Neuroinflammation in Olfactory Circuits Underlies Odor Hypersensitivity in a Rodent Model of Depression

Olfactory anhedonia and heightened aversion to unpleasant odors are well-documented features of depression in humans, yet the neural mechanisms linking chronic stress to altered olfactory perception remain poorly understood. We used the Unpredictable Chronic Mild Stress (UCMS) paradigm to examine how chronic stress affects olfactory avoidance behavior and glial cell morphology across multiple olfactory brain regions in male and female mice. UCMS-treated mice showed increased avoidance of aversive odorants in an odorized light/dark box assay, consistent with heightened aversive reactivity to odors following chronic stress. Using immunohistochemistry, we assessed microglial morphology and astrocyte density across six olfactory and limbic brain regions. Chronic stress produced region-specific glial remodeling: astrocyte counts were selectively elevated in the medial amygdala, and microglial process complexity was increased in the anterior olfactory nucleus and anterior piriform cortex. Microglial morphological complexity in the anterior piriform cortex was correlated with individual odor avoidance scores. These findings reveal that chronic stress induces regionally specific glial plasticity within olfactory sensory and affective networks and suggest that microglial remodeling in piriform cortex may contribute to stress-related changes in olfactory perception. Significance StatementChanges in sensory perception frequently accompany depression. While previous studies have implicated neuroinflammation in depression-related dysfunction within cortical and limbic structures, little is known about how chronic stress affects glial cells in olfactory processing regions. Here, we show that chronic stress induces glial remodeling in key olfactory areas, including the olfactory bulb, anterior piriform cortex, and medial amygdala, and that these changes correlate with heightened behavioral avoidance of aversive odors. These findings suggest that glial plasticity in sensory networks contributes to affective alterations in olfactory perception, revealing a potential mechanism by which mood disorders can influence sensory experience. This work advances our understanding of the neuroimmune basis of sensory-affective integration.