Claustrum-cortical reciprocal connections orchestrate allostatic responses following stress

Abstract

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 [->] CLAGad2inhibitory inputs constrained claustral output. Chronic stress induced hyperactivity in CLAGad2 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 summaryAcute stress engages a claustrum (CLA)-centered network with activation of Egr2 excitatory neurons, promoting anxiety-like behaviors. Chronic stress drives CLAG142 neurons into a hyperactive state, enhancing local inhibition and suppressing excitatory output to induce depressive-like behaviors. A reciprocal CLAE7182[->]ACC feedforward and ACC[->]CLAG142 feedback circuit forms a state-dependent regulatory hub governing stress adaptation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/673892v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@75d664org.highwire.dtl.DTLVardef@4e5c31org.highwire.dtl.DTLVardef@86b5f2org.highwire.dtl.DTLVardef@135045_HPS_FORMAT_FIGEXP M_FIG C_FIG