Astrocytic BDNF Modulates Sensitivity to Stress-Induced Anxiety-Like Behaviors

Abstract

Chronic stress exposure is a potent risk factor for anxiety, disrupting adaptive responses and increasing vulnerability. Astrocytes, as essential regulators of synaptic function and neuroimmune homeostasis, are implicated in mood regulation and neuropsychiatric pathogenesis. However, the precise molecular mechanisms of astrocytes involved in stress-induced anxiety remain poorly understood. In this study, we reveal a pivotal role of astrocytic brain-derived neurotrophic factor (BDNF) in modulating anxiety sensitivity through coordinated regulation with hippocampal CA1 neurons. Chronic restraint stress induces anxiety-like behaviors and disrupts presynaptic glutamatergic transmission in hippocampal CA1 neurons, with astrocytes potentially playing a central regulatory role in a Ca²⁺-dependent manner. Pharmacological manipulation confirms the involvement of BDNF/TrkB signaling, while knockdown of astrocytic BDNF further impairs synaptic function and exacerbates stress-induced anxiety. Transcriptomic analysis suggests interferon-related signaling pathways as potential downstream effectors, amplifying anxiety sensitivity through altered astrocytic activation and neuroimmune dynamics. Our study provides critical mechanistic insights into astrocytic regulation of anxiety sensitivity and highlights astrocytic BDNF as a promising therapeutic target for stress-related anxiety disorders.