前额叶缰核回路的双通路失调介导应激易感性
A dual-pathway dysregulation in prefrontal-habenular circuits mediates stress susceptibility.
摘要(中文译文)
慢性应激破坏情绪稳态，导致个体出现心理韧性或应激易感性，其机制尚不清楚。本研究在雄性小鼠内侧前额叶皮层背侧区（dmPFC）-外侧缰核（LHb）环路中鉴定出一条双通路机制，其中谷氨酸能与GABA能投射协同调控应激反应。慢性应激对这两条通路产生差异性调节，通过增强兴奋性输入并抑制抑制性输入，诱导dmPFC支配的LHb神经元出现易感性特异性的过度活跃，破坏长程兴奋/抑制（E/I）平衡。采用化学遗传学手段重现该失衡可加剧LHb过度活跃和应激易感性，而恢复平衡则促进心理韧性。机制上，应激易感小鼠的GABA能神经元中ATP-P2X2R信号受损，通过局部微环路导致兴奋性通路去抑制并削弱抑制性投射，从而造成E/I失衡。该破坏最终引起LHb过度活跃和应激易感性。综上，这些结果揭示ATP-P2X2R信号对相互拮抗的dmPFC-LHb通路的协调调控决定了应激易感性，为应激诱导的适应不良提供了双通路失调机制，并为抑郁症提供了潜在治疗靶点。
Abstract
Chronic stress disrupts emotional homeostasis, leading to resilience or susceptibility through unclear mechanisms. Here, we identify a dual-pathway mechanism in the dorsomedial prefrontal cortex (dmPFC)-lateral habenula (LHb) circuit in male mice, where glutamatergic and GABAergic projections coordinately regulate stress responses. Chronic stress differentially modulates these pathways, inducing susceptibility-specific hyperactivity in dmPFC-innervated LHb neurons by potentiating excitatory and suppressing inhibitory inputs, disrupting long-range excitatory/inhibitory (E/I) balance. Chemogenetic recapitulation of this imbalance exacerbates LHb hyperactivity and stress susceptibility, whereas restoring balance promotes resilience. Mechanistically, stress-susceptible mice exhibit impaired ATP-P2X2R signaling in GABAergic neurons, leading to disinhibition of the excitatory pathway via local microcircuits and weakening of the inhibitory projection, resulting in E/I imbalance. This disruption ultimately causes LHb hyperactivity and susceptibility. Collectively, these results reveal that coordinated regulation of opposing dmPFC-LHb pathways by ATP-P2X2R signaling gates stress susceptibility, providing a dual-pathway dysregulation mechanism for stress-induced maladaptation and a potential therapeutic target for depression.
如何引用
AMA
Jijin Wu, Xiaohan Tong, Ruizhe Sun, Yang Tan, Bingjie Liu, Xianwei Liu, et al. A dual-pathway dysregulation in prefrontal-habenular circuits mediates stress susceptibility.. Nature communications. 2026; doi:10.1038/s41467-026-74754-x.
APA
Jijin Wu, Xiaohan Tong, Ruizhe Sun, Yang Tan, Bingjie Liu, Xianwei Liu, et al (2026). A dual-pathway dysregulation in prefrontal-habenular circuits mediates stress susceptibility.. Nature communications. https://doi.org/10.1038/s41467-026-74754-x
GB/T 7714
Jijin Wu, Xiaohan Tong, Ruizhe Sun, Yang Tan, Bingjie Liu, Xianwei Liu, et al. A dual-pathway dysregulation in prefrontal-habenular circuits mediates stress susceptibility.[J]. Nature communications, 2026 doi:10.1038/s41467-026-74754-x.
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