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Abstract

Anxiety disorders are the most widespread class of mental health disorders in the United States, affecting an estimated 30% of adults at some point in their lives. A number of pharmacological and psychological treatments have been developed with some degree of success, but a significant portion of individuals remain resistant to treatment. Physical exercise has emerged as a potentially promising alternative treatment option, but its neurobiological effects are poorly characterized in humans due to ethical/practical reasons. To that end, animal models have been used to characterize neurobiological effects associated with changes in tests of anxiety-like behavior, including the Elevated Plus Maze (EPM) and Novelty- Suppressed Feeding (NSF). Voluntary wheel-running in mice has been shown to decrease anxiety-like behavior in these tasks, leading researchers to search for the biological mechanisms that might be mediating this effect. One candidate mechanism is neurogenesis, which has been extensively shown to be increased by wheel-running and correlate with decreased anxiety-like behavior. Nonetheless, recent evidence suggests that neurogenesis may not be the only contributor to running-induced reductions in anxiety-like behavior. Perineuronal nets (PNNs) represent another possible contributor to this effect, due to their mode of action at the synapse, an area of prime importance in psychiatric disorders. Furthermore, though neurogenesis predominantly occurs in the hippocampus (where PNNs have largely been studied as well) recent work also suggests that neurobiological effects should be studied in the broader anxiety-like/defensive circuitry, including the basolateral amygdala (BLA), medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC). We thus investigated the effects of voluntary wheel- running on behavior in the EPM and NSF, neurogenesis, and PNNs in the hippocampus and broader anxiety-like/defensive circuitry of C57BL/6J mice. We found running to have mixed effects on behavior: in the adolescent cohort, it was shown to consistently decrease anxiety-like behavior, but these effects were less consistent in the adult cohort. In the adolescent cohort, runner mice showed increased neurogenesis and decreased PNN density in the dorsal dentate gyrus of the hippocampus in association with decreased anxiety-like/defensive behavior. In the adult cohort, runner mice showed decreased PNN density in the dorsal dentate gyrus of the hippocampus in association with mixed behavioral effects, and no PNN differences were observed in the broader/anxiety-like circuitry. Findings, limitations, and suggestions for future work are discussed. The characterizations of the neurobiological effects of running and their relation to running-induced behavioral changes presented in the current work may provide clues for future research and development of effective treatments for the millions of individuals with anxiety disorders.