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Primary Cilia Mediate Stress Vulnerability and Exercise Antidepressant Adaptation: Evidence for Ventral Hippocampal Astrocytic Ciliary Remodeling by Exercise

ABSTRACT: 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, 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE315845 | GEO | 2026/04/15

REPOSITORIES: GEO

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Project description:Stress susceptibility varies across individuals, influenced by genetic, molecular, and environmental factors. Considering the individual differences in response to stress, however, approaches for exercise treatment as an antidepressant and anxiolytic intervention are also not exempt from variability in effectiveness among individuals, and insight into the biology of those variations can be gained by examining the individual adaptation to exercise. Here, we investigated the efficacy of voluntary wheel running (VWR) exercise as a disease-modifying intervention for stress-susceptible (SS) mice subjected to chronic restraint stress (CRST). Multidimensional behavior analysis revealed significant variability in the efficacy of VWR among individuals, with some mice showing substantial behavior phenotypic improvements (e.g., behavior despair, anhedonia, aversion to open space, and compulsive behavior) (SES) while others displayed limited or no benefits (SER). Furthermore, transcriptomic analysis of the ventral hippocampus (vHPC), a critical brain region involved in emotional regulation and processing, demonstrated that SES mice exhibited molecular signatures promoting adaptive changes by restoring cellular repair, energy availability, and synaptic plasticity observed in SS mice, whereas SER mice exhibited limited behavior resilience and distinct transcriptomic profiles enriched in structural adaptation without functional resilience and glia cell differentiation, particularly marked by astrocyte activation or differentiation. These findings suggest that while VWR can alleviate multiple concurrent behavior symptoms in stress-susceptible mice; however, its efficacy is influenced by distinct biological processes. Collectively, our work highlights the importance of a multivariate framework for behavior assessment and genetic underpinnings to better understand the often-overlooked variability in response to stress and the therapeutic efficacy of exercise in stress-related disorders.

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Primary Cilia Mediate Stress Vulnerability and Exercise Antidepressant Adaptation: Evidence for Ventral Hippocampal Astrocytic Ciliary Remodeling by Exercise

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