Sex-specific signatures of brain-wide induction of ΔFOSB and altered co-activation networks in a mouse model for exercise training

Physical exercise training promotes brain health, yet the underlying mechanisms remain incompletely understood. Repeated neuronal activation results in accumulation of the transcription factor {Delta}FOSB, a long-lived splice variant of FOSB. We have previously demonstrated in rats that long-term voluntary wheel running (VWR), a behavioral paradigm that mimics exercise training in humans, altered {Delta}FOSB expression in a brain-wide manner, and that it reorganized co-activation networks. Here, we used a similar approach, now in mice, to map neuronal activation patterns following long-term VWR. Young-adult male and female C57BL/6JOlaHsd mice were allowed to run for four weeks on horizontal wheels, after which {Delta}FOSB immunoreactivity was quantified across 46 brain regions associated with stress regulation, cognition and reward-related behavior. Subsequently, network analysis was applied to assess VWR-mediated changes in patterns of interregional {Delta}FOSB co-activation and network topology. Male and female mice ran equal distances and VWR blunted bodyweight gain and final fat mass in both sexes. VWR modulated {Delta}FOSB expression across several cortical, striatal, hippocampal and thalamic regions. Network analysis revealed a sex-specific network reorganization, 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, sex-dependent adaptations in brain (in)activation, reshaping network organization in distinct ways across sexes. Because {Delta}FOSB regulates many target genes, our findings indicate that long-term VWR induces widespread transcriptional alterations throughout the mouse brain. More focused follow-up studies are required to investigate the impact of these specific alterations on stress regulation, cognition and reward-related behavior. SIGNIFICANCE STATEMENTExercise training promotes brain health, but the underlying mechanisms remain elusive. Here, we studied {Delta}FOSB, a very stable transcription factor involved in neuroplasticity, after four weeks of running in mice. We show this altered {Delta}FOSB expression in a subset of 46 brain regions implicated in stress regulation, cognition and reward, notably with sex-specific signatures. This was accompanied by specific changes in {Delta}FOSB co-activation networks, including decreased network density and increased cortical centrality in males, and greater network efficiency in females. Our mouse {Delta}FOSB brain map following running improves our understanding of how exercise training impacts brain plasticity and offers a framework for more mechanistic future studies into running-mediated changes in stress regulation, cognition and reward-related behavior.