A red nucleus–VTA glutamate pathway underlies exercise reward and the therapeutic effect of exercise on cocaine use

作者：Yi He, Graziella Madeo, Ying Liang, Cindy Zhang, Briana J. Hempel, Xiaojie Liu, Lianwei Mu, Shui Liu, Guo‐Hua Bi, Ewa Galaj, Hai‐Ying Zhang, Hui Shen, Ross A. McDevitt, Eliot L. Gardner, Qing-song Liu, Zheng‐Xiong Xi · 发表于：Science Advances · 年份：2022 · DOI：10.1126/sciadv.abo1440 · 被引用次数：29 · 研究领域：Neurotransmitter Receptor Influence on Behavior、Neural dynamics and brain function、Neuroscience and Neuropharmacology Research

Physical exercise is rewarding and protective against drug abuse and addiction. However, the neural mechanisms underlying these actions remain unclear. Here, we report that long-term wheel-running produced a more robust increase in c-fos expression in the red nucleus (RN) than in other brain regions. Anatomic and functional assays demonstrated that most RN magnocellular portion (RNm) neurons are glutamatergic. Wheel-running activates a subset of RNm glutamate neurons that project to ventral tegmental area (VTA) dopamine neurons. Optogenetic stimulation of this pathway was rewarding, as assessed by intracranial self-stimulation and conditioned place preference, whereas optical inhibition blocked wheel-running behavior. Running wheel access decreased cocaine self-administration and cocaine seeking during extinction. Last, optogenetic stimulation of the RNm-to-VTA glutamate pathway inhibited responding to cocaine. Together, these findings indicate that physical exercise activates a specific RNm-to-VTA glutamatergic pathway, producing exercise reward and reducing cocaine intake.