Working out the active brain Identification of molecular and network adaptations underlying the beneficial effects of exercise on brain health

Physical exercise promotes brain health, yet the underlying neurobiological mechanisms and the factors shaping differences in individual responses remain incompletely understood. This dissertation examines how long-term voluntary wheel running (VWR), a rodent model of self-reinforcing exercise training, influences molecular, cellular, network, and neuroimmune processes.
In rats, VWR selectively reduced dopamine D2/3 receptor availability in the nucleus accumbens, without altering dopamine transporter availability or either measure in the dorsal striatum. Across male and female rats and mice, VWR induced widespread, sex-dependent changes in ΔFOSB, a marker of repeated neuronal activation, particularly in striatal, hippocampal, and cortical regions. ΔFOSB-based co-activation networks revealed greater cortical centrality and sex-dependent changes in network topology and efficiency upon VWR.
Comparing running wheel designs demonstrated that wheel characteristics shape running behavior and subsequent skeletal muscle gene expression, adult hippocampal neurogenesis, and neuronal responses to acute stress, despite broadly similar regional ΔFOSB accumulation. When we extend our studies to a disease context in mouse models of colorectal cancer, VWR also modulated peripheral T cell profiles and hippocampal microglial morphology and density during immune checkpoint inhibitor therapy, particularly anti-CTLA-4 treatment, suggesting potential neuroimmune benefits.
Together, these findings identify VWR as a multilevel, context-dependent intervention that reshapes brain plasticity and organization. Its effects vary with sex, species, running dynamics, and context, highlighting the importance of these factors in experimental design and interpretation. This work provides a foundation for investigating causal relationships between exercise-induced biological adaptations and behavioral outcomes, ultimately informing exercise interventions tailored to individual biology and clinical needs.