Nature sub-journal: Long-term isolation increases male aggression and causes differential neural circuit mechanisms of female social impairment

Click on the blue word to focus on our adolescence is a critical period for brain function remodeling
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Early adverse life stress causes a series of behavioral disorders such as anxiety, increased aggressive behavior, and social impairment in adulthood
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The prefrontal cortex (PFC), the basolateral amygdala (BLA), and the ventral tegmental area (VTA) exhibited marked neuronal changes during the stress process described above
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On April 27, 2022, Zhen Yan's research team at the State University of New York at Buffalo revealed the circuit and molecular mechanism of long-term social isolation-induced differences in behavioral disorders between male and female mice
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Social isolation enhances male, but not female, aggressive behavior in mice.
Both adolescent female and male mice exhibit anxiety-like behaviors after 5 weeks of social isolation
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In addition, male mice showed increased aggression, which was not present in female mice
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Immunofluorescence experiments showed that the neuronal activity in the PFC brain region of male mice was weakened and the neuronal activity in the BLA region was enhanced after chronic social isolation
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Figure 1: Chemical regulation of the PFC→BLA loop.
Chemical genetics.
Chronic activation of PFC→BLA attenuates chronic social isolation-induced aggressive behavior in male mice
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Inhibition of this neural circuit can induce aggressive behavior in group-housed male mice
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To further explore how the BLA region is involved in the aggressive behavior of chronically isolated male mice, the researchers found by single-cell sequencing that the biological process with the most abundant and up-regulated genes enriched in the BLA region of socially isolated male mice was aggressive behavior
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Those genes associated with aggressive behavior were not altered in the BLA of socially isolated female mice
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Figure 2: CREB protein inhibitor attenuates aggressive behavior The transcription factor CREB is highly correlated with the above-mentioned up-regulated genes, and the level of phosphorylated CREB protein in its active form is significantly increased in the BLA region of socially isolated male mice
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Injecting a CREB protein inhibitor into the BLA region of male mice during social isolation can significantly reduce their aggressive behavior and reduce the expression of genes associated with aggressive behavior
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Social isolation causes female, but not male, social impairment in mice Interestingly, social isolation can cause social behavior impairment (reduced communication with unfamiliar peers) in female mice, which is not seen in male mice obstacles
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Fiber-optic calcium imaging showed that during socialization with unfamiliar companion mice, the activity of pyramidal neurons in the PFC region of female mice undergoing social isolation decreased, but this decrease in activity was not present in male mice
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Immunofluorescence experiments found that neuronal activity in both the PFC and VTA brain regions of socially isolated female mice was reduced
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Chemogenetic inhibition of the PFC→VTA circuit can significantly induce social avoidance behavior in group-housed female mice, while activation of this neural circuit in chronically isolated female mice can significantly enhance social behavior
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In order to further explore how the VTA region is involved in the social impairment of female mice caused by chronic isolation, the researchers found through single-cell sequencing that the most abundant biological process of genes enriched and down-regulated in the VTA region of chronically isolated female mice was the neuropeptide signaling pathway.
The up-regulated genes are synapse-related signaling
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Among them, the neuropeptide genes Hcrt, Pomc, Pmch and Tph2 (the gene encoding orexin Hcrt is most obviously down-regulated) are key node genes connecting other enriched down-regulated genes
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Figure 3: Orexin improves social impairment in female mice.
Virus tracing experiments found that the VTA region receives innervation from orexinergic neurons in the lateral hypothalamus
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Intraperitoneal injection of orexin in chronically isolated female mice increases dopaminergic neuronal activity in the VTA and significantly improves social impairment
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Collectively, we found that chronic segregation induces sex-differential sexual behavior disorder, the PFC-BLA loop mediates increased aggressive behavior in male mice, and this increased aggression can be blocked by CREB protein inhibitors, the PFC-VTA loop Mediates social impairment in female mice, which is alleviated by orexin
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[References] 1.
https://doi.
org/10.
1038/s41380-022-01574-y The pictures in the text are from the references