Voluntary physical activity modulates brain ΔFOSB and alters co-activation 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 nuclear transcription factor ΔFOSB, a long-lived splice variant of FOSB. Long-term voluntary wheel running (VWR), a behavioral paradigm that mimics exercise training in humans, altered brain ΔFOSB immunoreactivity signatures and reorganized co-activation 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 four weeks on horizontal saucer-like wheels, after which ΔFOSB immunoreactivity was quantified in 46 brain regions associated with stress regulation, cognition- and reward-related behavior. Network analysis was applied to assess VWR-mediated changes in interregional ΔFOSB co-activation 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, cognition- and reward-related behavior. Significance statement Regular physical activity promotes brain health, but the underlying mechanisms remain incompletely understood. Here, we quantified ΔFOSB, a transcription factor involved in neuroplasticity, in 46 brain regions associated with stress regulation, cognition- and reward-related behavior after four weeks of VWR in individually-housed male and female mice. We show altered ΔFOSB immunoreactivity in a subset of these brain regions in both male and female runners. This was accompanied by specific changes in ΔFOSB co-activation networks. These large-scale mouse brain ΔFOSB signatures following VWR improve our understanding of how VWR impacts brain plasticity in mice and offers a framework for mechanistic and functional studies into ΔFOSB-mediated changes in stress regulation, cognition- and reward-related behavior following VWR.