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Poly(I:C)-induced long-term behavioral deficits are accompanied by epigenetic changes in microglia of male mice (ChIP-seq)

ABSTRACT: While the exact mechanisms for a sex bias in the development of neuropsychiatric disorders remain only vaguely understood, there is increasing evidence that an early life immune activation contributes to the disease pathogenesis. By administering the double stranded RNA analogue polyriboinosinic:polyribocytidilic acid (poly(I:C)) we mimicked an early viral infection in neonatal female and male mice. As a consequence, male adolescent mice presented long-term behavioral deficits including impaired social behavior and defective spatial working and recognition memory. Notably, behavioral changes were completely absent in female mice. In male mice, poly(I:C) led to an increased number of infiltrating T cells in the brain parenchyma, an enhanced interferon-g (IFNg) signaling, and an epigenetic reprogramming of microglial cells. These reprogrammed microglial cells showed increased phagocytic activity, which resulted in the excessive loss of dendritic spines in male mice only. We corroborated these findings in a murine neonatal infection of mice with murine cytomegalovirus (MCMV) and found sustained aversive behavioral effects and a lower number of excitatory synapses within the hippocampal brain region in young adult male, but not in female mice. Together, our results highlight the crucial role of the early postnatal period for normal brain development: identical immune stimulation during this period led to distinct sex-specific long-term behavioral deficits, indicating that sex is potentially an underappreciated factor when investigating neuropsychiatric disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE147443 | GEO | 2023/03/24

REPOSITORIES: GEO

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Project description:Background: Adolescent cannabis use leads to long-lasting behavioral changes involving cognitive and reward processes. However, the underlying molecular mechanisms are not well understood. To address this limitation, we performed gene network analyses using transcriptomic data from mice exposed during adolescence to Δ-9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis. Methods: We injected vehicle or THC in female and male mice during the entire adolescence period. Two weeks following the last exposure, we measured recognition memory, social interaction and anxiety-related behaviors. We generated 120 RNA-seq datasets from 5 brain regions for each mouse. We performed differential gene expression analysis and constructed co-expression networks to identify THC-induced transcriptional alterations at the level of individual genes, gene networks, biological pathways, and cellular specificity. Further, we integrated THC-correlated gene networks with human traits from genome-wide association studies and performed key driver analysis to identify potential regulators of disorder-associated networks. Results: THC impaired cognitive behaviors of mice, with memory being more impacted in females, which coincided with larger transcriptional alterations in the female brain. Gene network analyses identified brain region-, cell type- and sex- specific co-expressed genes (“modules”) dysregulated by THC. THC-induced memory deficits in females were correlated with disruption of gene networks involved in endocannabinoid signaling and inflammation. Additional THC-correlated modules in both sexes involved converging pathways related to dopamine signaling and addiction processes. Moreover, the connectivity map of THC-correlated modules uncovered intra- and inter-region molecular circuitries influenced by THC. Further, modules altered by THC treatment were enriched in genes relevant for human cognition and schizophrenia. Conclusions: These findings provide novel insights concerning the genes, cell types, and pathways underlying persistent behavioral deficits induced by adolescent exposure to THC in a sex-specific manner, and highlight the connection between adolescent cannabis use and neuropsychiatric disorders in humans.

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Poly(I:C)-induced long-term behavioral deficits are accompanied by epigenetic changes in microglia of male mice (ChIP-seq)

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