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

Study Author Yi He, Ph.D.Featured Paper of the Month – January 2023

Published in Science Advances by Yi He and Zheng-Xiong Xi, et al. of the NIDA IRP Addiction Biology Unit.

Summary

It is well known that physical exercise is rewarding and protective against drug abuse and addiction. However, the neural mechanisms underlying these actions are not fully understood. In this report, we found that prolonged daily voluntary wheel-running produced a more robust increase in c-fos expression in the red nucleus (RN) than in other brain regions. Subsequent neuronal tracing imaging and electrophysiological assays demonstrated that most RN neurons are glutamatergic in its magnocellular portion (RNm) and wheel-running activates a subset of RNm glutamate neurons that project to the neighboring ventral tegmental area (VTA), particularly to contralateral VTA dopamine neurons. Selective stimulation of this pathway is rewarding, as assessed by optical intracranial self-stimulation (oICSS) and conditioned place preference (CPP), whereas optical inhibition of this pathway blocked wheel-running behavior, suggesting that the RN-to-VTA glutamate pathway, at least in part, underlies exercise reward. Furthermore, wheel-running or direct stimulation of this pathway inhibited cocaine self-administration and cocaine seeking during extinction, suggesting that this newly identified local circuit that links the motor circuitry and brain reward system at least in part underlies its therapeutic anti-cocaine effects. Together, these findings not only expand our understanding of how physical activity produces exercise reward but also help us understanding how regular physical exercise produces such a wide range of therapeutic benefits as anti-cocaine use, anti-depression, anti-anxiety, and anti-obesity.

Publication Information

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

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

In: Sci Adv, vol. 8, no. 35, pp. eabo1440, 2022, ISSN: 2375-2548.

Abstract | Links

@article{pmid36054363,
title = {A red nucleus-VTA glutamate pathway underlies exercise reward and the therapeutic effect of exercise on cocaine use},
author = {Yi He and Graziella Madeo and Ying Liang and Cindy Zhang and Briana Hempel and Xiaojie Liu and Lianwei Mu and Shui Liu and Guo-Hua Bi and Ewa Galaj and Hai-Ying Zhang and Hui Shen and Ross A McDevitt and Eliot L Gardner and Qing-Song Liu and Zheng-Xiong Xi},
url = {https://pubmed.ncbi.nlm.nih.gov/36054363/},
doi = {10.1126/sciadv.abo1440},
issn = {2375-2548},
year = {2022},
date = {2022-09-01},
urldate = {2022-09-01},
journal = {Sci Adv},
volume = {8},
number = {35},
pages = {eabo1440},
abstract = {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.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

Close

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.

Close

  • https://pubmed.ncbi.nlm.nih.gov/36054363/
  • doi:10.1126/sciadv.abo1440

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