Giovanni Laviola | Istituto Superiore di Sanità (original) (raw)
Papers by Giovanni Laviola
Scientific Reports, Jul 5, 2018
. This is a pathogenic hypothesis linking repeated exposures to Group-A-beta-hemolytic streptococ... more . This is a pathogenic hypothesis linking repeated exposures to Group-A-beta-hemolytic streptococcus (GAS), autoantibodies targeting selected brain nuclei and neurobehavioral abnormalities. To persistently elevate glucocorticoid concentrations, we supplemented lactating SJL/J mice with corticosterone (CORT; 80 mg/L) in the drinking water. Starting in adolescence (postnatal day 28), developing offspring were exposed to four injections -at bi-weekly intervals -of a GAS homogenate and tested for behavioral, immunological, neurochemical and molecular alterations. GAS mice showed increased perseverative behavior, impaired sensorimotor gating, reduced reactivity to a serotonergic agonist and inflammatory infiltrates in the anterior diencephalon. Neonatal CORT persistently increased circulating glucocorticoids concentrations and counteracted these alterations. Additionally, neonatal CORT increased peripheral and CNS concentrations of the anti-inflammatory cytokine IL-9. Further, upstream regulator analysis of differentially expressed genes in the striatum showed that the regulatory effect of estradiol is inhibited in GAS-treated mice and activated in GAS-treated mice exposed to CORT. These data support the hypothesis that elevations in glucocorticoids may promote central immunomodulatory processes. Neonatal experiences persistently adjust individual adaptation towards future challenges 1 . While adverse events may relate to an increased risk of pathology 2 , stimulating neonatal conditions may favor resilience towards future environmental insults 3 . Although these considerations originally pertained to emotional 4 and cognitive 5 domains, they have been recently extended to the immune system. For example, Bakker and collaborators 6 observed that neonatal dexamethasone administration -exerting a long-term reduction of corticosterone reactivity -increased individual susceptibility to an experimental autoimmune disease in rats. Meagher et al. 7 reported that brief (15-min/day) and long (180-min/day) maternal separations during the first two weeks of life increased vulnerability to acute Theiler's virus infection 7 . Importantly, also in this study, exposure to neonatal stressors resulted in a
Neuroscience & Biobehavioral Reviews, 2003
Brain development, sex differences and stress: implications for psychopathology This special issu... more Brain development, sex differences and stress: implications for psychopathology This special issue of Neuroscience and Biobehavioral Reviews comprises contributions from scientists who enthusiastically discussed and confronted their ideas during the international Satellite Conference of the 11th Annual Meeting of the International Behavioral Neuroscience Society (IBNS), titled "Brain Development, Sex Differences and Stress: Implications for Psychopathology" held in the Island of Capri (Italy), 23 June, 2002. The intent was to gather scientists from multiple disciplines (neurobiology, psychoneuroendocrinology, physiology, psychology, psychiatry, psychobiology, behavioral pharmacology) who share a common interest in the interaction between the environment and brain development. The present volume is comprised of both review and original data manuscripts from a number of prominent authors actively researching the impact of environment on brain development at the level of behavior and physiology. Needless to say, the effects of early stress are a major concern in society as it is linked to a number of neuropsychiatric disorders. From the outset of this editorial exercise, it was our aim to produce a final volume that was broad and comparative in terms of species, the nature of environmental factors, and the behavioural, neurobiological and physiological endpoints. Approximately half of this special edition journal covers work on the effects of early exposure to stress or insult as it relates to psychopathology. The preclinical findings span from prenatal to postnatal exposure to stress in mouse, rat, and primate, with implications for anxiety, depression, drug abuse, and schizophrenia. The second half provides studies that describe clinical effects of early childhood stress on enduring structural and functional changes in the brain and their contribution to various psychiatric conditions. We have tried to create a comprehensive, yet cohesive, compendium of papers that provides 'something for everyone' in the field of stress and development. Increasing evidence supports the view that the interaction of perinatal exposure to adversity with individual genetic liabilities may increase an individual's
Frontiers in Neuroscience, Jun 30, 2016
Accumulating evidence suggests that Tourette's Syndrome (TS) -a multifactorial pediatric disorder... more Accumulating evidence suggests that Tourette's Syndrome (TS) -a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances -can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes isomorphic to tics and scarce knowledge about the immunological phenomena favoring the transition from natural adaptive immunity to pathological outcomes.
Neuropharmacology, Dec 1, 2018
Deficits in empathy, the ability to share an emotion of another individual, constitute a hallmark... more Deficits in empathy, the ability to share an emotion of another individual, constitute a hallmark of several psychopathological conditions, including conduct disorder. The co-occurrence of excess rates of aggression, general violation of societal norms and callous-unemotional traits confers specific risk for adult psychopathy. In the present study, we relied on a recently devised experimental model of conduct disorder in mice to test the potential efficacy of intranasal oxytocin administration. Two subgroups of BALB/cJ male mice exhibiting opposite profiles in emotional contagion (i.e. socially transmitted adoption of another's emotional states) underwent a series of tests mapping onto reactive aggression, information processing, perseverative behaviour, punishment-related emotional memory, physiological arousal and hormonal stress reactivity, with or without intranasal oxytocin administration (5.0 or 20.0 µg/kg). Collectively, our data indicate that a trait of markedly reduced emotional contagion is associated with a behavioural syndrome of sensorimotor gating deficits, impaired emotional memory, increased aggression and stereotyped behaviours, dysregulations in the circadian rhythms of activity and body temperature and dampened physiological reactivity to external stressors. Moreover, in the absence of changes in oxytocin receptor density in the neural network involved in empathy-like behaviour, we showed that oxytocin administration normalised emotional contagion, aggression and behavioural stereotypies, thereby ameliorating the phenotype of mice characterised by deficient empathy-like behaviour. Besides, oxytocin led to a lower, more prolonged neuroendocrine response of the HPA-axis to stress in all mice. Ultimately, current data support the notion that oxytocin may constitute a valid therapeutic approach in disturbances characterised by abnormal aggression and excess callousness.
Cambridge University Press eBooks, Oct 5, 2014
Psychoneuroendocrinology, Sep 1, 2021
The co-occurrence of excess rates of aggression, general violation of societal norms and callous-... more The co-occurrence of excess rates of aggression, general violation of societal norms and callous-unemotional trait confers specific risk for adult psychopathy. With the aim to address experimentally a model of conduct disorder, we investigated the male offspring of individual mouse dams characterized by high basal plasma corticosterone concentration (HC trait). Notably, classification indices correlated selectively in these females with quite poor maternal care devoted to their offspring. Contrary to their HC mothers, adult male offspring exhibited an integrated profile of dampened physiological reactivity to external stressors co-occurring poor sociability/emotional contagion, impaired punishment-induced memory, and exacerbated aggression. A significant reduction of glucocorticoid and opioid mu receptors' expression in frontal cortex of model HC offspring was also evidenced. Moreover, in the absence of changes in oxytocin receptor in behaviorally-relevant neural areas, we showed that intranasal oxytocin administration (0 or 20.0 µg/kg) selectively modulated specific components of the behavioral phenotype. Ultimately, current data support the notion that maternally-inoculated environmental stress early in development may represent a critical risk factor in disturbances characterised by abnormal aggression and excess callousness.
European Neuropsychopharmacology, 2019
Italian journal of anatomy and embryology, 2013
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with onset in the first 3 years o... more Autism spectrum disorder (ASD) is a neurodevelopmental disorder with onset in the first 3 years of life, with an incidence in Italy of 6–10 new cases per 10,000 children per year. Affected children show impaired social interactions, repetitive or stereotypical behaviors and interests. Disruption/dysregulation of neuroimmune functioning, whether expressed in the patient or during the course of the individual’s brain development, are implicated in Idiopathic ASD (1). Quantitative and qualitative differences in immune function between children with ASD and typically developing controls have been demonstrated, including evidence for increased neuroinflammation and cytokine production in brain specimens obtained from individuals with ASD(2). Peripheral innate immune activation is starting to be recognized as a prominent feature of diseases affecting the central nervous system.(3) In a recent study we have shown that elevated levels of the pro-inflammatory cytokines including interleukin-1, interleukin-6, interleukin-12, interleukin-23, tumor necrosis factor-alpha and BDNF were present in sera of autistic patients (4).We have recently observed that the levels of IL-18 detected in the sera of autistic children were rather lower than those measured in the sera of matched healthy children. We decided to inquire if an alteration in the amount of IL-18 in different areas of the CNS and in the serum was also detectable in Reeler eterozygous mice, a mouse model of autism, compared to wild type mice. IL-18 was localized in different brain regions by immunohistochemistry and in whole brain homogenates by western blots. Quantitative analysis of the cytokine in serum was performed by ELISA.
PLOS ONE, Dec 4, 2017
Deficits in empathy have been proposed to constitute a hallmark of several psychiatric disturbanc... more Deficits in empathy have been proposed to constitute a hallmark of several psychiatric disturbances like conduct disorder, antisocial and narcissistic personality disorders. Limited sensitivity to punishment, shallow or deficient affect and reduced physiological reactivity to environmental stressors have been often reported to co-occur with limited empathy and contribute to the onset of antisocial phenotypes. Empathy in its simplest form (i.e. emotional contagion) is addressed in preclinical models through the evaluation of the social transmission of emotional states: mice exposed to a painful stimulus display a higher response if in the presence of a familiar individual experiencing a higher degree of discomfort, than in isolation. In the present study, we investigated whether a reduction of emotional contagion can be considered a predictor of reduced sociality, sensitivity to punishment and physiological stress reactivity. To this aim, we first evaluated emotional contagion in a group of Balb/cJ mice and then discretised their values in four quartiles. The upper (i.e. Emotional Contagion Prone, ECP) and the lower (i.e. Emotional Contagion Resistant, ECR) quartiles constituted the experimental groups. Our results indicate that mice in the lower quartile are characterized by reduced sociability, impaired memory of negative events and dampened hypothalamic-pituitary-adrenocortical reactivity to external stressors. Furthermore, in the absence of changes in oxytocin receptor density, we show that these mice exhibit elevated concentrations of oxytocin and vasopressin and reduced density of BDNF receptors in behaviourallyrelevant brain areas. Thus, not only do present results translate to the preclinical investigation of psychiatric disturbances, but also they can contribute to the study of emotional contagion in terms of its adaptive significance.
Developmental Medicine & Child Neurology, 2020
AimTo investigate the association between circulating anti‐dopamine D2 receptor (D2R) autoantibod... more AimTo investigate the association between circulating anti‐dopamine D2 receptor (D2R) autoantibodies and the exacerbation of tics in children with chronic tic disorders (CTDs).MethodOne hundred and thirty‐seven children with CTDs (108 males, 29 females; mean age [SD] 10y 0mo [2y 7mo], range 4–16y) were recruited over 18 months. Patients were assessed at baseline, at tic exacerbation, and at 2 months after exacerbation. Serum anti‐D2R antibodies were evaluated using a cell‐based assay and blinded immunofluorescence microscopy scoring was performed by two raters. The association between visit type and presence of anti‐D2R antibodies was measured with McNemar’s test and repeated‐measure logistic regression models, adjusting for potential demographic and clinical confounders.ResultsAt exacerbation, 11 (8%) participants became anti‐D2R‐positive (‘early peri‐exacerbation seroconverters’), and nine (6.6%) became anti‐D2R‐positive at post‐exacerbation (‘late peri‐exacerbation seroconverters...
Annali dell'Istituto superiore di sanità, 1993
In women the first days postpartum are often associated with the onset of major emotional upheava... more In women the first days postpartum are often associated with the onset of major emotional upheaval. Both the cause and the significance of this emotional vulnerability are largely unexplored. A complex interrelationship of emotional and endocrine factors suggests the possibility of a borderline endocrine/neurotransmitter condition, which can be precipitated to some extent by environmental factors. Increased risks are not limited only to nutritional deficiency, infections, and metabolic disorders, since several surveys have shown that women frequently take psychotherapeutic agents at some time during their pregnancy. In this frame, behavioural analysis in animal models appears to be a valuable and sensitive tool for detecting subtle alterations in CNS function, which can be produced by early exposure to psychotropic agents devoid of major teratogenic potential, be they therapeutic drugs or drugs of abuse. The approach has considerable relevance in view of the fact that all or most of...
Annali dell'Istituto superiore di sanità, 1988
Behavioural Pharmacology, 1998
Neuroscience & Biobehavioral Reviews, Nov 1, 2022
Psychopharmacology, Apr 6, 2019
Rationale Deficits in empathy constitute a distinctive feature of several psychopathologies, incl... more Rationale Deficits in empathy constitute a distinctive feature of several psychopathologies, including conduct disorder (CD). The co-occurrence of callous-unemotional (CU) traits, excess rates of aggression and violation of societal norms confers specific risk for adult psychopathy. To date, the off-label use of methylphenidate (MPH) constitutes the drug treatment of choice. Objectives Herein, we tested the therapeutic potential of MPH in a recently devised mouse model recapitulating the core phenotypic abnormalities of CD. Methods Two subgroups of BALB/cJ male mice exhibiting opposite profiles of emotional contagion (i.e. socially transmitted adoption of another's emotional states) were investigated for reactive aggression, sociability, attention control, anxiety-related behaviours and locomotor activity, in response to MPH administration (0.0, 3.0 or 6.0 mg/kg). Results Our data indicate that mice selected for excess callousness exhibit phenotypic abnormalities isomorphic to the symptoms of CD: stability of the low emotional contagion trait, increased aggression and reduced sociability. In accordance with our predictions, MPH reduced aggression and increased sociability in callous mice; yet, it failed to restore the low responsiveness to the emotions of a conspecific in pain, isomorphic to CU traits. Conclusions Although our data support the notion that MPH may contribute to the management of excess aggression in CD patients, additional studies shall identify specific treatments to target the callousness domain. The latter, unaffected by MPH in our experimental model, demands focused consideration whereby it constitutes a specifier associated with a worse prognosis.
Scientific Reports, Aug 3, 2020
International Journal of Developmental Neuroscience, Nov 1, 2010
Neurosteroids that act as GABAA modulators, as allopregnanolone (AlloP), not only play important ... more Neurosteroids that act as GABAA modulators, as allopregnanolone (AlloP), not only play important roles in brain development, and specially in the maturation of the hippocampus, but also in adult behaviour. The aim of the present work is to screen whether developmentally altered neurosteroid levels influence the normal behavioural response to novelty measured in the open field test after adult intrahippocampal administrations of AlloP, a GABAA positive modulating neurosteroid, or pregnenolone sulphate (PregS), a GABAA negative modulator. Pups received AlloP (10 mg/kg, s.c.), a 5alpha-reductase inhibitor (finasteride, 50 mg/kg, s.c.) or vehicle from the fifth to the ninth postnatal day. At 90 days old a bilateral cannula was implanted into the hippocampus. After recovery, animals received AlloP (0.2 g/0.5 l), PregS (5 ng/0.5 l) or vehicle in each hippocampus 5 min before they were tested. Intrahippocampal AlloP and PregS decreased total novelty-directed locomotor activity in neonatal control rats. Instead, in neonatal AlloP-treated rats only PregS decreased open field activity, whereas in neonatal finasteride treated rats the intrahippocampal injections had no effects. The decreased of activity induced by intrahippocampal PregS injection was higher in neonatal AlloP-treated rats than in controls. Neonatal treatments did not affect anxiety relevant scores (inner activity, time spent in and number of entries into the inner zone in the first five minutes). Intrahippocampal AlloP and PregS decreased, however, inner activity and time spent in the inner zone independently of the neonatal treatment. But since the overall activity is reduced, the reduced activity in the centre could be suggest more an overall reduction in motor activity (or exploratory drive) than increased anxiety. Results indicate that the effects of intrahippocampal neurosteroids administration on novelty-directed activity are different in function of the neonatal treatment, possibly related to alterations in hippocampal GABAA receptors maturation, suggesting neurobiological adaptations that remain until the adulthood.
Behavioural Processes, 2022
Although both human and non-human animals, in everyday life, deal with risky decisions in a socia... more Although both human and non-human animals, in everyday life, deal with risky decisions in a social environment, few studies investigated how social dimension influences risk preferences (i.e., if consequences on others feeds back over own choice). Here, we assessed whether the presence of a conspecific, acting as a potential competitor for the same food resource, influenced risky decision-making in male rats. Subjects received a series of choices between a safe option (always yielding a small yet optimal reward, solely to itself) and a risky option (yielding a larger but suboptimal reward, one third of times to itself and two third of times delivered to the other half cage); rats were tested twice, both "alone" and "paired" with a conspecific, recipient of own-lost food and hence acting as potential competitor. Results showed that focal subjects were more risk-prone when paired with a conspecific than when tested alone. However, rats exhibited also a higher motivational conflict with a competing bystander present than alone: data suggest that the primary drive was to increase "own" food rather than either a competitive or prosocial tendency. Overall, for rats tested in a risky-choice task, a competitive social context increased the salience and attractiveness of larger food outcomes, as observed in humans and great apes. This was leading to the economically irrational response of selecting the "binge-but-risky" option, notwithstanding uncertainty about the actual recipient of such food.
Scientific Reports, Jul 5, 2018
. This is a pathogenic hypothesis linking repeated exposures to Group-A-beta-hemolytic streptococ... more . This is a pathogenic hypothesis linking repeated exposures to Group-A-beta-hemolytic streptococcus (GAS), autoantibodies targeting selected brain nuclei and neurobehavioral abnormalities. To persistently elevate glucocorticoid concentrations, we supplemented lactating SJL/J mice with corticosterone (CORT; 80 mg/L) in the drinking water. Starting in adolescence (postnatal day 28), developing offspring were exposed to four injections -at bi-weekly intervals -of a GAS homogenate and tested for behavioral, immunological, neurochemical and molecular alterations. GAS mice showed increased perseverative behavior, impaired sensorimotor gating, reduced reactivity to a serotonergic agonist and inflammatory infiltrates in the anterior diencephalon. Neonatal CORT persistently increased circulating glucocorticoids concentrations and counteracted these alterations. Additionally, neonatal CORT increased peripheral and CNS concentrations of the anti-inflammatory cytokine IL-9. Further, upstream regulator analysis of differentially expressed genes in the striatum showed that the regulatory effect of estradiol is inhibited in GAS-treated mice and activated in GAS-treated mice exposed to CORT. These data support the hypothesis that elevations in glucocorticoids may promote central immunomodulatory processes. Neonatal experiences persistently adjust individual adaptation towards future challenges 1 . While adverse events may relate to an increased risk of pathology 2 , stimulating neonatal conditions may favor resilience towards future environmental insults 3 . Although these considerations originally pertained to emotional 4 and cognitive 5 domains, they have been recently extended to the immune system. For example, Bakker and collaborators 6 observed that neonatal dexamethasone administration -exerting a long-term reduction of corticosterone reactivity -increased individual susceptibility to an experimental autoimmune disease in rats. Meagher et al. 7 reported that brief (15-min/day) and long (180-min/day) maternal separations during the first two weeks of life increased vulnerability to acute Theiler's virus infection 7 . Importantly, also in this study, exposure to neonatal stressors resulted in a
Neuroscience & Biobehavioral Reviews, 2003
Brain development, sex differences and stress: implications for psychopathology This special issu... more Brain development, sex differences and stress: implications for psychopathology This special issue of Neuroscience and Biobehavioral Reviews comprises contributions from scientists who enthusiastically discussed and confronted their ideas during the international Satellite Conference of the 11th Annual Meeting of the International Behavioral Neuroscience Society (IBNS), titled "Brain Development, Sex Differences and Stress: Implications for Psychopathology" held in the Island of Capri (Italy), 23 June, 2002. The intent was to gather scientists from multiple disciplines (neurobiology, psychoneuroendocrinology, physiology, psychology, psychiatry, psychobiology, behavioral pharmacology) who share a common interest in the interaction between the environment and brain development. The present volume is comprised of both review and original data manuscripts from a number of prominent authors actively researching the impact of environment on brain development at the level of behavior and physiology. Needless to say, the effects of early stress are a major concern in society as it is linked to a number of neuropsychiatric disorders. From the outset of this editorial exercise, it was our aim to produce a final volume that was broad and comparative in terms of species, the nature of environmental factors, and the behavioural, neurobiological and physiological endpoints. Approximately half of this special edition journal covers work on the effects of early exposure to stress or insult as it relates to psychopathology. The preclinical findings span from prenatal to postnatal exposure to stress in mouse, rat, and primate, with implications for anxiety, depression, drug abuse, and schizophrenia. The second half provides studies that describe clinical effects of early childhood stress on enduring structural and functional changes in the brain and their contribution to various psychiatric conditions. We have tried to create a comprehensive, yet cohesive, compendium of papers that provides 'something for everyone' in the field of stress and development. Increasing evidence supports the view that the interaction of perinatal exposure to adversity with individual genetic liabilities may increase an individual's
Frontiers in Neuroscience, Jun 30, 2016
Accumulating evidence suggests that Tourette's Syndrome (TS) -a multifactorial pediatric disorder... more Accumulating evidence suggests that Tourette's Syndrome (TS) -a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances -can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes isomorphic to tics and scarce knowledge about the immunological phenomena favoring the transition from natural adaptive immunity to pathological outcomes.
Neuropharmacology, Dec 1, 2018
Deficits in empathy, the ability to share an emotion of another individual, constitute a hallmark... more Deficits in empathy, the ability to share an emotion of another individual, constitute a hallmark of several psychopathological conditions, including conduct disorder. The co-occurrence of excess rates of aggression, general violation of societal norms and callous-unemotional traits confers specific risk for adult psychopathy. In the present study, we relied on a recently devised experimental model of conduct disorder in mice to test the potential efficacy of intranasal oxytocin administration. Two subgroups of BALB/cJ male mice exhibiting opposite profiles in emotional contagion (i.e. socially transmitted adoption of another's emotional states) underwent a series of tests mapping onto reactive aggression, information processing, perseverative behaviour, punishment-related emotional memory, physiological arousal and hormonal stress reactivity, with or without intranasal oxytocin administration (5.0 or 20.0 µg/kg). Collectively, our data indicate that a trait of markedly reduced emotional contagion is associated with a behavioural syndrome of sensorimotor gating deficits, impaired emotional memory, increased aggression and stereotyped behaviours, dysregulations in the circadian rhythms of activity and body temperature and dampened physiological reactivity to external stressors. Moreover, in the absence of changes in oxytocin receptor density in the neural network involved in empathy-like behaviour, we showed that oxytocin administration normalised emotional contagion, aggression and behavioural stereotypies, thereby ameliorating the phenotype of mice characterised by deficient empathy-like behaviour. Besides, oxytocin led to a lower, more prolonged neuroendocrine response of the HPA-axis to stress in all mice. Ultimately, current data support the notion that oxytocin may constitute a valid therapeutic approach in disturbances characterised by abnormal aggression and excess callousness.
Cambridge University Press eBooks, Oct 5, 2014
Psychoneuroendocrinology, Sep 1, 2021
The co-occurrence of excess rates of aggression, general violation of societal norms and callous-... more The co-occurrence of excess rates of aggression, general violation of societal norms and callous-unemotional trait confers specific risk for adult psychopathy. With the aim to address experimentally a model of conduct disorder, we investigated the male offspring of individual mouse dams characterized by high basal plasma corticosterone concentration (HC trait). Notably, classification indices correlated selectively in these females with quite poor maternal care devoted to their offspring. Contrary to their HC mothers, adult male offspring exhibited an integrated profile of dampened physiological reactivity to external stressors co-occurring poor sociability/emotional contagion, impaired punishment-induced memory, and exacerbated aggression. A significant reduction of glucocorticoid and opioid mu receptors' expression in frontal cortex of model HC offspring was also evidenced. Moreover, in the absence of changes in oxytocin receptor in behaviorally-relevant neural areas, we showed that intranasal oxytocin administration (0 or 20.0 µg/kg) selectively modulated specific components of the behavioral phenotype. Ultimately, current data support the notion that maternally-inoculated environmental stress early in development may represent a critical risk factor in disturbances characterised by abnormal aggression and excess callousness.
European Neuropsychopharmacology, 2019
Italian journal of anatomy and embryology, 2013
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with onset in the first 3 years o... more Autism spectrum disorder (ASD) is a neurodevelopmental disorder with onset in the first 3 years of life, with an incidence in Italy of 6–10 new cases per 10,000 children per year. Affected children show impaired social interactions, repetitive or stereotypical behaviors and interests. Disruption/dysregulation of neuroimmune functioning, whether expressed in the patient or during the course of the individual’s brain development, are implicated in Idiopathic ASD (1). Quantitative and qualitative differences in immune function between children with ASD and typically developing controls have been demonstrated, including evidence for increased neuroinflammation and cytokine production in brain specimens obtained from individuals with ASD(2). Peripheral innate immune activation is starting to be recognized as a prominent feature of diseases affecting the central nervous system.(3) In a recent study we have shown that elevated levels of the pro-inflammatory cytokines including interleukin-1, interleukin-6, interleukin-12, interleukin-23, tumor necrosis factor-alpha and BDNF were present in sera of autistic patients (4).We have recently observed that the levels of IL-18 detected in the sera of autistic children were rather lower than those measured in the sera of matched healthy children. We decided to inquire if an alteration in the amount of IL-18 in different areas of the CNS and in the serum was also detectable in Reeler eterozygous mice, a mouse model of autism, compared to wild type mice. IL-18 was localized in different brain regions by immunohistochemistry and in whole brain homogenates by western blots. Quantitative analysis of the cytokine in serum was performed by ELISA.
PLOS ONE, Dec 4, 2017
Deficits in empathy have been proposed to constitute a hallmark of several psychiatric disturbanc... more Deficits in empathy have been proposed to constitute a hallmark of several psychiatric disturbances like conduct disorder, antisocial and narcissistic personality disorders. Limited sensitivity to punishment, shallow or deficient affect and reduced physiological reactivity to environmental stressors have been often reported to co-occur with limited empathy and contribute to the onset of antisocial phenotypes. Empathy in its simplest form (i.e. emotional contagion) is addressed in preclinical models through the evaluation of the social transmission of emotional states: mice exposed to a painful stimulus display a higher response if in the presence of a familiar individual experiencing a higher degree of discomfort, than in isolation. In the present study, we investigated whether a reduction of emotional contagion can be considered a predictor of reduced sociality, sensitivity to punishment and physiological stress reactivity. To this aim, we first evaluated emotional contagion in a group of Balb/cJ mice and then discretised their values in four quartiles. The upper (i.e. Emotional Contagion Prone, ECP) and the lower (i.e. Emotional Contagion Resistant, ECR) quartiles constituted the experimental groups. Our results indicate that mice in the lower quartile are characterized by reduced sociability, impaired memory of negative events and dampened hypothalamic-pituitary-adrenocortical reactivity to external stressors. Furthermore, in the absence of changes in oxytocin receptor density, we show that these mice exhibit elevated concentrations of oxytocin and vasopressin and reduced density of BDNF receptors in behaviourallyrelevant brain areas. Thus, not only do present results translate to the preclinical investigation of psychiatric disturbances, but also they can contribute to the study of emotional contagion in terms of its adaptive significance.
Developmental Medicine & Child Neurology, 2020
AimTo investigate the association between circulating anti‐dopamine D2 receptor (D2R) autoantibod... more AimTo investigate the association between circulating anti‐dopamine D2 receptor (D2R) autoantibodies and the exacerbation of tics in children with chronic tic disorders (CTDs).MethodOne hundred and thirty‐seven children with CTDs (108 males, 29 females; mean age [SD] 10y 0mo [2y 7mo], range 4–16y) were recruited over 18 months. Patients were assessed at baseline, at tic exacerbation, and at 2 months after exacerbation. Serum anti‐D2R antibodies were evaluated using a cell‐based assay and blinded immunofluorescence microscopy scoring was performed by two raters. The association between visit type and presence of anti‐D2R antibodies was measured with McNemar’s test and repeated‐measure logistic regression models, adjusting for potential demographic and clinical confounders.ResultsAt exacerbation, 11 (8%) participants became anti‐D2R‐positive (‘early peri‐exacerbation seroconverters’), and nine (6.6%) became anti‐D2R‐positive at post‐exacerbation (‘late peri‐exacerbation seroconverters...
Annali dell'Istituto superiore di sanità, 1993
In women the first days postpartum are often associated with the onset of major emotional upheava... more In women the first days postpartum are often associated with the onset of major emotional upheaval. Both the cause and the significance of this emotional vulnerability are largely unexplored. A complex interrelationship of emotional and endocrine factors suggests the possibility of a borderline endocrine/neurotransmitter condition, which can be precipitated to some extent by environmental factors. Increased risks are not limited only to nutritional deficiency, infections, and metabolic disorders, since several surveys have shown that women frequently take psychotherapeutic agents at some time during their pregnancy. In this frame, behavioural analysis in animal models appears to be a valuable and sensitive tool for detecting subtle alterations in CNS function, which can be produced by early exposure to psychotropic agents devoid of major teratogenic potential, be they therapeutic drugs or drugs of abuse. The approach has considerable relevance in view of the fact that all or most of...
Annali dell'Istituto superiore di sanità, 1988
Behavioural Pharmacology, 1998
Neuroscience & Biobehavioral Reviews, Nov 1, 2022
Psychopharmacology, Apr 6, 2019
Rationale Deficits in empathy constitute a distinctive feature of several psychopathologies, incl... more Rationale Deficits in empathy constitute a distinctive feature of several psychopathologies, including conduct disorder (CD). The co-occurrence of callous-unemotional (CU) traits, excess rates of aggression and violation of societal norms confers specific risk for adult psychopathy. To date, the off-label use of methylphenidate (MPH) constitutes the drug treatment of choice. Objectives Herein, we tested the therapeutic potential of MPH in a recently devised mouse model recapitulating the core phenotypic abnormalities of CD. Methods Two subgroups of BALB/cJ male mice exhibiting opposite profiles of emotional contagion (i.e. socially transmitted adoption of another's emotional states) were investigated for reactive aggression, sociability, attention control, anxiety-related behaviours and locomotor activity, in response to MPH administration (0.0, 3.0 or 6.0 mg/kg). Results Our data indicate that mice selected for excess callousness exhibit phenotypic abnormalities isomorphic to the symptoms of CD: stability of the low emotional contagion trait, increased aggression and reduced sociability. In accordance with our predictions, MPH reduced aggression and increased sociability in callous mice; yet, it failed to restore the low responsiveness to the emotions of a conspecific in pain, isomorphic to CU traits. Conclusions Although our data support the notion that MPH may contribute to the management of excess aggression in CD patients, additional studies shall identify specific treatments to target the callousness domain. The latter, unaffected by MPH in our experimental model, demands focused consideration whereby it constitutes a specifier associated with a worse prognosis.
Scientific Reports, Aug 3, 2020
International Journal of Developmental Neuroscience, Nov 1, 2010
Neurosteroids that act as GABAA modulators, as allopregnanolone (AlloP), not only play important ... more Neurosteroids that act as GABAA modulators, as allopregnanolone (AlloP), not only play important roles in brain development, and specially in the maturation of the hippocampus, but also in adult behaviour. The aim of the present work is to screen whether developmentally altered neurosteroid levels influence the normal behavioural response to novelty measured in the open field test after adult intrahippocampal administrations of AlloP, a GABAA positive modulating neurosteroid, or pregnenolone sulphate (PregS), a GABAA negative modulator. Pups received AlloP (10 mg/kg, s.c.), a 5alpha-reductase inhibitor (finasteride, 50 mg/kg, s.c.) or vehicle from the fifth to the ninth postnatal day. At 90 days old a bilateral cannula was implanted into the hippocampus. After recovery, animals received AlloP (0.2 g/0.5 l), PregS (5 ng/0.5 l) or vehicle in each hippocampus 5 min before they were tested. Intrahippocampal AlloP and PregS decreased total novelty-directed locomotor activity in neonatal control rats. Instead, in neonatal AlloP-treated rats only PregS decreased open field activity, whereas in neonatal finasteride treated rats the intrahippocampal injections had no effects. The decreased of activity induced by intrahippocampal PregS injection was higher in neonatal AlloP-treated rats than in controls. Neonatal treatments did not affect anxiety relevant scores (inner activity, time spent in and number of entries into the inner zone in the first five minutes). Intrahippocampal AlloP and PregS decreased, however, inner activity and time spent in the inner zone independently of the neonatal treatment. But since the overall activity is reduced, the reduced activity in the centre could be suggest more an overall reduction in motor activity (or exploratory drive) than increased anxiety. Results indicate that the effects of intrahippocampal neurosteroids administration on novelty-directed activity are different in function of the neonatal treatment, possibly related to alterations in hippocampal GABAA receptors maturation, suggesting neurobiological adaptations that remain until the adulthood.
Behavioural Processes, 2022
Although both human and non-human animals, in everyday life, deal with risky decisions in a socia... more Although both human and non-human animals, in everyday life, deal with risky decisions in a social environment, few studies investigated how social dimension influences risk preferences (i.e., if consequences on others feeds back over own choice). Here, we assessed whether the presence of a conspecific, acting as a potential competitor for the same food resource, influenced risky decision-making in male rats. Subjects received a series of choices between a safe option (always yielding a small yet optimal reward, solely to itself) and a risky option (yielding a larger but suboptimal reward, one third of times to itself and two third of times delivered to the other half cage); rats were tested twice, both "alone" and "paired" with a conspecific, recipient of own-lost food and hence acting as potential competitor. Results showed that focal subjects were more risk-prone when paired with a conspecific than when tested alone. However, rats exhibited also a higher motivational conflict with a competing bystander present than alone: data suggest that the primary drive was to increase "own" food rather than either a competitive or prosocial tendency. Overall, for rats tested in a risky-choice task, a competitive social context increased the salience and attractiveness of larger food outcomes, as observed in humans and great apes. This was leading to the economically irrational response of selecting the "binge-but-risky" option, notwithstanding uncertainty about the actual recipient of such food.