Noradrenergic Projections from the Locus Coeruleus to the Medial Prefrontal Cortex Enhances Stress Coping Behavior in Mice Following Long-Term Intermittent Fasting.

Intermittent fasting has been shown to alleviate stress, anxiety, and depressive symptoms. Although noradrenaline, also known as norepinephrine (NE), is implicated in stress regulation, the dynamics of NE release and the associated neural pathways during stress coping behaviors in fasting mice remain poorly understood. In this study, we employed the forced swimming test (FST) to evaluate the effects of intermittent fasting on stress coping behavior in mice. Our results demonstrate that mice subjected to long-term intermittent fasting exhibited significantly more active coping behaviors in the FST compared to control mice. In contrast, acute fasting did not produce similar effects. Using the fluorescent GRAB-NE sensor to measure NE release with sub-second temporal resolution during the FST, we found that intermittent fasting modulates the locus coeruleus-medial prefrontal cortex (LC-mPFC) pathway, which underlies these behavioral adaptations. Moreover, chemogenetic activation of LC-mPFC projections strongly promoted active coping in the FST. These findings suggest that enhanced LC-mPFC activity mediates the increased active coping behavior observed in fasting mice. This study provides new insights into the neural mechanisms through which intermittent fasting may ameliorate depressive-like behaviors, offering potential therapeutic targets for stress-related disorders.