A noncanonical parasubthalamic nucleus–to–extended amygdala circuit converts chronic social stress into anxiety
Na Liu, … , Shumin Duan, Han Xu
Na Liu, … , Shumin Duan, Han Xu
Published August 15, 2025
Citation Information: J Clin Invest. 2025;135(16):e188246. https://doi.org/10.1172/JCI188246.
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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 8

CSDS downregulates the expression of Kcnd3 in PSTh glutamatergic neurons.

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CSDS downregulates the expression of Kcnd3 in PSTh glutamatergic neurons...
(A) Schematic diagram for RNA-sequencing and qPCR measurements to examine the potential molecular mechanisms of PSTh in regulating anxiety-like behavior. (B–D) Heatmaps (B), the most enriched Gene Ontology terms (C), and volcano plot (D) of DEGs (P < 0.05 and fold change ≥ 1.2) in PSTh neurons from unstressed control and CSDS mice. Significantly upregulated genes are in red (n = 415), while downregulated genes are shown in blue (n = 480). Additionally, numerous genes show no significant differences between 2 groups (n = 13,359). (E) Normalized expression (fragments per kilobase of transcript per million fragments mapped; FPKM) of genes encoding important ion channels in PSTh neurons. n = 3 (30 mice in total) for each group. (F) qPCR results for Kcnd3 level in PSTh neurons. n = 12 mice for the control, and n = 16 mice for the CSDS group. (G) Flow diagram and schematic illustration of virus injection for sparsely labeling PSThVglut2 neurons, enabling FISH verification of Kcnd3 in these neurons. (H) Microscopy images show Kcnd3 expression in PSThVglut2 neurons from a control (top) and a CSDS (bottom) mouse. Scale bars: 10 μm. (I) Quantification of the fractional area of Kcnd3 in PSThVglut2 neurons from control and CSDS groups. n = 5 mice for control, and n = 7 mice for CSDS group. Data are shown as the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; 2-tailed unpaired t test.