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: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.
Project description:MicroRNA (miRNA) dysregulation is well-documented in psychiatric disease, but miRNA dynamics during adolescent and early adult brain maturation, when symptoms first appear for many of these diseases, remain poorly understood. Here, we use RNA sequencing to examine miRNAs and their mRNA targets in cortex and hippocampus from early, mid-, and late adolescent and adult mice. We also use Quantitative Proteomics by tandem mass tag mass spectrometry (TMT-MS) to examine protein dynamics in cortex from the same subjects.
Project description:Typical adolescent neurodevelopment is marked by decreases in grey matter (GM) volume, increases in myelination, measured by fractional anisotropy (FA), and improvement in cognitive performance. To understand how epigenetic changes, methylation (DNAm) in particular, may be involved during this phase of development, we studied cognitive assessments, DNAm from saliva, and neuroimaging data from a longitudinal cohort of normally developing adolescents, aged nine to fourteen. We extracted networks of methylation with patterns of correlated change using a weighted gene correlation network analysis (WCGNA). Modules from these analyses, consisting of co-methylation networks, were then used in multivariate analyses with GM, FA, and cognitive measures to assess the nature of their relationships with cognitive improvement and brain development in adolescence. This longitudinal exploration of co-methylated networks revealed an increase in correlated epigenetic changes as subjects progressed into adolescence. Co-methylation networks enriched for pathways involved in neuronal systems, potassium channels, neurexins and neuroligins were both conserved across time as well as associated with maturation patterns in GM, FA, and cognition, revealing epigenetic mechanisms that could be involved in adolescent neural development.
Project description:The gut microbiome is an emerging factor in the neurobiology of disease. Blood-brain barrier (BBB) integrity is essential for proper brain function. However, the role the initial microbiome plays in BBB and brain development is unclear. In this study, we colonized germ-free pregnant mice with human full-term- or preterm-infant-derived gut microbiota, thereby establishing these communities in the resulting offspring. We discovered that mice harboring a full-term-associated microbiome exhibited stronger memory and learning capabilities and dramatically decreased early-life BBB permeability when compared to those with a prematurity-associated microbiome. Whole-brain single-cell RNA sequencing revealed downregulation of synaptic signaling genes in BBB cell types of mice with the prematurity-associated microbiome, indicating that microbiome maturity influences BBB transcriptional programs that support cognitive development. Comprehensive metagenomics and metabolomics uncovered bacterial populations and genomic pathways corresponding with decreased levels of circulating long-chain acylcarnitines and lysophosphatidylcholines in mice with the full-term-associated microbiome. Our findings highlight the microbiome as a therapeutic target for improving long-term neurodevelopmental outcomes due to its effect on the early-life BBB.