Chronic stress engenders marked inter-individual 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 (CRST) 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.
Hwang et al. (2026) studied this question.