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Molecular and cellular mechanisms for differential effects of chronic social isolation stress in males and females

Molecular Psychiatry volume 27, pages 3056–3068 (2022)Cite this article

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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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Fig. 1: Elevated aggression in socially-isolated (SI) males is linked to the altered PFC to BLA pathway.
Fig. 2: Optogenetic recording shows the diminished feedforward inhibition in BLA principal neurons from PFC projections in stressed males.
Fig. 3: Isolation stress-induced transcriptional changes in the BLA of male mice and aggressive behaviors are blocked by CREB inhibition.
Fig. 4: In vivo calcium imaging shows the attenuated activation of PFC neurons by social stimuli in SI females.
Fig. 5: Social withdrawal in SI females is linked to the altered PFC to VTA pathway.
Fig. 6: Transcriptomic studies reveal the key role of VTA orexin signaling in female responses to isolation stress.

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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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  1. Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA

    Zi-Jun Wang, Treefa Shwani, Ping Zhong, Fengwei Yang, Kelcie Schatz, Freddy Zhang & Zhen Yan

  2. Department of Physics, College of Arts and Sciences, State University of New York at Buffalo, Buffalo, NY, USA

    Junting Liu & Arnd Pralle

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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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