Zbtb16 regulates social cognitive behaviors and neocortical development
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ABSTRACT:
PROVIDER: PRJNA649716 | ENA |
REPOSITORIES: ENA
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Project description:Recent genomic studies suggest that a single gene is involved in multiple diseases, however it is unclear what mechanism destined for different diseases by a single gene. Mutations of ZBTB16 are associated with autism spectrum disorder (ASD) and schizophrenia (SCZ), but how ZBTB16 fates ASD or SCZ are unknown. Here we show the deletion of Zbtb16 in mice leads to both ASD- and SCZ-like behaviors such as social impairment, repetitive behaviors, risk-taking behaviors, and cognitive impairment. To elucidate the mechanism underlying the behavioral phenotypes, we carried out histological studies and observed impairments in thinning of neocortical layer 6 (L6) and a reduction of TBR1+ neurons in the prefrontal cortex (PFC) of Zbtb16 KO mice. Furthermore, we found increased dendritic spines and microglia as well as developmental defects in oligodendrocytes and neocortical myelination in the PFC of Zbtb16 KO mice. Using a genomics approach, we identified the Zbtb16-transcriptome that includes genes involved in both ASD and SCZ pathophysiology and neocortical maturation such as neurogenesis and myelination. Co-expression networks further identified Zbtb16-correlated modules that are unique to ASD or SCZ respectively. Our study provides insight into the differential role of the single gene ZBTB16 in ASD and SCZ.
2021-05-12 | GSE155424 | GEO
Project description: Not available
| S-EPMC8068730 | biostudies-literature
Project description:The neurobiological origins of social behaviors are incompletely understood. Here we utilized synthetic biology approaches to reprogram the function of ZFP189, a transcription factor whose expression and function in rodent prefrontal cortex was previously demonstrated to be protective against stress-induced social deficits. We created novel synthetic ZFP189 transcription factors including ZFP189VPR, which activates the transcription of target genes and therefore exerts opposite functional control from the endogenous, transcriptionally repressive ZFP189WT. Following viral delivery of these synthetic ZFP189 transcription factors to mouse prefrontal cortex, we observe that ZFP189-mediated transcriptional control promotes mature dendritic spine morphology on transduced pyramidal neurons. Interestingly, inversion of ZFP189-mediated transcription in this brain area, achieved by viral delivery of synthetic ZFP189VPR, precipitates social behavioral deficits in terms of social interaction, motivation, and the cognition necessary for the maintenance of social hierarchy, without other observable behavioral deficits. RNA sequencing of virally manipulated prefrontal cortex tissues reveals that ZFP189 transcription factors of opposing regulatory function have opposite influence on the expression of genetic transposable elements as well as genes that participate in adaptive immune functions. Collectively, this work reveals that ZFP189 function in the prefrontal cortex coordinates structural and transcriptional neuroadaptations necessary for complex social behaviors, and does so by regulating transposable element-rich regions of DNA to control the expression of immune-related genes. Given the evidence for a co-evolution of social behavior and the brain immune response, we posit that ZFP189 may have evolved to augment brain transposon-associated immune function as a way of enhancing an animal’s capacity for functioning in social groups.
2024-02-09 | GSE246064 | GEO
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
2023-09-18 | GSE242910 | GEO
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.
2021-07-07 | PXD026978 | Pride
Project description:ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation of complex behaviors, including models of several psychiatric disorders. Here, we demonstrate that Baz1b, an accessory subunit of the ISWI family of chromatin remodeling complexes, is upregulated in the nucleus accumbens (NAc), a key brain reward region, in both chronic cocaine-treated mice and mice that are resilient to chronic social defeat stress. In contrast, no regulation is seen in mice that are susceptible to this chronic stress. Viral-mediated overexpression of Baz1b, along with its associated subunit Smarca5, in mouse NAc is sufficient to potentiate both rewarding responses to cocaine, including cocaine self-administration, and resilience to chronic social defeat stress. However, despite these similar, proreward behavioral effects, genome-wide mapping of BAZ1B in NAc revealed mostly distinct subsets of genes regulated by these chromatin remodeling proteins after chronic exposure to either cocaine or social stress. Together, these findings suggest important roles for BAZ1B and its associated chromatin remodeling complexes in NAc in the regulation of reward behaviors to distinct emotional stimuli and highlight the stimulus-specific nature of the actions of these regulatory proteins. BAZ1B (WSTF) ChIP-seq of mouse. Cocaine vs Saline, 3 biological replicates. In social defeat model: Normal control vs Susceptible vs Resilient, 3 biological replicates.
2016-07-30 | E-GEOD-85005 | biostudies-arrayexpress
Project description:Population-based studies show cannabis use doubles the risk of developing schizophrenia especially when use occurs in early adolescence (prior to age 15). However, the cause-and-effect mechanisms are largely unknown. To investigate the effect of cannabis on brain maturation and relation to the development of psychosis-like behaviours in adulthood, we treated young adolescent mice with vehicle or cannabis extract once a day for 2 weeks between postnatal days 14 and 28, and then collected hippocampal tissue for microarray analysis 12 weeks later. We identify a total of 78 differentially expressed genes (25 upregulated and 53 downregulated; p<0.05, fold change ± 1.2) and validate increases in dopamine D2 receptor (Drd2) and fatty acid amide hydrolase (Faah). Changes in Faah expression were limited to the hippocampus however Drd2 also increased in striatum but not prefrontal cortex or amygdala. When tested in adulthood with a behavioural panel relevant to schizophrenia, cannabis-treated mice displayed lower anxiety in the elevated zero-maze, decreased social preference, increased social novelty preference, mild cognitive impairments in a spatial version of the novel object recognition task and absence of latent inhibition when compared to vehicle controls. Adolescent treatment with cannabis extract thus lead to long-lasting changes in gene expression within the hippocampus which together result in behavioural deficits consistent with the negative and positive symptoms of schizophrenia.
2018-02-17 | GSE58437 | GEO
Project description:Affymetrix Mouse Genome 430 2.0 GeneChip microarrays were used to analyze murine neocortical and cerbellar astrocytes generated from postnatal (PN) day 1 wild-type (ICR) pups. Experiment Overall Design: Three samples each of murine neocortical and cerebellar astrocytes were analyzed.
2008-06-13 | E-GEOD-5582 | biostudies-arrayexpress
Project description:Affymetrix Mouse Genome 430 2.0 GeneChip microarrays were used to analyze murine neocortical and cerbellar astrocytes generated from postnatal (PN) day 1 wild-type (ICR) pups. Keywords: neocortical astrocyte, cerebellar astrocyte, murine, postnatal day 1
2007-03-14 | GSE5582 | GEO
Project description:Innate social behaviors, such as mating and fighting, are fundamental to animal reproduction and survival. However, social engagements are associated with risks for the individual, such as pathogenic infection and physical injury. Little is known about the neural mechanism that allows for appropriate risk assessment and the suppression of hazardous social interactions. We have identified the posteromedial nucleus of the cortical amygdala (COApm) as a locus required for the suppression of mating with an unhealthy female and aggressive behaviors towards a dominant male intruder. Using anatomical tracing, functional imaging, and circuit-level epistatic analyses, we show that suppression of social engagements is mediated by the COApm projections onto the glutamatergic population of the medial amygdalar nucleus (MEA). We further show that this projection that governs social engagements is demarcated by expression of both the neuromodulator thyrotropin-releasing hormone (TRH) in the COApm and the TRH-receptor (TRHR) in the postsynaptic MEA glutamatergic neurons. Modulating TRH-expressing neurons as well as infusing TRHR ligand into the MEA phenocopy functional manipulation of the COApm-MEA circuit. We have, therefore, uncovered a novel neural mechanism that endows animals with the ability to modulate innate reproductive and aggressive social interactions according to the health and threat status of reciprocating individuals. Deficits in such a mechanism may lead to the spread of disease, while uncontrolled engagement may lead to pathological conditions, such as social withdrawal and depression.
2021-02-22 | GSE167176 | GEO