Claustrum–ACC reciprocal circuits modulate stress responses across acute and chronic states

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SUMMARY Anxiety is an evolutionarily conserved response that supports threat detection and survival, yet dysregulated stress responses can drive its progression into pathological states. Here, we identify the claustrum (CLA) as a central hub that links acute stress responses to chronic affective dysfunction through cell-type-specific circuit dynamics. Acute social defeat stress robustly activated the CLA and induced anxiety-like behaviors in mice. Multimodal profiling revealed transcriptional and functional plasticity within CLA neurons, with Egr2-expressing excitatory and Gad2-expressing inhibitory populations exhibiting distinct adaptations to acute versus chronic stress. We further delineate a reciprocal CLA–anterior cingulate cortex (ACC) circuit that bidirectionally regulates stress responses in which glutamatergic CLAEgr2 → ACC projections promoted anxiety-like behaviors, whereas top-down ACC → CLA Gad2 inhibitory inputs constrained claustral output. Chronic stress induced hyperactivity in CLA Gad2 inhibitory neurons and reshaped excitatory neuron dynamics, leading to increased intrinsic excitability, local circuit imbalance, and ultimately, depression-like phenotypes. These findings define a dynamic claustrum-centered circuit that governs the transition from adaptive anxiety to maladaptive affective states through balanced Egr2–Gad2 activity, and show that chronic-stress driven disruption of this excitatory-inhibitory equilibrium impairs stress coping and drives pathological behavioral outcomes. Graphic summary Acute stress engages a claustrum (CLA)-centered network with activation of Egr2⁺ excitatory neurons, promoting anxiety-like behaviors. Chronic stress drives CLA G142⁺ neurons into a hyperactive state, enhancing local inhibition and suppressing excitatory output to induce depressive-like behaviors. A reciprocal CLA E7182→ ACC feedforward and ACC→CLA G142 feedback circuit forms a state-dependent regulatory hub governing stress adaptation.

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