Claustrum-cortical reciprocal connections orchestrate allostatic responses following stress

Anxiety, whilst often viewed as a disorder, is an evolutionarily conserved mechanism that facilitates threat detection and survival. However, when stress regulation becomes maladaptive, this adaptive response can shift into pathology. Here, we identify the claustrum (CLA) as a key hub for allostasis following stress, integrating Gad2 (GABAergic)-vGluT1 (glutamatergic) microcircuits. We report that acute social defeat stress activated the CLA and induced hypervigilance and anxiety-like behaviors. Multimodal analyses revealed transcriptional plasticity in CLA neurons, and fiber photometry revealed anticipatory activation of Gad2 neurons and reactive activation of vGluT1+ neurons. We further delineated a reciprocal GABAergic-glutamatergic circuit between the CLA and the anterior cingulate cortex (ACC) that orchestrates allostasis following stress via opposing mechanisms: (1) glutamatergic CLA-ACC projections that amplify threat responses, and (2) two distinct GABAergic inhibitory pathways - intrinsic CLAGad2+ activity and top-down ACC-CLAGad2+ modulation. Chronic stress drives persistent hyperactivation of CLAGad2+ neurons, suppressing CLA glutamatergic activity and leading to depression-like behaviors. Our results identify a dynamic CLA circuit that gates stress responses via CLAGad2+ neurons acting as a brake under acute stress. Chronic stress amplifies this inhibition, thereby disturbing circuit balance and driving behavioral despair affective pathology.