Regular light-intensity exercise accelerates contextual fear extinction with reduced dorsal CA3 activation in male...

Exercise has gained attention as a low-cost, non-pharmacological approach for stress-related disorders such as post-traumatic stress disorder (PTSD). Regular light-intensity exercise (LIE), which is feasible even for vulnerable populations, has been reported to promote contextual fear memory (CFM) extinction learning, a critical process for alleviating PTSD. However, its underlying neural signatures remain unclear. Given that LIE effectively promotes hippocampal brain-derived neurotrophic factor and adult hippocampal neurogenesis (AHN), both key modulators that facilitate CFM extinction, a hippocampus-dependent mechanism of fear suppression is likely to underlie this effect. Specifically, CFM recall depends on the reactivation of dorsal hippocampal neurons that were recruited during acquisition, particularly in the CA3, and AHN suppresses this reactivation. Therefore, we hypothesized that LIE reduces dorsal CA3 (dCA3) recruitment during CFM extinction learning. To test this, male rats underwent LIE using a treadmill exercise model with intensity defined relative to the lactate threshold, and hippocampal neuronal activity during CFM extinction learning was evaluated using a contextual fear conditioning and c-Fos immunohistochemistry. Our results showed that regular LIE reduced neuronal activity in the dCA3 during CFM extinction learning, and this reduction was positively correlated with decreased freezing behavior. Additionally, neuronal activity in the ventral dentate gyrus, implicated in anxiety regulation, was attenuated by regular LIE. These findings reveal a selective hippocampal neural signature of the LIE-facilitated CFM extinction learning, suggesting that reduced fear recall-as well as anxiety-related hippocampal recruitment underlies its behavioral efficacy. Collectively, our study provides neurobiological support for LIE as a clinically feasible strategy for PTSD.