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 CLA ^Gad2+ activity and top-down ACC−CLA ^Gad2+ modulation. Chronic stress drives persistent hyperactivation of CLA ^Gad2+ neurons, suppressing CLA glutamatergic activity and leading to depression-like behaviors. Our results identify a dynamic CLA circuit that gates stress responses via CLA ^Gad2+ neurons acting as a brake under acute stress. Chronic stress amplifies this inhibition, thereby disturbing circuit balance and driving behavioral despair affective pathology.