Abstract
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.
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Data availability
All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The RNA-seq data generated in this study have been deposited in the GEO public repository under accession code GSE198725.
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Acknowledgements
We thank Xiaoqing Chen and Kaijie Ma for their excellent technical support. We also thank the support of the Genomics and Bioinformatics Core of the State University of New York at Buffalo. This work was supported by grants from the National Institutes of Health (R01-MH108842 and R01-MH126443 to ZY, R01-MH111872 to AP and K01-DA050908 to ZJW).
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ZJW performed behavioral, immunohistochemical, biochemical, and molecular biological experiments, analyzed data, and wrote the paper; TS performed DREADD experiments and analyzed data. JL and AP designed and performed calcium imaging experiments and analyzed data. PZ performed optogenetic and electrophysiological experiments and analyzed data. FY analyzed genomic data. KS performed some immunohistochemical experiments. FZ performed some behavioral and biochemical experiments. ZY designed experiments, supervised the project, and wrote the paper.
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Wang, ZJ., Shwani, T., Liu, J. et al. Molecular and cellular mechanisms for differential effects of chronic social isolation stress in males and females. Mol Psychiatry 27, 3056–3068 (2022). https://doi.org/10.1038/s41380-022-01574-y
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DOI: https://doi.org/10.1038/s41380-022-01574-y
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