He Yi, Madeo Graziella, Liang Ying, Zhang Cindy, Hempel Briana, Liu Xiaojie, Mu Lianwei, Liu Shui, Bi Guo-Hua, Galaj Ewa, Zhang Hai-Ying, Shen Hui, McDevitt Ross A, Gardner Eliot L, Liu Qing-Song, Xi Zheng-Xiong
Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA.
Cellular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA.
Sci Adv. 2022 Sep 2;8(35):eabo1440. doi: 10.1126/sciadv.abo1440.
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.
体育锻炼有益且能预防药物滥用和成瘾。然而，这些作用背后的神经机制仍不清楚。在此，我们报告长期的转轮运动在红核（RN）中比在其他脑区产生了更强的c-fos表达增加。解剖学和功能分析表明，大多数红核大细胞部（RNm）神经元是谷氨酸能的。转轮运动激活了投射到腹侧被盖区（VTA）多巴胺能神经元的一部分RNm谷氨酸能神经元。通过颅内自我刺激和条件性位置偏爱评估，对该通路的光遗传学刺激是有奖励作用的，而光抑制则阻断了转轮运动行为。提供转轮减少了可卡因自我给药以及消退期间对可卡因的觅求。最后，对RNm到VTA谷氨酸能通路的光遗传学刺激抑制了对可卡因的反应。总之，这些发现表明体育锻炼激活了一条特定的从RNm到VTA的谷氨酸能通路，产生运动奖赏并减少可卡因摄入。
