Voluntary Physical Activity Modulates Brain ΔFOSB and Alters Coactivation Networks in Male and Female Mice

Regular physical activity promotes brain health, yet the underlying mechanisms remain incompletely understood. Repetitive activation of neurons results in accumulation of the transcription factor ΔFOSB, a long-lived splice variant of FOSB. Long-term voluntary wheel running (VWR), a behavioral paradigm that mimics human exercise training, altered brain ΔFOSB immunoreactivity signatures and reorganized coactivation networks in Wistar rats. Here, we used a similar approach to determine large-scale ΔFOSB brain signatures following long-term VWR in mice. Young-adult individually housed male and female C57BL/6J^OlaHsd mice were allowed to run for 4 weeks on horizontal saucer-like wheels, after which ΔFOSB immunoreactivity was quantified in 46 brain regions associated with stress regulation and cognition- and reward-related behavior. Network analysis was applied to assess VWR-mediated changes in interregional ΔFOSB coactivation patterns and network topology. Male and female mice ran equal distances, and VWR blunted body weight gain and terminal gonadal white adipose tissue mass in both sexes. VWR modulated ΔFOSB immunoreactivity across several cortical, striatal, hippocampal, and thalamic regions. Network analysis revealed substantial network reorganizations, with reduced overall network density and increased cortical centrality in males, and greater global efficiency (i.e., small-worldness) in females. Thus, VWR induced large-scale adaptations in brain (in)activation, reshaping network organization in distinct ways in both sexes. Because ΔFOSB regulates many target genes, impacting, e.g., neuron excitability, our findings suggest that long-term VWR induces widespread transcriptional alterations throughout the mouse brain. Functional and mechanistic follow-up studies are necessary to determine the impact of these alterations on stress regulation and cognition- and reward-related behavior.