Stress and Exercise Elicit Opposing Glial Transcriptional Programs in the Striatum Associated with Persistent Physical Inactivity

Regular physical activity is essential for physical and mental health, whereas physical inactivity is a major contributor to chronic disease risk. Psychological stress can disrupt motivational systems that regulate movement and thereby promote inactivity. We previously reported that acute tail-shock stress induces persistent physical inactivity in voluntary wheel running (VWR) in male rodents. To identify molecular adaptations associated with this sustained behavioral change, we analyzed single-nucleus RNA sequencing (snRNA-seq) datasets from the striatum, a key region for motor control and reward processing, with a focus on glial cell-type-specific transcriptional responses to stress and exercise. In oligodendrocytes, stress-regulated differentially expressed genes (DEGs) were predominantly upregulated and enriched for ribosomal, protein stabilization, and myelin-associated pathways, whereas genes related to synaptic structure were downregulated. In contrast, exercise elicited a broader transcriptional response, including upregulation of pathways involved in synapse assembly, nervous system development, and neurotransmission, alongside downregulation of ribosomal and protein-folding processes. In astrocytes, DEGs under both exercise and stress were enriched for neuronal/cytoskeletal processes, including regulation of postsynaptic structure, actin polymerization, and actomyosin organization, indicating a mechanistic signature of structural remodeling. Notably, stress and exercise regulated a substantially overlapping set of DEGs in both glial cell types, with many shared genes exhibiting opposite directionality between conditions. Together, these findings provide a molecular framework linking stress exposure to persistent physical inactivity and implicate oligodendrocytes and astrocytes as potential cellular substrates of stress–exercise interactions. Ongoing work will determine how combined stress and exercise exposures shape glial transcriptional programs associated with long-term inactivity. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.