Primary cilia mediate stress vulnerability and exercise-induced antidepressant adaptation: evidence for ventral...

Chronic stress engenders marked interindividual heterogeneity in vulnerability to depression and anxiety, indicating that distinct neurobiological processes shape susceptibility and resilience. To identify the mechanisms underlying this divergence, male C57BL/6J mice subjected to chronic restraint stress were stratified into stress-susceptible or resilient phenotypes using multidimensional behavioral clustering. To examine how exercise modifies these stress-defined endophenotypes, we used a graded treadmill paradigm in which low-, moderate-, and high-intensity exercises were parametrically defined relative to the ventilatory threshold (VT). Only low-intensity exercise performed below VT produced robust antidepressant and anxiolytic effects in susceptible mice. Whole-brain c-Fos mapping revealed the selective recruitment of the ventral hippocampus (vHPC) during low-intensity exercise. Chemogenetic silencing of vHPC neurons abolished these behavioral benefits, indicating that vHPC engagement is essential for exercise-induced resilience. Transcriptomic profiling of vHPC showed that this adaptive state was associated with the coordinated modulation of primary cilium-associated gene networks. Morphometric analyses confirmed that chronic stress-induced pronounced elongation of primary cilia, particularly in astrocytes, whereas low-intensity exercise restored both ciliary length and the proportion of ciliated astrocytes. These structural recalibrations coincided with reduced expression of proinflammatory cytokines, including IL-1α and fractalkine, suggesting that astrocytic cilia act as a key interface linking stress signaling to neuroimmune regulation. Collectively, these findings outline a mechanistic cascade in which exercise below the VT engages vHPC circuits, reorganizes cilia-related transcriptional programs, and restores astrocyte and inflammatory homeostasis, converting stress-susceptible states into resilient phenotypes.NEW & NOTEWORTHY Chronic stress produced distinct stress-susceptible and stress-resilient phenotypes in mice. Exercise intensity was critical: low-intensity running below the ventilatory threshold alleviated depression- and anxiety-like behaviors and normalized basal corticosterone levels. These benefits required ventral hippocampal activity, as chemogenetic silencing blunted the behavioral rescue. Stress susceptibility was associated with elongation and increased prevalence of astrocytic primary cilia in the vHPC, which were reversed by low-intensity exercise, accompanied by transcriptomic reprogramming and alteration in proinflammatory cytokine expression.