Brain-wide induction of ΔFOSB and altered co-activation networks in a rat model for exercise training

Exercise training promotes brain health, yet the underlying mechanisms remain unclear. ∆FOSB, a transcription factor involved in neuroplasticity, stress-, cognition- and reward-related behavior, accumulates in response to repetitive neuronal stimulation due to its unusual protein stability and can thus serve as a proxy for chronic neuronal activation. This study employed voluntary wheel running (VWR), an animal model for exercise training, in male and female Wistar rats to quantify VWR-induction of ∆FOSB in 44 brain regions implicated in stress, cognition and reward. Using network analysis, we examined broader patterns of co-activation and changes in network topology (e.g. centrality, small-world-likeness) of this comprehensive map of brain regions. Four weeks of VWR improved metabolic health, independent of sex, and females ran more than males. Notably, semi-automated quantification of ∆FOSB-immunoreactivity revealed VWR regulation of ∆FOSB in several cortical, striatal, hippocampal, hypothalamic and midbrain regions, which was more pronounced in females. VWR altered several parameters of ∆FOSB co-activation networks, decreasing network density while increasing global efficiency in both sexes, and was associated with greater cortical centrality. These findings demonstrate that VWR-mediated chronic neuronal activation extends beyond previously studied brain regions and that habitual VWR shifts hierarchy to more cortical regions. Because ∆FOSB overexpression is associated with lower neuronal excitability, the current ∆FOSB brain atlas and network co-activation dataset extends our understanding of the impact of VWR on brain neuroplasticity and provides a framework for future mechanistic studies into ∆FOSB-mediated changes in neuronal excitability during habitual VWR and subsequent effects on stress-, cognition- and reward-related behavior.