Transcriptomic reprogramming of the medial amygdala in chronic stress: Implications of ER proteostasis and neuropeptide signaling for anxiety-like behaviors.

Abstract

Chronic stress is a pivotal risk factor for the etiology of anxiety disorders. However, the molecular maladaptations within the medial amygdala (MeA) remain insufficiently characterized. Here, we investigated the MeA transcriptomic landscape to elucidate mechanisms underlying stress-induced anxiety and identify potential therapeutic targets. We established a mouse model using a 10-day chronic restraint stress paradigm, which resulted in robust anxiety-like phenotypes validated by multiple behavioral tests. RNA sequencing identified 193 differentially expressed genes. Bioinformatic analyses revealed a dominant upregulation of endoplasmic reticulum (ER) protein processing and chaperone-mediated refolding. This indicates a coordinated transcriptional upregulation of endoplasmic reticulum proteostasis components, consistent with an adaptive response to proteotoxic stress. Beyond proteostasis, the MeA transcriptome exhibited significant transcriptional reprogramming in neuroactive ligand-receptor interactions, synaptic organization, and lipid metabolism. Network analysis further pinpointed two functional modules: a highly connected ER chaperone hub centered on Hspa5 (BiP) and a neuropeptide signaling cluster involving Nms, Kng2, Agt, and Pmch. Importantly, site-specific pharmacological inhibition of Hspa5 within the MeA successfully attenuated CRS-induced anxiety-like behaviors. Collectively, these findings demonstrate that chronic stress orchestrates extensive transcriptomic reprogramming in the MeA characterized by the recruitment of proteostasis mechanisms and neuropeptide reorganization. Our study highlights Hspa5-mediated regulation as a promising mechanistic target with functional/causal evidence for the treatment of anxiety disorders.