A noncanonical parasubthalamic nucleus–to–extended amygdala circuit converts chronic social stress into anxiety
Na Liu, Jun Wang, Huan Wang, Bin Gao, Zheng Lin, Tian-Le Xu, Shumin Duan, Han Xu
Na Liu, Jun Wang, Huan Wang, Bin Gao, Zheng Lin, Tian-Le Xu, Shumin Duan, Han Xu
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Research Article Cell biology Neuroscience

A noncanonical parasubthalamic nucleus–to–extended amygdala circuit converts chronic social stress into anxiety

Abstract

Anxiety disorders pose a substantial threat to global mental health, with chronic stress identified as a major etiologic factor. Over the past few decades, extensive studies have revealed that chronic stress induces anxiety states through a distributed neuronal network of interconnected brain structures. However, the precise circuit mechanisms underlying the transition from chronic stress to anxiety remain incompletely understood. Employing the chronic social defeat stress (CSDS) paradigm in mice, we uncovered a critical role of the parasubthalamic nucleus (PSTh) in both the induction and expression of anxiety-like behavior. The anxiogenic effect was mediated by an excitatory trisynaptic circuitry involving the lateral parabrachial nucleus (LPB), PSTh, and bed nucleus of the stria terminalis (BNST). Furthermore, CSDS downregulated Kv4.3 channels in glutamatergic neurons of the PSTh. Reexpression of these channels dampened neuronal overexcitability and alleviated anxiety-like behavior in stressed animals. In parallel with the well-known anxiety network centered on the amygdala, here we identify a noncanonical LPB-PSTh-BNST pathway in the transformation of stress into anxiety. These findings suggest that the PSTh may serve as a potential therapeutic target for anxiety-related disorders.

Authors

Na Liu, Jun Wang, Huan Wang, Bin Gao, Zheng Lin, Tian-Le Xu, Shumin Duan, Han Xu

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Figure 2

Inhibition of PSTh glutamatergic neurons during social defeat alleviates CSDS-induced anxiety-like behavior.

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Inhibition of PSTh glutamatergic neurons during social defeat alleviates...
(A) Experimental scheme showing pharmacogenetic inhibition of PSThVglut2 neurons during CSDS procedure and the measurement of anxiety-like behavior. (B) Schematic description and representative image of hM4D expression. Scale bar: 200 μm. (C) Raw traces (left) and statistical comparison of spike firing (right) in response to 80 pA current stimulus before and after CNO application (10 μM). n = 7 neurons from 2 mice. (D) Representative movement traces of an EYFP (left) and a hM4D mouse (right) in the EPM test or OFT after CSDS. (E–I) Behavioral statistics of EYFP and hM4D mice in the EPM test, including time spent (E), number of entries (F), distance traveled (G) in open arms, time spent in closed arms (H), and the open/closed ratio (I). (J–N) Behavioral statistics in the OFT, including time spent (J), number of entries (K), distance traveled (L) in the center zone, time spent in corner zones (M), and total distance traveled (N). n = 13 mice for the CSDS+EYFP group, and n = 12 mice for the CSDS+hM4D group. Data are shown as the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; 2-tailed unpaired t test.