Abnormal Social Behavior Research Articles

Maternal exposure to triclosan during lactation alters social behaviors and the hippocampal ultrastructure in adult mouse offspring

We recently reported that exposure to triclosan (TCS), a broad-spectrum antibacterial agent, affects social behaviors in adult mice, however, the long-lasting effects of TCS exposure during early life on social behaviors are still elusive. The present study aimed to investigate the long-lasting impacts of adding TCS to the maternal drinking water during lactation on the social behaviors of adult mouse offspring and to explore the potential mechanism underlying these effects. The behavioral results showed that TCS exposure decreased body weight, increased depression-like behavior and decreased social dominance in both male and female offspring, as well as increased anxiety-like behavior and bedding preference in female offspring. In addition, enzyme-linked immunosorbent assay (ELISA) indicated that TCS exposure increased peripheral proinflammatory cytokine levels, altered serum oxytocin (OT) levels, and downregulated the expression of postsynaptic density protein 95 (PSD-95) in the hippocampus. Morphological analysis by transmission electron microscopy (TEM) demonstrated that exposure to TCS induced morphological changes to synapses and neurons in the hippocampus of offspring. These findings suggested that TCS exposure during lactation contributed to abnormal social behaviors accompanied by increased peripheral inflammation and altered hippocampal neuroplasticity, which provides a deeper understanding of the effects of TCS exposure during early life on brain function and behavioral phenotypes.

The Anti-social Brain in Schizophrenia: A Role of CaMKII?

Current pharmacological therapy has limited effects on the cognitive impairments and negative symptoms associated with schizophrenia. Therefore, understanding the molecular underpinnings of this disorder is essential for the development of effective treatments. It appears that a reduction in calcium/calmodulin-dependent protein kinase II (α-CaMKII) activity is a common mechanism underlying the abnormal social behavior and cognitive deficits associated with schizophrenia. In addition, in a previous study social interaction with a partner of the same sex and weight increased the activity of α-CaMKII in rats. Here, we propose that boosting of CaMKII signaling, in a manner that counteracts this neuropsychiatric disease without disrupting the normal brain function, might ameliorate the abnormalities in social cognition and the negative symptoms of schizophrenia.

Social behavior and spatial orientation in rat strains with genetic predisposition to catatonia (GC) and stereotypes (PM).

Various psychopathologies, including schizophrenia, bipolar disorder and major depression, are associated with abnormalities in social behavior and learning. One of the syndromes that may also take place in these disorders is catatonia. Catatonia is a psychomotor syndrome in which motor excitement, stereotypy, stuporous state, including the phenomenon of “waxy flexibility” (catalepsy), can be observed. Rats with genetic catatonia (GC) and pendulum-like movements (PM) of the anterior half of the body have physiological and behavioral changes similar to those observed in schizophrenia and depression in humans and can be considered as incomplete experimental models of these pathologies. The social behavior of the GC and PM rats has not been previously studied, and the cognitive abilities of animals of these strains are also insufficiently studied. To determine whether the GC and PM rats have changes in social behavior and spatial learning, behavioral phenotyping was performed in the resident-intruder test, three-chamber test, Barnes maze test. Some deviations in social behavior, such as increased offensive aggression in PM rats in the resident-intruder test, increased or decreased social interactions depending on the environment in different tests in GC, were shown. In addition, principal component analysis revealed a negative association between catatonic freezing and the socialization index in the three-chamber test. Decreased locomotor activity of GС rats can adversely affect the performance of tasks on spatial memory. It has been shown that PM rats do not use a spatial strategy in the Barnes maze, which may indicate impairment of learning and spatial memory.

Maternal exposure to bisphenol S induces neuropeptide signaling dysfunction and oxidative stress in the brain, and abnormal social behaviors in zebrafish (Danio rerio) offspring

Recent studies show that bisphenol S (BPS) induces multiple adverse effects in exposed organisms; however, the maternal effects of BPS exposure remain poorly understood. Here, we expose adult female zebrafish to environmentally relevant concentrations of BPS (0, 1, 10, 30 μg/L) and 1 μg/L of 17-β-estradiol (E2) as a positive control for 60 days. Females were then paired with BPS-unexposed males and their offspring were raised in control water for 6 months. Maternal exposure to BPS was found to alter social behavior and anxiety response in a dose-specific manner in male offspring. Group preferences and social cohesion were significantly reduced by maternal exposure to 1 and 10 μg/L BPS, respectively. Additionally, maternal exposure to 1 and 30 μg/L BPS and E2 decreased offspring stress responses during the novel tank test. The impaired social behavior was associated with elevated arginine-vasotocin (AVT) level as well as with the altered expression of genes involved in AVT signaling pathway (AVT, avpr1aa) and enzymatic antioxidant genes (cat and Mn-sod) in the brain. Collectively, these results suggest that maternal exposure to environmentally relevant concentrations of BPS alters social behavior in zebrafish offspring, which is likely mediated by oxidative stress and disruption of neuropeptide signaling pathways in the brain.

Chronic social stress during early development elicits unique behavioral changes in adulthood.

Chronic social stress is known to induce inflammation in the brain, and early-life stress affects the brain and social behavior in adulthood. To study the relationship between social stress in childhood development and social behavior in adulthood, we subjected mice to a sequential early-life social stresses and characterized their adult behavioral phenotypes. C57BL/6 mice were sequentially subjected to maternal separation (MS), social defeat (SD), and social isolation (SI) in that order. The body weights of the MS/SD/SI mice were measured. Behavioral tasks related to anxiety, depression, locomotion, learning/memory, and repetitive/compulsive-like behavior were conducted. Social behaviors suggesting sociability, social interaction, aggression, and social fear were investigated. MS/SD/SI mice weighed less than the control mice. At 7 and 8 weeks of age. These mice displayed normal behaviors in anxiety-, depression-, and learning/memory-related tasks, but they exhibited increased locomotor activity and a low level of repetitive/compulsive-like behavior. Notably, they exhibited increased social interaction, impaired empathy-related fear, reduced predator fear, and increased defensive aggressiveness. Social stress during childhood development resulted in behavioral alterations, and MS/SD/SI mice generated by mimicking child abuse or maltreatment showed unique abnormalities in social behaviors. MS/SD/SI mice might be useful not only to study the relationship between social stress and brain inflammation but also psychosocial behaviors observed in individuals with brain disorders, such as psychopaths.

Differential epitranscriptome and proteome modulation in the brain of neonatal mice exposed to isoflurane or sevoflurane.

Repeated neonatal exposure to anesthetics may disturb neurodevelopment and cause neuropsychological disorders. The m6A modification participates in the gene regulation of neurodevelopment in mouse fetuses exposed to anesthetics. This study aims to explore the underlying molecular mechanisms of neurotoxicity after early-life anesthesia exposure. Mice were exposed to isoflurane (1.5%) or sevoflurane (2.3%) for 2h daily during postnatal days (PND) 7-9. Sociability, spatial working memory, and anxiety-like behavior were assessed on PND 30-35. Synaptogenesis, epitranscriptome m6A, and the proteome of brain regions were evaluated on PND 21. Both isoflurane and sevoflurane produced abnormal social behaviors at the juvenile age, with different sociality patterns in each group. Synaptogenesis in the hippocampal area CA3 was increased in the sevoflurane-exposed mice. Both anesthetics led to numerous persistent m6A-induced alterations in the brain, associated with critical metabolic, developmental, and immune functions. The proteins altered by isoflurane exposure were mainly associated with epilepsy, ataxia, and brain development. As for sevoflurane, the altered proteins were involved in social behavior. Social interaction, the modulation patterns of the m6A modification, and protein expression were altered in an isoflurane or sevoflurane-specific way. Possible molecular pathways involved in brain impairment were revealed, as well as the mechanism underlying behavioral deficits following repeated exposure to anesthetics in newborns.

Integrin \u03b23 in forebrain Emx1-expressing cells regulates repetitive self-grooming and sociability in mice

BackgroundAutism spectrum disorder (ASD) is characterized by repetitive behaviors, deficits in communication, and overall impaired social interaction. Of all the integrin subunit mutations, mutations in integrin β3 (Itgb3) may be the most closely associated with ASD. Integrin β3 is required for normal structural plasticity of dendrites and synapses specifically in excitatory cortical and hippocampal circuitry. However, the behavioral consequences of Itgb3 function in the forebrain have not been assessed. We tested the hypothesis that behaviors that are typically abnormal in ASD—such as self-grooming and sociability behaviors—are disrupted with conditional Itgb3 loss of function in forebrain circuitry in male and female mice.MethodsWe generated male and female conditional knockouts (cKO) and conditional heterozygotes (cHET) of Itgb3 in excitatory neurons and glia that were derived from Emx1-expressing forebrain cells during development. We used several different assays to determine whether male and female cKO and cHET mice have repetitive self-grooming behaviors, anxiety-like behaviors, abnormal locomotion, compulsive-like behaviors, or abnormal social behaviors, when compared to male and female wildtype (WT) mice.ResultsOur findings indicate that only self-grooming and sociability are altered in cKO, but not cHET or WT mice, suggesting that Itgb3 is specifically required in forebrain Emx1-expressing cells for normal repetitive self-grooming and social behaviors. Furthermore, in cKO (but not cHET or WT), we observed an interaction effect for sex and self-grooming environment and an interaction effect for sex and sociability test chamber.LimitationsWhile this study demonstrated a role for forebrain Itgb3 in specific repetitive and social behaviors, it was unable to determine whether forebrain Itgb3 is required for a preference for social novelty, whether cHET are haploinsufficient with respect to repetitive self-grooming and social behaviors, or the nature of the interaction effect for sex and environment/chamber in affected behaviors of cKO.ConclusionsTogether, these findings strengthen the idea that Itgb3 has a specific role in shaping forebrain circuitry that is relevant to endophenotypes of autism spectrum disorder.

Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder.

Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD‐93 protein reduction) a novel clinically relevant Dlg2 +/− rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N‐Methyl‐D‐aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD‐93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2 +/− rats show a potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, and partially dissimilar to behavioural deficits previously reported in Dlg2 +/− mouse models demonstrating issues surrounding the comparison of models with different aetiology and species. Intact performance on many of the behavioural domains assessed here, such as anxiety and reward processing, will remove these as confounds when continuing investigation into this model using more complex cognitive tasks.

The Consequential Increase of Alcoholism and Substance Abuse During Covid- Its Causes and Implications

Covid-19 is not just a virus which is risking human lives everyday, but it is a phenomenon which has inflicted major changes on the long-term global survival and economic strategies. The pandemic has brought about major diversions in the world order, which philosophers and scientists have predicted to occur once in a century’s time. Covid-19 has also affected the personal health, physical and psychological of all human beings. It has forced people to change their social behaviors significantly, which has had consequential effect on their mental health. One significant result of the pandemic is the increased consumption of alcohol and other psychoactive substances among people. As people are forced to lock themselves up inside their homes, some have resorted to exercising, biking, running, and meditation to maintain sanity, while others have boosted their addictive behavior by consuming more alcohol and drugs to make staying-indoors more entertaining. Nielsen has reported a 54% rise in the national consumption of alcohol on the week of March 21st 2020, as compared to the same in 2019. The online sales of alcohol have also risen enormously from 2019 to 2020. The study aims to address the problem of increased alcoholism and substance abuse during Covid-19 by understanding the causes of this rise. The method is based on analysis and comparison of available survey reports, to find out exactly what amount of human consumption has increased during the pandemic. From the findings we can conclude that alcoholism and substance abuse has risen significantly during Covid-19, and psychological distress, anxiety and depression can be some major causes for this abnormal social behavior. It can also be implied that this increased alcoholism is likely to affect the physical health, neural and social behavior, and the work life of many human beings through the pandemic.

Oxytocin normalizes altered circuit connectivity for social rescue of the Cntnap2 knockout mouse

The neural basis of abnormal social behavior in autism spectrum disorders (ASDs) remains incompletely understood. Here we used two complementary but independent brain-wide mapping approaches, mouse resting-state fMRI and c-Fos-iDISCO+ imaging, to construct brain-wide activity and connectivity maps of the Cntnap2 knockout (KO) mouse model of ASD. At the macroscale level, we detected reduced functional coupling across social brain regions despite general patterns of hyperconnectivity across major brain structures. Oxytocin administration, which rescues social deficits in KO mice, strongly stimulated many brain areas and normalized connectivity patterns. Notably, chemogenetically triggered release of endogenous oxytocin strongly stimulated the nucleus accumbens (NAc), a forebrain nucleus implicated in social reward. Furthermore, NAc-targeted approaches to activate local oxytocin receptors sufficiently rescued their social deficits. Our findings establish circuit- and systems-level mechanisms of social deficits in Cntnap2 KO mice and reveal the NAc as a region that can be modulated by oxytocin to promote social interactions.

Arsenic exposure via drinking water during pregnancy and lactation induces autism-like behaviors in male offspring mice

Exposure to arsenic (As), an environmental toxicant, causes damages to the central nervous system (CNS) structure and function. Emerging epidemiological studies support that exposure to As, especially during the critical periods of the CNS development, may act as an environmental risk factor of autism spectrum disorders (ASD), which is characterized by behavioral changes, including abnormal social behaviors, restricted interests and repetitive behaviors. However, direct evidence supporting the cause-effect relationship between As exposure and the risk of ASD is still missing. Thus, we aimed to investigate whether As exposure during pregnancy and lactation led to autism-like behaviors in offspring mice in the present study. We established a mice model of exposure to As via drinking water during pregnancy and lactation and conducted a battery of behavioral tests to evaluate social behaviors, repetitive behaviors, anxiety behaviors and learning and memory ability in offspring mice. We found that perinatal exposure to As caused autism-like behaviors in male offspring, which demonstrated by abnormal social behaviors and repetitive behaviors. Anxiety-like behaviors, and learning and memory impairments, known as concomitant behavioral phenotypes in mice with autism-like behaviors, were also observed. Decreases of synaptic density, especially in cortex, hippocampus and cerebellum, are extensively observed in both ASD patients and animal models of ASD. Thus, immunofluorescence staining and western blotting were used to observe the expression of PSD-95 and SYP, well-known markers for presynaptic and postsynaptic membranes, to assess the synaptic density in offspring cortex, hippocampus and cerebellum. We found perinatal exposure to As decreased the expression of PSD-95 and SYP in these brain regions. This indicated that perinatal exposure to As caused decreases of synaptic density, a typical autism-like cellular alteration in brains, which may contribute to autism-like behaviors in offspring.

Investigating the Neurobiology of Abnormal Social Behaviors.

Investigating the Neurobiology of Abnormal Social Behaviors.

S100B dysregulation during brain development affects synaptic SHANK protein networks via alteration of zinc homeostasis

Autism Spectrum Disorders (ASD) are caused by a combination of genetic predisposition and nongenetic factors. Among the nongenetic factors, maternal immune system activation and zinc deficiency have been proposed. Intriguingly, as a genetic factor, copy-number variations in S100B, a pro-inflammatory damage-associated molecular pattern (DAMP), have been associated with ASD, and increased serum S100B has been found in ASD. Interestingly, it has been shown that increased S100B levels affect zinc homeostasis in vitro. Thus, here, we investigated the influence of increased S100B levels in vitro and in vivo during pregnancy in mice regarding zinc availability, the zinc-sensitive SHANK protein networks associated with ASD, and behavioral outcomes. We observed that S100B affects the synaptic SHANK2 and SHANK3 levels in a zinc-dependent manner, especially early in neuronal development. Animals exposed to high S100B levels in utero similarly show reduced levels of free zinc and SHANK2 in the brain. On the behavioral level, these mice display hyperactivity, increased stereotypic and abnormal social behaviors, and cognitive impairment. Pro-inflammatory factors and zinc-signaling alterations converge on the synaptic level revealing a common pathomechanism that may mechanistically explain a large share of ASD cases.

IQSEC2 Deficiency Results in Abnormal Social Behaviors Relevant to Autism by Affecting Functions of Neural Circuits in the Medial Prefrontal Cortex.

IQSEC2 is a guanine nucleotide exchange factor (GEF) for ADP-ribosylation factor 6 (Arf6), of which protein is exclusively localized to the postsynaptic density of the excitatory synapse. Human genome studies have revealed that the IQSEC2 gene is associated with X-linked neurodevelopmental disorders, such as intellectual disability (ID), epilepsy, and autism. In this study, we examined the behavior and synapse function in IQSEC2 knockout (KO) mice that we generated using CRIPSR/Cas9-mediated genome editing to solve the relevance between IQSEC2 deficiency and the pathophysiology of neurodevelopmental disorders. IQSEC2 KO mice exhibited autistic behaviors, such as overgrooming and social deficits. We identified that up-regulation of c-Fos expression in the medial prefrontal cortex (mPFC) induced by social stimulation was significantly attenuated in IQSEC2 KO mice. Whole cell electrophysiological recording identified that synaptic transmissions mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), N-methyl-D-aspartate receptor (NMDAR), and γ-aminobutyric acid receptor (GABAR) were significantly decreased in pyramidal neurons in layer 5 of the mPFC in IQSEC2 KO mice. Reexpression of IQSEC2 isoform 1 in the mPFC of IQSEC2 KO mice using adeno-associated virus (AAV) rescued both synaptic and social deficits, suggesting that impaired synaptic function in the mPFC is responsible for social deficits in IQSEC2 KO mice.

Psychological and behavioral functioning of children and adolescents during long-term home-schooling

Objective: To study the characteristics and risk factors of psychological and behavioral problems of children and adolescents of different ages and genders in long-term home-schooling during the coronavirus disease-2019 pandemic. Further, to provide scientific basis for more targeted psychological intervention and coping strategies in the future. Methods: A cross-sectional survey using an online questionnaire was conducted on students aged 6-16 years old in five representative cities of North (Beijing), East (Shanghai), West (Chongqing), South (Guangzhou) and Middle (Wuhan) in China. In this study, the social behavior and psychological abnormalities which was defined as the positive of any dimension were investigated in multiple dimensions during long-term home-schooling. The influencing factors of psycho-behavioral problems were analyzed by Logistic regression, and the confounding factors were corrected with graded multivariable adjustment. Results: A total of 6 906 valid questionnaires were collected including 3 592 boys and 3 314 girls, of whom 3 626 were children (6-11 years old) and 3 280 were adolescents (12-16 years old). The positive detection rate of psychosocial-behavioral problems were 13.0% (900/6 906) totally, 9.6% (344/3 592) in boys and 16.8% (556/3 314) in girls respectively, and 7.3%(142/1 946) in boys aged 6-11, 14.0%(235/1 680) in girls aged 6-11, 12.3%(202/1 646) in boys aged 12-16, 19.6%(321/1 634) in girls aged 12-16 respectively. There were significant differences between the psychological problems group and the non-psychological problems group in gender, parent-offspring conflict, number of close friends, family income change, sedentary time, homework time, screen exposure time, physical activity, dietary problems (χ²=78.851, 285.264, 52.839, 26.284, 22.778, 11.024, 10.688, 36.814, 70.982, all P<0.01). The most common symptoms in boys aged 6-11 years were compulsive activity, schizoid and depression, in girls aged 6-11 years were schizoid/compulsive activity, hyperactivity and social withdrawal, in boys aged 12-16 years were hyperactivity, compulsive activity and aggressive behavior, and in girls aged 12-16 years were schizoid, anxiety/compulsive activity and depression/withdrawal, respectively. After graded multivariable adjustment, besides the common risk factors, homework time and online study time were the risk factors of 6-11 years old groups [boys OR(95%CI): 1.750 (1.32-2.32), 1.214(1.00-1.47), girls: 1.579(1.25-1.99), 1.222(1.05-1.42), all P<0.05], videogames time were the risk factors of 12-16 years old groups [ boys: 2.237 (1.60-3.13), girls: 1.272 (1.00-1.61), all P<0.05]. Conclusions: Some children and adolescents may have psychological and behavioral problems during long-term home-schooling. The psychological and behavioral manifestations differed in age and gender subgroups, which deserve special attention in each subgroups. Schools, families and specialists should actively provide precise psychological support and comprehensive intervention strategies according to special features and risk factors.

μ-Opioid Receptor (Oprm1) Copy Number Influences Nucleus Accumbens Microcircuitry and Reciprocal Social Behaviors.

The μ-opioid receptor regulates reward derived from both drug use and natural experiences, including social interaction, through actions in the nucleus accumbens. Here, we studied nucleus accumbens microcircuitry and social behavior in male and female mice with heterozygous genetic knockout of the μ-opioid receptor (Oprm1+/-). This genetic condition models the partial reduction of μ-opioid receptor signaling reported in several neuropsychiatric disorders. We first analyzed inhibitory synapses in the nucleus accumbens, using methods that differentiate between medium spiny neurons (MSNs) expressing the D1 or D2 dopamine receptor. Inhibitory synaptic transmission was increased in D2-MSNs of male mutants, but not female mutants, while the expression of gephyrin mRNA and the density of inhibitory synaptic puncta at the cell body of D2-MSNs was increased in mutants of both sexes. Some of these changes were more robust in Oprm1+/- mutants than Oprm1-/- mutants, demonstrating that partial reductions of μ-opioid signaling can have large effects. At the behavioral level, social conditioned place preference and reciprocal social interaction were diminished in Oprm1+/- and Oprm1-/- mutants of both sexes. Interaction with Oprm1 mutants also altered the social behavior of wild-type test partners. We corroborated this latter result using a social preference task, in which wild-type mice preferred interactions with another typical mouse over Oprm1 mutants. Surprisingly, Oprm1-/- mice preferred interactions with other Oprm1-/- mutants, although these interactions did not produce a conditioned place preference. Our results support a role for partial dysregulation of μ-opioid signaling in social deficits associated with neuropsychiatric conditions.SIGNIFICANCE STATEMENT Activation of the μ-opioid receptor plays a key role in the expression of normal social behaviors. In this study, we examined brain function and social behavior of female and male mice, with either partial or complete genetic deletion of μ-opioid receptor expression. We observed abnormal social behavior following both genetic manipulations, as well as changes in the structure and function of synaptic input to a specific population of neurons in the nucleus accumbens, which is an important brain region for social behavior. Synaptic changes were most robust when μ-opioid receptor expression was only partially lost, indicating that small reductions in μ-opioid receptor signaling can have a large impact on brain function and behavior.

Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time.

Despite a growing understanding of the molecular and developmental basis of autism spectrum disorder (ASD), how the neuronal encoding of social information is precisely disrupted in ASD and whether it contributes to abnormal social behavior remains unclear. Here, we disrupted and then restored expression of the ASD-associated gene Shank3 in adult male mice while tracking the encoding dynamics of neurons in the medial prefrontal cortex (mPFC) over weeks. We find that Shank3 disruption led to reduction of neurons encoding the experience of other mice and increase in neurons encoding the animal’s own. This shift was associated with loss of ability by neurons to distinguish other-from-self and, therefore, the inability to encode social agency. Restoration of Shank3 expression in the mPFC reversed this encoding imbalance and increased sociability over 5-8 weeks. These findings reveal a neuronal encoding process that is necessary for social behavior and that may be disrupted in ASD.

The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

BackgroundAutism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice.ResultsMice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice.ConclusionsThe microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD.23y8Eg2qi-yqeo7gGCFq9cVideo abstract

Social Interactions of Dat-Het Epi-Genotypes Differing for Maternal Origins: The Development of a New Preclinical Model of Socio-Sexual Apathy.

Social interaction is essential for life but is impaired in many psychiatric disorders. We presently focus on rats with a truncated allele for dopamine transporter (DAT). Since heterozygous individuals possess only one non-mutant allele, epigenetic interactions may unmask latent genetic predispositions. Homogeneous “maternal” heterozygous offspring (termed MAT-HET) were born from dopamine-transporter knocked-out (DAT-KO) male rats and wild-type (WT) mothers; “mixed” heterozygous offspring (termed MIX-HET) were born from both DAT-heterozygous parents. Their social behavior was assessed by: partner-preference (PPT), social-preference (SPT) and elicited-preference (EPT) tests. During the PPT, focal MIX-HET and MAT-HET males had a choice between two WT females, one in estrous and the other not. In the SPT, they met as stimulus either a MIX-HET or a WT male. In the EPT, the preference of focal male WT rats towards either a MIX- or a MAT-HET stimulus was tested. MIX-HET focal males showed an abnormal behavior, seeming not interested in socializing either with a female in estrous or with another male if MIX-HET. Focal MAT-HET males, instead, were very attracted by the female in estrous, but totally ignored the MIX-HET male. We assessed the expression of noradrenaline transporter (NET) in prefrontal cortex, hippocampus and hypothalamus, finding differences between the two offspring. MIX-HETs’ hypothalamus and hippocampus showed less NET than MAT-HETs, while the latter, in turn, showed higher NET than WTs. These behavioral differences between heterozygous groups may be attributed to different maternal cares received. Results allow preclinical understanding of epigenetic factors involved in social-behavior abnormalities, typical of many psychiatric disorders.

Oxytocin ameliorates impaired social behavior in a Chd8 haploinsufficiency mouse model of autism

BackgroundAutism spectrum disorder (ASD) is characterized by the core symptoms of impaired social interactions. Increasing evidence suggests that ASD has a strong genetic link with mutations in chromodomain helicase DNA binding protein 8 (CHD8), a gene encoding a chromatin remodeler. It has previously been shown that Chd8 haplodeficient male mice manifest ASD-like behavioral characteristics such as anxiety and altered social behavior. Along with that, oxytocin (OT) is one of the main neuropeptides involved in social behavior. Administration of OT has shown improvement of social behavior in genetic animal models of ASD. The present study was undertaken to further explore behavioral abnormalities of Chd8 haplodeficient mice of both sexes, their link with OT, and possible effects of OT administration. First, we performed a battery of behavioral tests on wild-type and Chd8+/∆SL female and male mice. Next, we measured plasma OT levels and finally studied the effects of intraperitoneal OT injection on observed behavioral deficits.ResultsWe showed general anxiety phenotype in Chd8+/∆SL mice regardless of sex, the depressive phenotype in Chd8+/∆SL female mice only and bidirectional social deficit in female and male mice. We observed decreased level of OT in Chd+/∆SL mice, possibly driven by males. Mice injected by OT demonstrated recovery of social behavior, while reduced anxiety was observed only in male mice.ConclusionsHere, we demonstrated that abnormal social behaviors were observed in both male and female Chd8+/∆SL mice. The ability of peripheral OT administration to affect such behaviors along with altered plasma OT levels indicated a possible link between Chd8 + /∆SL and OT in the pathogenesis of ASD as well as the possible usefulness of OT as a therapeutic tool for ASD patients with CHD8 mutations.