saline(p<0.05; Dunnett t-test), on the other hand CREB mRNAremained unaffected. Following a chronic treatment withEscitalopram, BDNF, CREB and CaRF mRNA levels weresignificantly decreased with respect to the group treatedwith saline in hippocampus (p<0.05; Dunnett t-test),while a 21 day treatment with escitalopram failed toproduce changes in gene expression in prefrontal cortex.These results showed that escitalopram is able todifferentially affect BDNF, CREB and CaRF expressionwith respect to treatment duration and that the observedeffects are area-specific.Consequently, to further investigate the possiblemolecular mechanisms underlying the observed effectson gene expression we evaluated by western blottingsome of the main signalling pathways regulating CREB aswell as BDNF expression, such as p38 MAPK (Mitogen-Activated Protein Kinase), CaMKII (Calcium CalmodulineKinase), ERK 1/2 (Extracellular Signal-Regulated Kinase)and CREB itself [1].Our study demonstrates that:1. A subchronic treatment with escitalopram inducesBDNF and CaRF expression in prefrontal cortexprobably through activation of p38 MAPK signallingpathway.2. A 21 day escitalopram treatment reduces hippocampalBDNF, CaRF, CREB gene expression and also CREBphosphorylated nuclear levels.Spatially distinct signalling pathways may be involvedin mediating the differential effect on gene expressionobserved following either a subchronic or a chronictreatment with escitalopram.
2007
- Repetitive acute pain in infants born preterm: an age-specific nonpharmacological approach
[Abstract in Rivista]
Petrilli, Greta; Rovelli, R; Barera, G; Blom, Johanna Maria Catharina
abstract
Purpose of the study: to examine the age-related
effectiveness of simple non-pharmacological interventions
in reducing procedural pain in ex-preterm infants during
a series of repetitive immunizations.
Background: Infant pain is of critical interest, especially
with respect to premature infants often exposed to
protracted pain and recurring painful procedures. Despite
the accumulating evidence that preterm neonates are
highly sensitive to pain and that neonatal procedural pain
is harmful and may lead to changes in neural development,
treatment for painful procedures is limited. Children
born preterm routinely undergo a series of monthly
immunizations in order to prevent upper respiratory
infections. These painful immunizations impact on an
infant that experienced a mean of 14 stressful and painful
procedures a day, during the period of hospitalization,
which may have lasted for months. Given this, special
attention is required to the development and use of age
appropriate approaches that reduce the impact of painful
procedures and to improve the treatment of repetitive pain
in this particular group of vulnerable neonates.
Methods: A Single Case Experimental Desing was
used. 37 Italian children born pre-term were assigned to
four non-pharmacological interventions (1: 25% sucrose
solution in combination with oral stimulation by a pacifier;
2: visual–auditory distraction; 3: play interaction and
4: blowing soap bubbles). Reflecting the maturational level
of the infants, considering age corrected for gestational
age, each infant received the first intervention at his first
immunization (out of five) and whenever no pain relieve
was obtained, the next immunization was performed
with the second intervention. Assessment of video-taped
behaviour and crying, time to first cry, time to stop cry and
total time required for the immunization procedure were
used as outcome measures and assess by six independent
observers.
Results and Conclusions: following the maturation of
the infant, visual-auditory distraction (using the more complex capacity of visual auditory integration), play
interaction and blowing soap bubbles (using the capacity
to participate in interactive play) all proved to be effective
in delaying distress, reducing the facial display of pain and
especially in reducing the time necessary to calm and console
the infant. In addition, negative hospital experiences,
length of stay together with gestational age and weight at
birth should be considered important factors that influence
the initial reaction to the first immunization. Sucrose in
the presence of a pacifier significantly reduced pain and
distress up to an age of 60 weeks corrected for gestational
age. Furthermore these factors may underlie the extended
efficacy of oral sucrose combined with a pacifier by altering
the responsiveness of the immature nervous system
to adverse events. This observation extends the effects of
sucrose plus pacifier much beyond the period in which
they are effective in term neonates. Finally, adjusting the
method of non-pharmacological intervention according to
age and maturational level will not only lead to the highest
efficacy of pain management but will also lead to a reduction
in stress as well as in time spend for the medical staff.
2006
- Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in a rat model of depression
[Abstract in Rivista]
Capone, Giacomo; Alboni, Silvia; Benatti, Cristina; Tascedda, Fabio; Blom, Johanna Maria Catharina; J., Mendlewicz; Brunello, Nicoletta
abstract
Depression currently ranks fourth among the major causesof disability worldwide and by 2020, it is estimated thatunipolar major depression will rank second as a sourceof lost disability-adjusted life years (DALYs) worldwide(Murray and Lopez, 1997). To date however no singleagent is effective in all patients treated, probably due tothe different neurobiological alterations occurring for thedisorder and to individual differences in pharmacogeneticand pharmacodynamic parameters.Different therapies have been proposed to amelioratethe clinical responses of antidepressant drugs throughaugmentation or combination strategies.Another achievement in the development of newtreatments is to reduce the latency of clinical effect ofantidepressant drugs known to be characterized by 4-6weeks lag phase.Evidence has accumulated suggesting that majordepression is associated with dysfunction of inflammatorymediators and that psychiatric symptoms may occur duringinflammatory diseases. Moreover antidepressants show ananti-inflanmlatory action possibly related to their clinicalefficacy. In fact, an improvement in psychiatric symptomshas been recently reported in patients treated with antiinflammatorydrugs for other indications.These data imply that inflammation may be involved inthe pathogenesis of depression and that anti-inflanm~atorydrugs may be used as an adjunctive therapy.Among anti-inflammatory drugs acetylsalicylic acid(ASA) has been shown to act on the brain serotonergicsystem and to have a neuroprotective effect in vitro aswell as in vivo.Aim of the present study was to evaluate the effectsof combined treatment fluoxetine (FLX) plus ASA andASA alone in a behavioural model of depression:the chronic escape deficit (Gambarana et al., 2001).The chronic escape deficit model is based on themodified reactivity of rats to external stimuli inducedby exposure to unavoidable stress and allows evaluatingthe capacity of a treatment to revert the condition ofescape deficit. In this model, FLX alone needs to beadministered for at least 3 weeks in order to revert thiscondition.Our results showed that ASA (45 mg/kg) did not possessantidepressant properties in the chronic escape deficitmodel at any time tested. A combined treatment of FLX(5 mg/kg) and ASA (45 mg/kg) completely reverted thecondition of escape deficit as early as after 7 days, theeffect being already partially present after 4 days. Theeffect was maintained after 14 and 21 days of treatment.In the same experimental condition the effect of FLX(5 mg/kg) was significant only at 21 days, as previouslydemonstrated by other groups.The exact nature of the mechanisms underlying theabove behavioural effects are still unknown, neverthelessseveral hypotheses can be formulated. Further biochemicaland genetic researches could help to clarify the targets ofaction of the combined treatment FLX plus ASA for thedevelopment of more active and faster acting molecules.
2006
- Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of depression
[Articolo su rivista]
Brunello, Nicoletta; Alboni, Silvia; Capone, Giacomo; Benatti, Cristina; Blom, Johanna Maria Catharina; Tascedda, Fabio; Kriwin, P; Mendlewicz, J.
abstract
Evidence has accumulated suggesting that major depression is associated with dysfunction of inflammatory mediators. Moreover, antidepressants show an antiinflammatory action possibly related to their clinical efficacy. An improvement in psychiatric symptoms has been recently reported in patients treated with antiinflammatory drugs for other indications. These data imply that inflammation may be involved in the pathogenesis of depression and that anti-inflammatory drugs may be used as an adjunctive therapy. The aim of the present study was to evaluate the behavioural effect of the co-administration of acetylsalicylic acid (ASA, 45 mg/kg or 22.5 mg/kg) and fluoxetine (FLX, 5 mg/kg) in the chronic escape deficit model of depression. The chronic escape deficit model is based on the modified reactivity of rats to external stimuli induced by exposure to unavoidable stress and allows evaluation of the capacity of a treatment to revert the condition of escape deficit. In this model, FLX alone needs to be administered for at least 3 weeks to revert this condition. Our results show that combined treatment of fluoxetine and ASA completely reverted the condition of escape deficit by as early as 7 days, the effect being already partially present after 4 days. The effect was maintained after 14 and 21 days of treatment. ASA alone was ineffective at any time tested and the effect of fluoxetine was significant only at 21 days. These results, together with clinical data from preliminary results, suggest that ASA might accelerate the onset of action of selective serotonin reuptake inhibitor antidepressants.
2006
- Behavioural and molecular effects of the combined treatment fluoxetine plus acetylsalicylic acid in a rat model of depression
[Abstract in Rivista]
Alboni, Silvia; Capone, Giacomo; Benatti, Cristina; Tascedda, Fabio; Blom, Johanna Maria Catharina; Mendlewicz, J; Brunello, Nicoletta
abstract
Current treatments for depression are inadequate for many patients,
and different therapies have been proposed to ameliorate the
clinical responses of antidepressant drugs through augumentation
or combination strategies. Another achievement in the development
of new treatments is to reduce the latency of clinical effect of
antidepressant drugs known to be characterized by 4−6 weeks lag
phase. Evidence has accumulated suggesting that major depression
is associated with dysfunction of inflammatory mediators and that
psychiatric symptoms may occur during inflammatory diseases.
Moreover antidepressants show an anti-inflammatory action possibly
related to their clinical efficacy. In fact, an improvement
in psychiatric symptoms has been recently reported in patients
treated with anti-inflammatory drugs for other indications. These
data imply that inflammation may be involved in the pathogenesis
of depression and that anti-inflammatory drugs may be used
as an adjunctive therapy. Among the anti-inflammatory drugs
the Acetylsalicylic acid has been shown to act on the brain
serotonergic system and to have a neuroprotective effect toward brain damage. Aim of the present study was to evaluate the effects
of combined treatment fluoxetine (FLX) plus acetylsalicylic acid
(ASA) in a behavioural model of depression: the chronic escape
deficit. The chronic escape deficit model is based on the modified
reactivity of rats to external stimuli induced by exposure to unavoidable
stress and allows evaluating the capacity of a treatment
to revert the condition of escape deficit. In this model, FLX alone
needs to be administered for at least 3 weeks in order to revert
this condition. Our results showed that ASA (45 mg/kg) did not
possess antidepressant properties in the chronic escape deficit
model at any time tested. A combined treatment of FLX (5 mg/kg)
and ASA (45 mg/kg) completely reverted the condition of escape
deficit as early as after 7 days, the effect being already partially
present after 4 days. The effect was maintained after 14 and
21 days of treatment. In the same experimental condition the effect
of FLX (5 mg/kg) was significant only at 21 days, as previously
demonstrated by other groups. The exact nature of the mechanisms
underlying the above behavioural effects are still unknown, nevertheless
several hypotheses can be formulated. Moreover, because
a role for the neurotrophin BDNF was proposed in the clinical response
to antidepressant treatment, we have determined the effect
of combined treatment FLX plus ASA on hippocampal BDNF
mRNA and protein in the same behavioural model. Ours data
demonstrated that the hippocampal levels of BDNF mRNA were
significantly increased with respect to control groups (naive and
stressed) only in the animals responding (number of escape 10
out of 30 trials) to the combined treatment. Further biochemical
and genetic researches could help to clarify the targets of action
of the combined treatment FLX plus ASA for the development of
more active and faster molecules.
2006
- Early postnatal chronic inflammation produces long-term changes in pain behavior and N-methyl-D-aspartate receptor subtype gene expression in the central nervous system of adult mice
[Articolo su rivista]
Blom, Johanna Maria Catharina; Benatti, Cristina; Alboni, Silvia; Capone, Giacomo; Ferraguti, Chiara; Brunello, Nicoletta; Tascedda, Fabio
abstract
The objective of this study was to test whether postnatal chronic inflammation resulted in altered reactivity to pain later in life when reexposed to the same inflammatory agent and whether this alteration correlated with brain-region-specific patterns of N-methyl-D-aspartate (NMDA) receptor subtype gene expression. Neonatal mouse pups received a single injection of complete Freund's adjuvant (CFA) or saline into the left hind paw on postnatal day 1 or 14. At 12 weeks of age, both neonatal CFA- and saline-treated animals received a unilateral injection of CFA in the left hind paw. Adult behavioral responsiveness of the left paw to a radiant heat source was determined in mice treated neonatally with saline or CFA before and after receiving CFA as adults. Twenty-four hours later, brains were dissected and NMDA receptor subunit gene expression was determined in four different brain areas by using an RNase protection assay. The results indicated that NMDA receptor subtype gene expression in adult mice exposed to persistent neonatal peripheral inflammation was brain region specific and that NMDA gene expression and pain reactivity differed according to the day of neonatal CFA exposure. Similarly, adult behavioral responsiveness to a noxious radiant heat source differed according to the age of neonatal exposure to CFA. The data suggest a possible molecular basis for the hypothesis that chronic persistent inflammation experienced early during development may permanently alter the future behavior and the sensitivity to pain later in life, especially in response to subsequent or recurrent inflammatory events
2006
- Effective pain reduction of non-pharmacological interventions for procedural pain during repetitive immunizations of children born pre-term
[Abstract in Rivista]
Petrilli, Greta; Blom, Johanna Maria Catharina
abstract
Psychological distress is common during pregnancy but the field
of perinatal-psychology and related research as well as health
services have focused their attention essentially on the post-partunl
period.
New data suggest that stress and psychopathology during pregnancy
may be associated with significant risks for the mother and
the baby and may lead to detrimental effects for both. Maternal
psychopathology is related to reduced quality of life, higher rate
of risk behaviors, postpartunl psychopathology, and to a decline
in the quality of dyadic relationship. Antenatal stress and psychological
disease and their underlying neuroendocrine changes
are associated with poor pregnancy and birth outcomes. Maternal
stress and psychopathology together with fetal vulnerability and
other ~ediating factors, such as pharmachological treatment, may
determme long-term consequences by altering developmental processes,
affecting the structural development of certain brain areas
circuits, and systems, as well as brain functioning. '
~fter h~ving studied a sample obtained from the general population,
thIS study focused on a selected and high risk sample
of women diagnosed with psychopathology and recruited from a
center specialized in Women's lifecycle mood disorders (psicheDonna
Center-Milan).
General aim: The general aim of this study was threefold:
- to study different manifestations ofpsychological illness as well
as to detect risk and protective factors in this selected sample
of pregnant and postpartunl women
- to analyze the characteristics of these women in order to
understand the mechanisms underlying the interaction between
protective and risk factors which may predict the course of psychopathological
manifestations across pregnancy and beyond.
- to analyze, in follow-up, the choice and efficacy of pharmacological
and-or psychotherapy treatment of these women.
Methods: A sample of91 pregnant and postpartunl women was
enrolled from the Center. Women were subjected to a test battery
in order to evaluate:
- ~ndex ofpregnancy specific-related anxiety (PRAQ-R, Huizink)
- mdex of State Anxiety and of Trait Anxiety, as defined by
Spielberger (STAI-Y, Spielberger)
- ananmestic data and risk and protection factors (scale constructed
ad hoc and PDPI, Tatano Beck) - index of depressionlpostpartunl
depression (EPDS, Cox).
Conclusions and Considerations: Differences were found
between ~is sample and the one from the general population,
not only m test scores but overall in the role played by risk
and protection factors. The presence of pregnancy-related specific
anxiety (detected by PRAQ-R) was found more in the general population: a working hypothesis as to the underlying cause was
developed.
Women recruited from the Center are characterized by a peculiar
configuration of risk and protection factors, where a previous
history of psychopathology seems to play a prominent role in
defining the sample.
This type of evidence indicates a possible new key point
with respect to intervention and prevention, that is, the previous
history of psychopathology. Consequently we need to consider the
necessity of different approaches in the use of screening tools, and
in the development of preventive measures and healing programs,
and tailor all activities and interventions to the patient in order to
be effective. This has lead to new evidence-based perspectives for
intervention.
2006
- Effects of acute stress on brain-derived neurotrophic factor in the hippocampus of transgenic mouse model of depression
[Abstract in Rivista]
Alboni, Silvia; Blom, Johanna Maria Catharina; Corsini, Daniela; Benatti, Cristina; Capone, Giacomo; Ferraguti, Chiara; N., Barden; Tascedda, Fabio; Brunello, Nicoletta
abstract
Brain-Derived Neurotrophic Factor (BDNF) is a member of the neurotrophin family which includes a group of molecules important for the development and the maintenance of the nervous system. Since BDNF is highly expressed in the hippocampus, the action and regulation of this neurotrophin in this area has become subject of intense study. The gene codifying for BDNF is a stress responsive gene and alterations in its expression may be important in regulating some of the physiological and pathophysiological effects of chronic and acute stress in the hippocampus. Different studies show that several types of stress reduce BDNF expression in the hippocampus of control animals [Smith et al., 1995] and these works led to a neurotrophic hypothesis of depression [Nestler et al., 2002]. Nevertheless, the effect of stress on BDNF gene expression may differ between a "normal" and a "pathological" brain. In our study, we used transgenic mice with glucocorticoid receptor impaired (GRi) expression created [Pepin et al., 1992], as a tool to study the neuroendocrine changes observed in stress-related disorders, such as major depression. This GRi mouse model is characterized by dysfunctional glucocorticoid inhibitory feedback and an excessive activation of the hypothalamic pituitar~adrenal (HPA) axis, that can be restored by antidepressant drugs' treatment. The hypothesis was tested that a single period of 30 minutes of restraint stress affects BDNF expression in the hippocampus of GRi mice differently than in wildtype (WT) mice. Using RNase protection assay and in situ hybridization we had assessed the BDNF mRNA hippocampal levels, while the levels of BDNF and its precursor, pro-BDNF were analyzed by western blotting. Our results indicated that 30 minutes of restraint enhanced BDNF mRNA expression in the CA3 hippocampal subregion of GRi mice; the same stress procedure induced also a statistically significant increase of pro- BDNF level in hippocampus of GRi mice. No effect of acute stress was observed in the WT at the level of the expression of BDNE Moreover, we evaluated the effects of restraint on signalling pathways implicated in the regulation of BDNF expression (mitogen-activated protein kinase and calcium/calmodulin-dependent kinase cascades) that converge on the phosphorylation of CREB that we found down-regulated in the hippocampus of GRi mice and up-regulated in WT mice. Our data suggest that, in the presence of psychophysiological stress (restraint stress), GRi mice display altered hippocampal regulation in BDNF gene expression. Thus, life-long central GR dysfunction may negatively affects neural functioning by limiting the capacity to cope with change or acute stress, which could be a predisposing or determining factor in depression. Understanding the mechanisms underlying the induction of BDNF mRNA and accumulation of pro-BDNF in the hippocampus of GRi mice, may help to clarify the molecular basis of action of this neurotrophin and contribute to the development of new strategies reducing the vulnerability of neurons to stress, thus preventing neuropathological alterations in the hippocampus.
2005
- Neonatal persistent inflammation alters pain response and NMDA receptor expression in adult mice
[Abstract in Rivista]
Benatti, Cristina; Alboni, Silvia; Ferraguti, Chiara; Tascedda, Fabio; Blom, Johanna Maria Catharina; Brunello, Nicoletta
abstract
Infant pain is of critical interest, especially with respect to premature infants and other high-risk neonates that experience many invasive and traumatic procedures early in development. The early neonatal period is characterized by great plasticity and reorganization. Sustained activation of central nervous circuits, caused by protracted and recurrent pain, may cause long-lasting changes in central neural function thus affecting developmental outcome and behavioural responsiveness to pain or stress later in life. However little is known about the neurobiological substrates underlying this ``memory'' process. The aim of our study was twofold:to study whether timing of postnatal exposure to a persistent inflammatory insult alters the responsiveness to thermal pain in the adult animal;given the role of the NMDA receptor in pain processing as well as in learning and memory, to examine if NMDA receptor subtype gene expression in specific areas of the cns is influenced by neonatal inflammation.Methods: Newborn mice received a single injection of Complete Freund's Adjuvant (CFA) or saline on either postnatal day 1, 3 or 14 (P1, P3 and P14) into the left hind paw. At twelve weeks of age paw withdrawal latency (PWL) of each animal was tested both in basal condition and 24h after an unilateral injection of 100 μL of CFA in the left hind paw. Mice were then killed by cervical dislocation and cerebral areas were removed. Using a sensitive RNAse protection assay, NMDA receptor subunit (NR1, NR2A, NR2B, NR2C) gene expression was evaluated in different brain areas; all data were processed by one-way ANOVA (p < 0.05).Results: Baseline paw withdrawal latency was significantly decreased in animals exposed to CFA at day 1 and 14 as compared to their saline exposed counterparts. Animals exposed to CFA at postnatal day 3 showed a significant increase in paw withdrawal latency with respect to saline injected animals. Twenty-four hours later a unilateral injection of CFA into the left hind paw, a significant decrease in paw withdrawal latency was observed in all experimental groups with respect to baseline values. PWL of P1 saline treated animals after CFA exposure was significantly higher than P3 and P14 saline treated mice. Adult mice exposed to an injection with CFA on postnatal day 1 exhibited reduced expression of the NMDA receptor subtype NR1 and NR2C in the hippocampus while mRNA levels for NR2A and NR2B did not differ between CFA treated and untreated mice. Exposure to CFA on postnatal day 3 and 14 did not affect adult expression levels of NMDA receptor subunits in the hippocampus. NMDA receptor subunit expression displayed a different profile in the thalamus. Exposure to CFA at P1 and P3 did not alter NMDA receptor subunit expression while exposure to CFA at P14 resulted in enhanced expression of the NR2A and NR2B subunits.Conclusions: These findings indicate that changes in NMDA receptor subtype gene expression in adult mice exposed to persistent neonatal peripheral inflammation are brain region specific and that NMDA gene expression and pain reactivity differ according to the day of neonatal exposure to CFA.
2005
- New combination therapies from animal to human
[Abstract in Rivista]
Brunello, Nicoletta; Alboni, Silvia; Benatti, Cristina; Capone, Giacomo; Tascedda, Fabio; Blom, Johanna Maria Catharina; J., Mendlewicz
abstract
Evidence has accumulated suggesting that major depression is associated with dysfunction of inflammatory mediators. Antidepressants interfere with the synthesis and release of cytokines and do not exert behavioral effects in animal models of depression when hippocampal neurogenesis is blocked, a phenomenon which is occurring in the presence of inflammation. The anti-inflammatory drug acetylsalicylic acid (ASA), besides inhibiting the cyclooxigenase pathway, interacts with central serotonergic system, by increasing serotonin levels in cortex and reducing the density of different serotonin receptor subtypes. These neurochemical effects suggest a role of ASA in the treatment of depression. Therefore we studied the effect of ASA and fluoxetine combined treatment in a behavioral model of depression. The chronic escape deficit model is based on the modified reactivity of rats to external stimuli induced by exposure to unavoidable stress and allows evaluating the capacity of a treatment to revert the condition of escape deficit. Any kind of antidepressant drug needs to be administered for at least 3 weeks in order to revert this condition. The combined treatment of fluoxetine and ASA completely reverted the condition of escape deficit as early as after 7 days, the effect being already partially present after 4 days. The effect was maintained after 14 and 21 days of treatment. ASA alone was ineffective at any time tested and the effect of fluoxetine was significant only at 21 days. Given these preclinical results, an open clinical study has been started using the combination SSRI-ASA in treatment resistant depressed patients. Preliminary results suggest a potential accelerating effect of ASA in combination to SSRI.
2004
- Chronic treatment with desipramine and fluoxetine modulate BDNF, CaMKK alpha and CaMKK beta mRNA levels in the hippocampus of transgenic mice expressing antisense RNA against the glucocorticoid receptor
[Articolo su rivista]
J., Vinet; Carra, Serena; Blom, Johanna Maria Catharina; Brunello, Nicoletta; N., Barden; Tascedda, Fabio
abstract
Antidepressants up-regulate the cAMP response element binding protein (CREB) and the brain-derived neurotrophic factor (BDNF) in hippocampus and these effects contribute to the protection of hippocampal neurons from stressful stimuli such as high glucocorticoid levels. CREB can be activated by both protein kinase A and by Ca2+-calmodulin-dependent protein kinases (CaMKs), which are in turn phosphorylated by their upstream activators CaMKKalpha and CaMMKKbeta. Using in situ hybridization, we examined the effects of chronic treatment with fluoxetine (FLU) or desipramine (DMI) on BDNF, CaMKKalpha and CaMKKbeta mRNAs in the hippocampus of wild-type (Wt) and transgenic (TG) mice characterized by glucocorticoid receptor (GR) dysfunction. Basal levels of CaMKKbeta were down regulated in the CA3 region of TG mice. DMI decreased the expression of both CaMKKalpha and CaMMKKbeta in the CA3 region of Wt mice. FLU up-regulated BDNF mRNA levels in the CA3 of TG animals while both FLU and DMI increased BDNF gene expression in the dentate gyrus (DG) of TG animals. Our results demonstrate a different regulation of BDNF expression by antidepressant drugs in the hippocampus of Wt and TG animals. Moreover, for the first time, a role for CaMKKs in the mechanism of action of antidepressant agents, at least in the hippocampus, is reported. These data are discussed in view of interactions existing between CaMK pathway and GR-mediated gene transcription.
2004
- Regulation of CREB function in rat frontal cortex after combined treatment with Fluoxetine and Olanzapine
[Abstract in Rivista]
Capone, Giacomo; Alboni, Silvia; Blom, Johanna Maria Catharina; Ferraguti, Chiara; Brunello, Nicoletta; Tascedda, Fabio
abstract
Statement of the Study: Generally, drugs used in the treatment of depression
exert their therapeutic effect after 4/6 weeks and only in 60–65% of patients. The
search for an adequate and faster treatment of major depression is one of the main
challenges in neuropsychopharmacology. Recently, a clinical study of treatmentresistant
depressed patients without a psychotic component, showed that after
only one week of treatment, Fluoxetine (a selective serotonin reuptake inhibitor
antidepressant) and Olanzapine (an atypical antipsychotic agent) produced a
higher level of improvement than either monotherapy alone (Shelton et al., American
Journal of Psychiatry 158(1), 131–134, 2001). Furthermore, preclinical data,
using microdialysis, indicated that the combination of Olanzapine and Fluoxetine
resulted in an increase in the extracellular levels of dopamine and norepinephrine
in the rat prefrontal cortex, an effect that was significantly bigger than after treatment
with either drug alone (Zhang et al., Neuropsychopharmacology 23(3),250–
262, 2000). However, it is not yet completely understood which intracellular
signaling pathway could be involved in the fast response (seen in clinical trials)
to Fluoxetine plus Olanzapine co-treatment.
Methods: Since antidepressant and antipsychotic drugs affect the cyclic
adenosine monophosphate (cAMP) pathway, including the expression of the
cAMP response element binding protein (CREB), the levels of CREB mRNA
and CREB nuclear protein, total and phosphorylated, were studied in the frontal
cortex of rats using RNase protection assay and Western Blotting analysis
respectively. Four experimental groups were used: rats were treated for one,
five or ten days with either saline, Fluoxetine (ip 10 mg/Kg), Olanzapine (sc
1 mg/Kg) or combined Fluoxetine plus Olanzapine (10 mg/Kg and 1 mg/Kg).
Summary of Results: Our results show that the level of phosphorylated
CREB Ser133 was significantly increased in the frontal cortex of rats receiving
the combined treatment regimen (Fluoxetine plus Olanzapine) for five days. No
effect was observed in acutely and ten day treated rats.
Conclusion: This specific effect on CREB phosphorylation levels after five
days of combined treatment with Fluoxetine plus Olanzapine might represent
one of the mechanisms underlying the faster response to this therapy recently
observed in several clinical trials.
2004
- Restraint stress increases the expression of brain derived neurotrophic factor in the hippocampus of a mouse model of depression
[Abstract in Rivista]
Alboni, Silvia; Benatti, Cristina; Blom, Johanna Maria Catharina; Ferraguti, Chiara; Tascedda, Fabio; Barden, N; Brunello, Nicoletta
abstract
Statement of the study: Brain-Derived Neurotrophic Factor (BDNF) is a
member of the neurotrophin family which includes a group of molecules
important for the development and the maintenance of the nervous system.
Since BDNF is highly expressed in the hippocampus, the action and regulation
of BDNF in this particular area has become subject of intense study. Single or
repeated immobilization stress markedly reduces both BDNF mRNA and protein
levels in rat hippocampus. Consequently, BDNF is considered a stress-responsive
gene, and it has been recently suggested that alterations in the expression of this
growth factor may be important in regulating some of the physiological and
pathophysiological effects of stress on the hippocampus.
Stress-induced changes observed in the hippocampus of experimental animals
resulted in a novel hypothesis attributing a central role to neurotrophic factors
in both the etiology of depression and as well as in its treatment. However,
the effects of stress on neurotrophic factors in the hippocampus of depressed
patients remain unknown. In fact, the expression pattern of a large array of
genes affected by depression or antidepressant drugs, such as BDNF, may differ
between a normal and a pathological brain.
Methods: In these experiments, we used transgenic (TG) mice deficient in
glucocorticoid receptor (GR) functioning. This TG mouse was created as a model
to study the neuroendocrine changes occurring in stress-related disorders, such as
major depression. We evaluated the hypothesis that a single period of 30 minutes of restraint stress affects BDNF mRNA expression in the hippocampus of TG
mice differently than in WT mice.
Summary of results: BDNF mRNA was significantly increased by the stress
procedure only in the hippocampus of TG mice, the induction being specific for
the CA3 subregion as revealed by in situ hybridization.
Moreover, we found that stress down-regulated CREB phosphorylation in the
hippocampus of TG mice whereas it upregulated the level of phosphorylated
CREB Ser133 in WT mice.
Conclusion: These data suggest that, in the presence of emotional stress, lifelong
central glucocorticoid receptor dysfunction results in altered hippocampal
sensitivity, with respect to the level of neurotrophic gene expression.
The understanding of the mechanisms through which psychological stress
(such as restraint stress) induces BDNF mRNA in the hippocampus of TG
mice, may help to clarify the biological and molecular basis of the action of
neurotrophic factors and may contribute to the development of new strategies that
will ultimately reduce the vulnerability of neurons and prevent neuropathological
alterations in the hippocampus.
2003
- Cloning of mouse Ca2+/calmodulin-dependent protein kinase kinase beta (CaMKKbeta) and characterization of CaMKKbeta and CaMKKalpha distribution in the adult mouse brain.
[Articolo su rivista]
Vinet, Jonathan; Carra, Serena; Blom, Johanna Maria Catharina; Harvey, M; Brunello, Nicoletta; Barden, N; Tascedda, Fabio
abstract
The Ca(2+)/calmodulin-dependent protein kinase kinases alpha and beta (CaMKKs alpha and beta) are novel members of the CaM kinase family. The CaMKKbeta was cloned from mouse brain. The deduced amino acid sequence shared 96.43% homology with the rat CaMKKbeta. Both the alpha and beta isoforms were widely distributed throughout the adult mouse brain. Additionally, all peripheral tissues examined displayed CaMKK alpha and beta expression.
2003
- Psicofarmacologia clinica
[Traduzione in Volume]
Blom, Johanna Maria Catharina; Daniela, Tardito; Fabio, Fumagalli; Tascedda, Fabio
abstract
Il volume raccoglie le acquisizioni più recenti sull'utilizzo clinico delle principali classi di psicofarmaci impiegati nella terapia delle patologie psichiatriche di più rilevante intersse sociale. Si divide in due sezioni principali: le classi di farmaci psichiatrici e i trattamenti psicofarmacologici. Nella Sezione I, per ogni molecola all'interno di una specifica classe, sono commentati i dati di studi preclinici e in fase clinica; inoltre, sono illustrati gli aspetti farmacodinamici e farmacocinetici, le indicazioni terapeutiche, i dosaggi, gli effetti collaterali e le interazioni con altri farmaci, psichiatrici e non psichiatrici. La Sezione II presenta lo stato dell'arte della terapia farmacologica nelle principali malattie psichiatriche. Gli autori descrivono, inoltre, la farmacoterapia in speciali popolazioni, come i bambini e gli adolescenti, i pazienti affetti da malattie sistemiche e gli anziani. Alcuni capitoli son infine dedicati alla psicofarmacoterapia in situazioni particolari, quali la gravidanza, l'allattamento e le emergenze. Particolare cura è stata posta nelladattare la descrizione delle singole molecole alla realtà italiana: sono stati inseriti alcini farmaci non in commercio negli Stati Uniti ma venduti in Italia; inoltre, laddove la legislazione del nostro Paese differisce da quella americana, si è provveduto a fornire indicazioni di sicuro riferimento per lo specialista italiano. Questo volume è una preziosa fonte di informazioni per psichatri, psicofarmacologi, neurologi, geriatri e specializzandi, nonché un valido strumento di approfondimento per gli studenti delle Facoltà di Medicina e Farmacia.
2002
- Altered regulation of CREB by chronic antidepressant administration in the brain of transgenic mice with impaired glucocorticoid receptor function.
[Articolo su rivista]
Blom, Johanna Maria Catharina; Tascedda, Fabio; Carra, Serena; Ferraguti, Chiara; Barden, N; Brunello, Nicoletta
abstract
Various effects of antidepressant drugs on gene transcription have been described and altered gene expression has been proposed as being a common biological basis underlying depressive illness. One target for the common action of antidepressants is a modifying effect on the regulation of postreceptor pathways and genes related to the cAMP cascade. Recent studies have demonstrated that long-term antidepressant treatment resulted in sustained activation of the cyclic adenosine 3',5'-monophosphate system and in increased expression of the transcription factor cAMP response element binding protein (CREB). A transgenic animal model of depression with impaired glucocorticoid receptor function was used to investigate the effect of chronic antidepressant treatments on CREB expression in different brain areas. Wild-type and transgenic mice received one administration of saline, desipramine, or fluoxetine, daily for 21 days. The effects of antidepressants on CREB mRNA were analyzed using a sensitive RNase protection assay. Antidepressant treatment resulted in a neuroanatomically and animal specific expression pattern of CREB. Our findings suggest that life-long central glucocorticoid receptor dysfunction results in an altered sensitivity with respect to the effects of antidepressants on the expression of CREB.
2002
- Cognitive deficits and changes in gene expression of NMDA receptors after prenatal methylmercury exposure
[Articolo su rivista]
Baraldi, Mario; Zanoli, Paola; Tascedda, Fabio; Blom, Johanna Maria Catharina; Brunello, Nicoletta
abstract
Previous studies showed learning and memory deficit in adult rats that were prenatally exposed to methylmercury chloride (MMC) in an advanced stage of pregnancy (15 days). Under these conditions, the cognitive deficits found at 60 days of age paralleled particularly changes in the N-methyl-D-aspartate (NMDA) receptor characteristics. In the present study, we report the behavioral effects of a single oral dose of MMC (8 mg/kg) administered earlier at gestational day 8. The use of different learning and memory tests (passive avoidance, object recognition, water maze) showed a general cognitive impairment in the in utero-exposed rats tested at 60 days of age compared with matched controls. Considering the importance of the glutamatergic receptor system and its endogenous ligands in learning and memory process regulation, we surmised that MMC could affect the gene expression of NMDA receptor subtypes. The use of a sensitive RNase protection assay allowed the evaluation of gene expression of two families of NMDA receptors (NR-1 and NR-2 subtypes). The result obtained in 60-day-old rats prenatally exposed to MMC, showed increased mRNA levels of the NR-2B subunit in the hippocampus but not in the frontal cortex. The data suggest that the behavioral abnormalities of MMC-exposed rats might be ascribed to a neurotoxic effect of the metal that alters the gene expression of a specific NMDA receptor subunit in the hippocampus.
2001
- Modulation of glutamate receptors in response to the novel antipsychotic olanzapine in rats.
[Articolo su rivista]
Tascedda, Fabio; Blom, Johanna Maria Catharina; Brunello, Nicoletta; Zolin, K; Gennarelli, Massimo; Colzi, A; Bravi, D; Carra, Serena; Racagni, G; Riva, M. A.
abstract
BACKGROUND:A disturbance in glutamate neurotransmission has been hypothesized in schizophrenia. Hence, the beneficial effects of pharmacological treatment may be related to adaptive changes taking place in this neurotransmitter system.METHODS:In this study, we investigated the modulation of ionotropic and metabotropic glutamate receptors in the rat brain following acute or chronic exposure to the novel antipsychotic olanzapine.RESULTS:In accordance with the clear distinction between classical and atypical drugs, olanzapine did not alter glutamate receptor expression in striatum. Chronic, not acute, exposure to olanzapine was capable of up-regulating hippocampal mRNA levels for GluR-B and GluR-C, two alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)-forming subunits. This effect could be relevant for the improvement of schizophrenic alterations, which are thought to depend on dysfunction of the glutamatergic transmission within the hippocampal formation. We also found that the expression of group II glutamate metabotropic receptors was up-regulated in the frontal cortex after chronic exposure to clozapine, and to a lesser extent olanzapine, but not with haloperidol.CONCLUSIONS:The adaptive mechanisms taking place in glutamatergic transmission might prove useful in ameliorating some of the dysfunction observed in the brain of schizophrenic patients.
1999
- Regulation of ionotropic glutamate receptors in the rat brain in response to the atypical antipsychotic seroquel (quetiapine fumarate). .
[Articolo su rivista]
Tascedda, Fabio; E., Lovati; Blom, Johanna Maria Catharina; P., Muzzioli; Brunello, Nicoletta; G., Racagni; M. A., Riva
abstract
The interplay between dopamine and glutamate appears to
be relevant in the etiopathology of schizophrenia. Although
currently used antipsychotics do not interact with
glutamatergic receptors, previous results have
demonstrated that the expression profile of ionotropic
glutamate receptors can be regulated by drugs such as
haloperidol or clozapine. In the present investigation, the
mRNA levels for NMDA and AMPA receptor subunits
were measured after chronic treatment with the novel
antipsychotic agent Seroquel (quetiapine fumarate,
quetiapine) as compared to haloperidol and clozapine.
Similarly to the prototype atypical clozapine, quetiapine
reduced the mRNA expression for NR-1 and NR-2C, two
NMDA forming subunits, in the nucleus accumbens.
Furthermore, quetiapine, but not haloperidol or clozapine,
increased the hippocampal expression for the AMPA
subunits GluR-B and GluR-C. The differences between
classical and atypical antipsychotics, as well as among the
novel agents, might be relevant for specific aspects of their
therapeutic activity and could provide valuable information
for the role of glutamate in specific symptoms of
schizophrenia.
1996
- BetaCasomorphin causes hypoalgesia in 10-day-old-rats:evidence for central mediation
[Articolo su rivista]
Blass, Em; Blom, Johanna Maria Catharina
abstract
Two experiments determined behavioral effectiveness of β-casomorphins(β-CM) in 10-d-old rats by evaluating changes in heat escape latency from a 48°C stimulus applied to a forepaw. In one study rats were injected systemically with β-CM4, -5, or -7 at a dose range of 0.1-2.5 mg/kg. Onlyβ-CM5 was effective, and the dose-response relationship was graded. The second study evaluated the locus of action of β-CM5 through two experimental manipulations: first, by injecting it (0.25 μg) into the lateral ventricles and by attempting to block its effects with systemic injections of naloxone. Second, rats received intracerebroventricular injections of naloxone (0.25 μg) and systemic injections of β-CM.β-CM was effective centrally, suggesting central detection of the drug. Naloxone injected into the lateral ventricles blocked the effects of systemic administration of β-CM, implying that circulating β-CM or their precursors cause behavioral change through central mechanisms.
1995
- Adrenalectomy reduces FGF-1 and FGF-2 gene expression in specific rat brain regions but differently affects their induction by seizeres.
[Articolo su rivista]
Riva, Am; Fumagalli, F; Blom, Johanna Maria Catharina; Donati, E; Racagni, G.
abstract
We have previously reported that limbic seizures regulate the gene expression of fibroblast growth factor-2 (basic, FGF-2) according to a specific spatio-temporal pattern. In the present paper we have investigated the role of adrenal hormones on seizure-induced elevation of fibroblast growth factor-1 (acidic, FGF-1) and FGF-2 gene expression. Adrenalectomy reduces FGF-2 mRNA expression in specific brain regions, such as frontal cortex, hippocampus and striatum, whereas FGF-1 mRNA levels were decreased only in the frontal cortex. The injection of kainic acid in adrenalectomized rats produced a widespread increase of FGF-2 mRNA with a pattern similar to sham animals as indicated by in situ hybridization. In contrast, although kainate-induced elevation of FGF-1 mRNA in the hippocampus was not influenced by adrenalectomy, its induction in frontal cortex was prevented by this surgery procedure. Taken together, these data indicate that adrenal hormones play a role in the regulation of the gene expression for fibroblast growth factors, but different mechanisms are operative in their induction following seizure activity
1995
- Influence of photoperiod, green food, and water availability on reproduction in male california mice (Peromyscus californicus)
[Articolo su rivista]
Nelson, Rj; Gubernick, Dj; Blom, Johanna Maria Catharina
abstract
California mice (Peromyscus californicus) breed primarily during the winter rainy season and generally terminate breeding during the dry summer months. This pattern of reproduction could be regulated by day length, availability of green vegetation, or water availability. The effects of photoperiod and green vegetation on reproduction were examined in Experiment 1 by housing adult male P. californicus either in long (LD 14:10) or short (LD 8:16) photoperiods for 10 weeks with ad lib food and water availability. A subset of animals in each photoperiod treatment group also received supplements of fresh spinach thrice weekly. The effects of water availability were examined in Experiment 2 by housing adult males in long day length conditions for 10 weeks with ad lib or restricted (50% of ad lib) water availability. Neither photoperiod nor availability of green plant food significantly affected reproductive function in male California mice, although animals in long days with green food supplements displayed elevation of some reproductive organ masses. Short days did not suppress plasma LH or prolactin levels. Male P. californicus provide extensive care of the young during the short days of winter. The absence of photoperiod-induced changes in prolactin levels is consistent with the observation that elevated plasma prolactin titers are associated with male parental care in this species. In contrast, water restriction (simulated summer drought) reduced reproductive organ masses, as well as plasma levels of prolactin, and may act as an environmental cue to terminate breeding. Thus, water availability may regulate breeding in this species independently of photoperiod and food availability.
1995
- Learned conditioned immunosuppression is associated with increased risk of chemically-induced tumors.
[Articolo su rivista]
Blom, Johanna Maria Catharina; Tamarkin, L; Shiber, Jr; Nelson, Rj
abstract
Based on the hypothesis that certain aspects of the CNS and immune system interact and that altered immune function affects carcinogenesis, an animal model was developed to examine the effects of learned immunosuppression on the development of a chemically induced tumor. In two experiments, we evaluated whether mice, for which immunosuppression was associated with a neutral (conditioned) stimulus, would exhibit an increased susceptibility to tumor development upon reexposure to the conditioned stimulus, as compared to nonconditioned and control animals. A taste aversion conditioning paradigm, based on classical conditioning techniques, was employed to suppress immune function using the cytotoxic and immunosuppressive drug cyclophosphamide (CY) as the unconditioned stimulus and consequently increase the risk of chemically induced tumorigenesis. CY (100 mg/kg, intraperitoneal) was paired with saccharin in the drinking water (0.1%) of adult female mice (CF-1). Conditioned mice were exposed to saccharin twice in the absence of CY, on days 4 and 7 after the first exposure (day 1). All mice were injected with the chemical carcinogen 9,10-dimethylbenzanthracene (DMBA, 50 mg/kg, subcutaneous) on day 4 of conditioning. Two subsequent exposures to saccharin alone substantially increased the risk of developing DMBA-induced tumors (ranging from 83-91%), as compared to control animals (36%) that had not received this pairing. Mice that received all agents (i.e., CY, DMBA, and saccharin) in a slightly different order did not display elevated tumor incidence. Three separate exposures to CY also significantly increased the number of animals developing tumors in response to the carcinogen (75%). Mice were observed for at least 8 weeks after conditioning
1995
- Photoperiodic effects on steroid negative feedback in female prairie voles (Microtus ochrogaster).
[Articolo su rivista]
Moffatt, Ca; Gerber, Jm; Blom, Johanna Maria Catharina; Kriegsfield, Lj; Nelson, Rj
abstract
Breeding in prairie voles is mainly restricted to the autumn and winter of most years. The organization of estrus in female prairie voles is unusual because behavioral estrus is induced by chemosensory stimuli from the urine of adult conspecific males. Isolated females exhibit undetectable levels of estradiol and never display estrous behavior, yet exposure to male urine causes a cascade of endocrine changes that evoke estrogen secretion from the ovaries and estrous behavior within 24 hr. In the prairie vole, the extreme dependence of estrus on chemosensory stimuli raises the possibility that their ovaries may be less prominent in the regulation of gonadotropin secretion than in species with more endogenously organized estrous cycles. The present study examined the contribution of the ovaries in luteinizing hormone (LH) regulation in prairie voles. Females were maintained for 9 weeks in either long (LD 16:8) or short (LD 8:16) photoperiodic conditions, a blood sample was obtained, and then animals were either ovariectomized or received a sham procedure. Another blood sample was obtained a week later and assayed for serum LH. Blood serum LH levels were significantly reduced in short-day voles, compared to long-day animals. After ovariectomy both long-day and short-day voles exhibited equivalent elevations in LH levels. This study provides evidence that photoperiod is measured in female voles and the ovaries appear to produce sufficient steroids to suppress LH release.
1994
- Anti-idiotypic antibodies mimick structural and functional properties of IL-1β in its interaction with type I IL-1R.
[Articolo su rivista]
Soprano, E; Vogo, E; Verani, A; Blom, Johanna Maria Catharina; Siccardi, A; Vercelli, D. VIALE G.
abstract
We obtained affinity-purified polyclonal anti-id antibodies against mAb MhC1 and BrhC3, which recognize amino acids 133-147 at the N-terminus of mature human IL-1 beta. mAb MhC1 and BrhC3 have been shown to inhibit binding of IL-1 beta to type I IL-1R, and to neutralize IL-1 beta bioactivity in a number of in vitro assays. We show that affinity-purified antibodies against the MhC1 and BrhC3 idiotypes specifically bind to type I IL-1 beta IL-1R and that this binding is inhibited by both IL-1 beta and IL-1ra; anti-id antibodies were also able to trigger IL-1R-dependent events, such as IL-8 secretion by human skin fibroblasts and pyrogenic effect after injection in mice. These anti-id antibodies, therefore, behave as structural and functional "images" of IL-1 beta, both in vivo and in vitro. These data indicate the idiotypic strategy as a powerful tool to study the fine specificity of receptor-ligand interactions. Moreover, this is, to our knowledge, the first report showing that the "internal image" of a cytokine can be active in vivo
1994
- Day length affects immune cell numbers in deer mice: Interactions with age, sex, and prenatal photoperiod
[Articolo su rivista]
Blom, J. M. C.; Gerber, J. M.; Nelson, R. J.
abstract
The extent to which day length affects immune function was examined in the present study. Three goals were pursued: 1) to confirm and extend the observation that the immune systems of adult deer mice (Peromyscus maniculatus) are responsive to changes in photoperiod, 2) to examine the development of the photoperiod-associated changes in immune function, and 3) to discover whether photoperiodic information transmitted to the young during gestation influences immune function. In experiment 1, adult mice housed in short days had higher white blood cell and lymphocyte numbers than their long-day cohorts. Red blood cell and differential cell counts did not differ between long- and short-day animals. No sex differences were observed in the pattern of immune responses to photoperiod. The effect of photoperiod on immune cells in prepubertal animals was examined in experiment 2; a similar pattern of results was obtained as that for experiment 1, suggesting that the photoperiodic effect on the immune system is not mediated by sex steroid hormones. Prenatal and postnatal photoperiodic effects on immune cells were examined in experiment 3; pups gestated in one day length were cross-fostered to mothers in the same day length conditions or to mothers maintained in the alternative day length. The results of experiment 3 suggested that photoperiodic information transmitted from the mother to the young in utero subsequently affected immune systems of the pups. Animals gestated in short day lengths displayed higher immune status throughout life than mice gestated in long days. These results are discussed from an adaptive functional perspective.
1994
- Day length affects immune cell numbers in deer mice: The influence of age, sex, and in utero photoperiodic history
[Articolo su rivista]
Blom, Johanna Maria Catharina; Gerber, Jm; Nelson, Rj
abstract
The extent to which day length affects immune function was examined in the present study. Three goals were pursued: 1) to confirm and extend the observation that the immune systems of adult deer mice (Peromyscus maniculatus) are responsive to changes in photoperiod, 2) to examine the development of the photoperiod-associated changes in immune function, and 3) to discover whether photoperiodic information transmitted to the young during gestation influences immune function. In experiment 1, adult mice housed in short days had higher white blood cell and lymphocyte numbers than their long-day cohorts. Red blood cell and differential cell counts did not differ between long- and short-day animals. No sex differences were observed in the pattern of immune responses to photoperiod. The effect of photoperiod on immune cells in prepubertal animals was examined in experiment 2; a similar pattern of results was obtained as that for experiment 1, suggesting that the photoperiodic effect on the immune system is not mediated by sex steroid hormones. Prenatal and postnatal photoperiodic effects on immune cells were examined in experiment 3; pups gestated in one day length were cross-fostered to mothers in the same day length conditions or to mothers maintained in the alternative day length. The results of experiment 3 suggested that photoperiodic information transmitted from the mother to the young in utero subsequently affected immune systems of the pups. Animals gestated in short day lengths displayed higher immune status throughout life than mice gestated in long days. These results are discussed from an adaptive functional perspective.
1994
- Photoperiodic effects on tumor development and immune function.
[Articolo su rivista]
Nelson, Rj; Blom, Johanna Maria Catharina
abstract
Seasonal changes in adaptations associated with winter coping strategies have been frequently studied. Central among the suite of energy-saving, winter-coping strategies is the suspension of reproductive activities. The inhibition of reproduction by nontropical rodents is mediated by daylength changes. Although balanced annual energy budgets are critical, survival and subsequent reproductive success also require avoiding predators, illness, and early death. Because the stressors of winter could lead to suppressed immune function, we hypothesized that animals should have evolved survival strategies involving immunoenhancement. Short daylengths provide a predictive cue to individuals that could be used to enhance immune function in advance of stress-induced immunosuppression. In Experiment 1, adult female deer mice (Peromyscus maniculatus) were housed in either long (LD 16:8) or short (LD 8:16) days for 8 weeks, then injected with the chemical carcinogen 9,10-dimethyl-1,2-benzanthracene (DMBA) dissolved in dimethyl sulfoxide (DMSO) or with the DMSO vehicle alone. Animals were evaluated weekly for 8 weeks after injection. None of the animals treated with DMSO developed tumors in any of the experiments. Nearly 90% of the long-day deer mice injected with DMBA developed squamous cell carcinoma. None of the short-day deer mice injected with DMBA developed tumors. Small lesions developed at the site of injection; short-day females had less severe lesions and healed faster than long-day females. Immunoglobulin G (IgG) response to i.p. injection of sheep red blood cells (SRBC) did not differ photoperiodic conditions. The role of estrogens in the photoperiodic responses was evaluated in Experiment 2: Ovariectomized or sham-ovariectomized deer mice received estradiol benzoate replacement therapy or a control procedure in long daylengths for 8 weeks prior to injection of DMBA or DMSO, then were monitored for 8 additional weeks. Females treated with DMBA developed tumors at the same rate, regardless of estrogen manipulation. Estrogen did not affect healing rates. In Experiment 3, female deer mice were injected with a slurry of microspheres that either contained bromocriptine or were empty. Suppression of prolactin with bromocriptine resulted in a decrease of tumor incidence from 55.6% to 24% in long-day females 8 weeks after injection with DMBA. Healing rates were not affected by prolactin manipulations. Silastic capsules that were filled with either melatonin or cholesterol were implanted into long-day female deer mice in Experiment 4; 8 weeks later, females received an injection of either DMBA or DMSO, then were monitored for 8 weeks.(
1993
- 6-Methoxy-2-Benzoxazolinone and photoperiod: prenatal and postnatal influences on reproductive development in prairie voles (Microtus ochrogaster).
[Articolo su rivista]
Nelson, Rj; Blom, Johanna Maria Catharina
abstract
The effects of photoperiod and 6-methoxy-2-benzoxazolinone (6-MBOA) on the gonadal development of prairie voles was studied when this plant compound was available to pups in utero, during nursing, or postweaning. In part 1, pregnant voles exposed to long or short day lengths were fed food in which 6-MBOA was present (50 μg of 6-MBOA/g food) or absent prior to the birth of their young; all of these dams received a diet that lacked 6-MBOA after the pups were born. Other females were fed food without 6-MBOA throughout pregnancy, but received one of the diets during lactation. Short days inhibited reproductive development in male offspring, affected pup survival, and enhanced pelage development. Postnatal exposure to 6-MBOA did not affect the reproductive function of males. In contrast, prenatal exposure to 6-MBOA accelerated reproductive development among short-day males. Prenatal exposure to 6-MBOA did not affect survival of short-day males, but reduced survival of long-day pups. Prenatal 6-MBOA treatment affected the sex ratio of pups that survived until weaning (13:21; male:female) and of pups that died prior to weaning (26:5). In contrast, photoperiod did not affect reproductive function in female voles. Although reproductive function appears to be uncoupled from photoperiodic regulation, female prairie voles processed photoperiodic information; pelage development was enhanced among short-day females. In part II, breeding pairs were exposed to long or short days and fed food devoid of 6-MBOA prior to the birth of the young. On the day of birth, and for the following 3 weeks, either 6-MBOA-free or 6-MBOA-enriehed food was provided. After weaning, pups received their parents type of food until autopsy 3 or 7 weeks later. Again, photoperiod affected male, but not female, reproductive function. No consistent pattern of results from postnatal exposure to 6-MBOA was discerned for either males or females. Acceleration of reproductive function among short-day males because of prenatal influences may, be involved in the rapid rate of sexual maturation observed prior to peak population densities of microtine rodents. Because males of this species induce females into estrus, male prairie voles may depend on environmental cues to regulate reproductive function, while females may respond only to males. The physiological and ecological implications of these data are discussed
1992
- Photoperiod influences the critical caloric intake necessary to maintain reproduction among male deer mice (Peromyscus maniculatus).
[Articolo su rivista]
Nelson, R; Kita, M; Blom, Johanna Maria Catharina; RHYNE GREY, J.
abstract
The concept of critical day length is well established among rodents; reproductive function Is maintained when day lengths
are greater than some specific threshold. In addition to day length cues, seasonal breeding in deer mice can also be regulated
by food availability. The caloric threshold necessary to support reproduction remains unspecified for seasonally breeding rodents.
The present study examined the interaction between photoperiod and food availability on reproductive function in adult male
deer mice (Peromyscus maniculatus). A critical caloric intake profile was constructed in long (16L:8D) and short (8L:16D)
photoperiods; groups of deer mice in both photoperiods either received food ad libitum or 90, 80, or 70% of their individual
ad libitum food intake for 10 wk. At autopsy, paired testes, epididymides, and seminal vesicles were removed and weighed. Body
mass, total body fat, and total body water contents were also obtained. Short, as compared to long, day lengths inhibited the
reproductive systems of male deer mice. However, food consumption interacted with photoperiod to affect reproductive function.
Significant reductions in reproductive organ size as well as spermatogenic activity were observed among short-day mice after a
10% reduction in ad libitum food intake. Long-day animals required a 20% reduction in caloric intake to depress reproductive
function. Body mass and total body water content were generally unaffected by either photoperiod or food consumption. Total
body fat content was reduced in short- as compared to long-day mice. Individual reproductive responsiveness to short days
increased as food availability decreased. Reproductive organ mass and spermatogenic activity were comparable between longday
males restricted to 70% of their ad lib food intake and short-day males fed ad libitum; i.e., both groups exhibited significant
reproductive regression as compared to long-day males with unrestricted access to food. However, few of these ‘regressed’ males
were aspermic. In contrast, the inhibitory effects of short day lengths plus 30% restricted food intake caused virtually all mice
to stop spermatogenesis. Taken together, these results confirm that short photoperiods cause statistically significant reduction
in gonadal size and sperm production; however, food availability may determine whether the reduction in sperm number is
functionally significant.