Adolescent Social Isolation Reprograms the Medial Amygdala: Transcriptome and Sex Differences in Reward
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ABSTRACT: Adolescence is a sensitive window for reward- and stress-associated behavior. Although stress during this period causes long-term changes in behavior in males, how females respond is relatively unknown. Here we show that social isolation stress in adolescence, but not adulthood, induces persistent but opposite effects on anxiety- and cocaine-related behaviors in male vs. female mice, and that these effects are reflected in transcriptional profiles within the adult medial amygdala (meA). By integrating differential gene expression with co-expression network analyses, we identified crystallin mu (Crym), a thyroid hormone binding protein, as a key driver of these transcriptional profiles. Manipulation of Crym specifically within adult meA neurons recapitulates the behavioral and transcriptional effects of social isolation and re-opens a window of plasticity that is otherwise closed. Our results establish that meA is essential for sex-specific responses to stressful and rewarding stimuli through transcriptional programming that occurs during adolescence.
Project description:Stress is a major influence on mental health status; the ways that individuals respond to or copes with stressors determine whether they are negatively affected in the future. Stress responses are established by an interplay between genetics, environment, and life experiences. Psychosocial stress is particularly impactful during adolescence, a critical period for the development of mood disorders. In this study we compared two established, selectively-bred Sprague Dawley rat lines, the “internalizing” bred Low Responder (bLR) line versus the “externalizing” bred High Responder (bHR) line, to investigate how genetic temperament and adolescent environment impact future responses to social interactions and psychosocial stress, and how these determinants of stress response interact. Animals were exposed to social and environmental enrichment in adolescence prior to experiencing social defeat and were then assessed for social interaction and anxiety-like behavior. Adolescent enrichment caused bLR rats to display less social avoidance, more social interaction, less submission during defeat, and resilience to the prolonged effects of social stress on corticosterone, while enrichment caused bHR animals to show greater aggression during defeat and during a neutral social encounter, and decreased anxiety-like behavior. To gain insight into the development of social resilience in the anxious phenotype bLRs, RNA-seq was conducted on the hippocampus and nucleus accumbens, two brain regions that mediate stress regulation and social behavior. Gene sets previously associated with stress, social behavior, aggression and exploratory activity were enriched with differential expression in both regions, with a particularly large effect on gene sets that regulate social behaviors. These findings provide further evidence that adolescent enrichment can serve as an inoculating experience against future stressors. The ability to induce social resilience in a usually anxious line of animals by manipulating their environment has translational implications, as it underscores the feasibility of intervention strategies targeted at genetically vulnerable adolescent populations.
Project description:In humans, mutations in the transcription factor encoding gene, FOXP2, are associated with language and Autism Spectrum (ASD) Disorders, the latter characterized by deficits in social interactions. However, little is known regarding the function of Foxp2 in male or female social behavior. Our previous studies in mice revealed high expression of Foxp2 within the medial subnucleus of the amygdala (MeA), a limbic brain region highly implicated in innate social behaviors such as mating, aggression, and parental care. Here, using a comprehensive panel of behavioral tests in male and female Foxp2+/- heterozygous mice, we investigated the role Foxp2 plays in MeA-linked innate social behaviors. We reveal significant deficits in olfactory processing, social interaction, mating, aggressive and parental behaviors. Interestingly, some of these deficits displayed in a sex-specific manner. To examine the consequences of Foxp2 loss of function specifically in the MeA, we conducted a proteomic analysis of microdissected MeA tissue and found sex differences in a host of proteins implicated in neuronal communication, connectivity and dopamine signaling. Consistent with this, we discovered that MeA Foxp2-lineage cells were responsive to dopamine with differences between males and females. Thus, our findings reveal a central and sex-specific role for Foxp2 in social behavior and MeA function.
Project description:Adolescence is a critical period in cognitive and emotional development, characterized by high levels of social interaction and increases in risk-taking behavior including binge drinking. Adolescent exposure to social stress and binge ethanol have individually been associated with the development of social, emotional, and cognitive deficits, as well as increased risk for alcohol use disorder. Disruption of cortical development by early life social stress and/or binge drinking may partly underlie these enduring emotional, cognitive, and behavioral effects. The study goal is to implement a novel neighbor housing environment to identify the effects of adolescent neighbor housing and/or binge ethanol drinking on (1) a battery of emotional and cognitive tasks (2) adult ethanol drinking behavior, and (3) the nucleus accumbens and prefrontal cortex transcriptome. Adolescent male and female C57BL/6J mice were single or neighbor housed with or without access to intermittent ethanol. One cohort underwent behavioral testing during adulthood to determine social preference, expression of anxiety-like behavior, cognitive performance, and patterns of ethanol intake. The second cohort was sacrificed in late adolescence and brain tissue was used for transcriptomics analysis. As adults, single housed mice displayed decreased social interaction, deficits in the novel object recognition task, and increased anxiety-like behavior, relative to neighbor-housed mice. There was no effect of housing condition on adolescent or adult ethanol consumption. Adolescent ethanol exposure did not alter adult ethanol intake. Transcriptomics analysis revealed that adolescent housing condition and ethanol exposure resulted in differential expression of genes related to synaptic plasticity in the nucleus accumbens and genes related to methylation, the extracellular matrix and inflammation in the prefrontal cortex. The behavioral results indicate that social interaction during adolescence via the neighbor housing model may protect against emotional, social, and cognitive deficits. In addition, the transcriptomics results suggest that these behavioral alterations may be mediated in part by dysregulation of transcription in the frontal cortex or the nucleus accumbens
Project description:Chronic social isolation stress during adolescence induces susceptibility for neuropsychiatric disorders. Here we show that 5-week post-weaning isolation stress induces sex-specific behavioral abnormalities and neuronal activity changes in the prefrontal cortex (PFC), basal lateral amygdala (BLA), and ventral tegmental area (VTA). Chemogenetic manipulation, optogenetic recording, and in vivo calcium imaging identify that the PFC to BLA pathway is causally linked to heightened aggression in stressed males, and the PFC to VTA pathway is causally linked to social withdrawal in stressed females. Isolation stress induces genome-wide transcriptional alterations in a region-specific manner. Particularly, the upregulated genes in BLA of stressed males are under the control of activated transcription factor CREB, and CREB inhibition in BLA normalizes gene expression and reverses aggressive behaviors. On the other hand, neuropeptide Hcrt (Hypocretin/Orexin) is among the top-ranking downregulated genes in VTA of stressed females, and Orexin-A treatment rescues social withdrawal. These results have revealed molecular mechanisms and potential therapeutic targets for stress-related mental illness.
Project description:Purpose: This study assessed putative sex differences in miRNA expression in the bed nucleus of the stria terminalis (BNST)—a sexually dimorphic brain region implicated in anxiety—of adult male and female rats that had been exposed throughout adolescence to social isolation (SI) stress. Methods: Male and female Sprague-Dawley rats underwent SI during adolescence or remained grouped housed (GH) till adulthood. Small RNA sequencing was performed on tissue extracted from the anterodorsal BNST. Results: SI compared to GH induced more anxiogenic-like effects in females compared to males and sex-dependent changes in miRNA expression in the BNST. Conclusions: The current study shows that housing conditions (either SI or GH) during adolescence regulates miRNA expression in a sex-specific manner in the sexually dimorphic area of the adBNST
Project description:Early life stress (ELS), such as neglect and maltreatment, exhibits a strong impact on the mental and brain development of children. However, it is not fully understood how ELS affects the function in developing prefrontal cortex (PFC). In this study, we performed social isolation on weaned pre-adolescent mice and investigated how ELS could affect the function in behavior and transcriptome in PFC. We found that reductions of social interaction, social preference, and social novelty in ELS mice. Moreover, an increase of anxiety-like behavior was observed in ELS mice, but there were no changes in weight and repetitive behavior. To identify the gene involved in social behavior, we conducted transcriptome analysis and identified 15 differentially expressed genes (DEGs) in the PFC of ELS mice. These genes were involved in transcriptional regulation, stress, and synaptic signaling. We also found that a decreased number of neurons and an increased number of microglia in the PFC of ELS mice. These results suggest that ELS affects PFC cytoarchitecture by stress signal transduction and eventually alters mouse behavior. Our study demonstrates that ELS influences behavior, transcriptome and cytoarchitecture in the brain of adolescent mice.
Project description:Social dominance encompasses winning dyadic contests and gaining priority access to resources and reproduction. Disposition to dominance is influenced by environmental factors, particularly during early postnatal life and adolescence. A disinhibitory mPFC microcircuit has been implicated in the expression of dominance in the “tube test” paradigm of social competition in mice, but the neuronal and transcriptional plasticity associated with the environment induced increase in social dominance is not known. We previously reported that male pups raised by physically active (as opposed to sedentary) dams exhibit dominance and increased reproductive fitness, and here we show that social isolation from weaning also increases dominance. By using these preweaning and postweaning environmental models, we tested if dominance is associated with transcriptional plasticity and a specific transcriptional profile in one or more cell types in the mPFC. Given that the mPFC is composed of several cell types, we used single cell transcriptomics to characterize the influence of the preweaning maternal and postweaning social environment on cell-type specific gene expression. The preweaning maternal effect, but not postweaning social isolation, caused gene expression changes in a wide range of cell types including pyramidal neurons, various interneurons, and astrocytes. However, both the maternal effect and social isolation induced the coordinated downregulation of synaptic channel, receptor, and adhesion genes in parvalbumin positive (PV) interneurons. This suggests an impaired PV interneuron-mediated inhibition of pyramidal cells in animals predisposed to dominance, a notion consistent with dominant behavior being driven by the disinhibition of mPFC pyramidal neurons.
Project description:Social play is a well-conserved, dynamic behavior known to be sexually differentiated. In most species, males play more than females, a sex difference largely driven by the medial amygdala (MeA) yet the full mechanism establishing this bias is unknown. Here, we explore “the transcriptome of playfulness” in both sexes for the first time, demonstrating that the transcriptomic profile in the juvenile rat MeA associated with playfulness is markedly distinct in males and females. Parallel single-cell RNA-sequencing experiments from newborn rats suggest that inhibitory neurons drive this sex difference. Furthermore, we show that inhibitory neurons comprise the majority of play-active cells in the juvenile MeA, with males having more play-active cells than females, of which a greater proportion are GABAergic. Through integrative bioinformatic analyses, we further explore the expression, function, and cell-type specificity of key play-associated gene modules, providing valuable insight into the sex-biased mechanisms underlying this fundamental social behavior.
Project description:The lateral habenula (LHb) is an essential hub brain region modulating the monoamine system such as dopamine, serotonin. Hyperactivity of LHb has implications for psychiatric disorders such as depression, anxiety, and schizophrenia, which are commonly associated with social dysfunction. However, the role of LHb in social behavior has remained elusive. Here, we find that experiencing acute social isolation affects synaptic function in LHb and social behavior. After acute social isolation, long-term depression (LTD) in LHb is impaired and rescued by activating the 5-HT4 receptor (5-HT4R). Indeed, Htr4 expression in LHb is up-regulated following acute social isolation. Finally, acute social isolation enhances the social preference for familiars such as housing-mates to stranger conspecifics. Consistent with electrophysiological results, pharmacological activation of 5-HT4R in LHb restored innate social preference. These results suggest that acute social isolation influences social decisions with 5-HT4R-dependent synaptic modification in LHb.
Project description:This SuperSeries is composed of the following subset Series: GSE33090: Dramatic effects of social behavior on gene regulation in rhesus macaques [Individual_expression] GSE34127: Dramatic effects of social behavior on gene regulation in rhesus macaques [Cell type_expression] GSE34128: Dramatic effects of social behavior on gene regulation in rhesus macaques [Bisulfite_seq] Refer to individual Series