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 1

PSTh glutamatergic neurons are activated by various acute stressors.

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PSTh glutamatergic neurons are activated by various acute stressors. (A)...
(A) Schematic diagram of c-Fos staining. (B) c-Fos expression in the PSTh from a control (top) and a social defeat–exposed mouse (bottom). Scale bars: 200 μm. (C) The number of c-Fos-positive cells in control (n = 4) and stressed mice (n = 4). (D) Schematic illustration of fiber photometry recordings and representative image of GCaMP6m expression in PSTh glutamatergic neurons. Scale bar: 200 μm. (E) Representative raw traces and heatmaps showing GCaMP6m fluorescence changes of PSThVglut2 neurons evoked by various stressors. The red line indicates stimulus onset. (F) The peri-event plot shows average calcium transients in a social defeat–exposed mouse (left) or the entire group (right, n = 6). The thick line indicates the mean, and the shaded area indicates SEM. The dotted line marks onset of social defeat. (G) Statistical comparison of peak fluorescence signals before and after social defeat (n = 6). (H–M) The same as F and G but for Ca2+ responses to electrical shock (H and I; n = 6), air puff (J and K; n = 6), or forced swim (L and M; n = 5). Data are shown as the mean ± SEM. **P < 0.01; ***P < 0.001; ****P < 0.0001; 2-tailed unpaired t test.