Age-dependent alterations in key components of the nigrostriatal dopaminergic system and distinct motor phenotypes

Jiang-peng Fan1, Hui-zhen Geng2,3, Ya-wei Ji2,3, Tao Jia2,3, Jennifer B. Treweek4, An-an Li1, Chun-yi Zhou2,3,4, Viviana Gradinaru4, Cheng Xiao2,3,4
1 Jiangsu Province Key Laboratory in Brain diseases, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Xuzhou Medical University, Xuzhou 221004, China
2 Jiangsu Province Key Laboratory in Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou 221004, China
3 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou 221004, China
4 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
Correspondence to: Chun-yi Zhou:, Cheng Xiao:,
DOI: 10.1038/s41401-021-00713-5
Received: 24 February 2021
Accepted: 6 June 2021
Advance online: 9 July 2021


The nigrostriatal dopaminergic (DA) system, which includes DA neurons in the ventral and dorsal tiers of the substantia nigra pars compacta (vSNc, dSNc) and DA terminals in the dorsal striatum, is critically implicated in motor control. Accumulating studies demonstrate that both the nigrostriatal DA system and motor function are impaired in aged subjects. However, it is unknown whether dSNc and vSNc DA neurons and striatal DA terminals age in similar patterns, and whether these changes parallel motor deficits. To address this, we performed ex vivo patch-clamp recordings in dSNc and vSNc DA neurons, measured striatal dopamine release, and analyzed motor behaviors in rodents. Spontaneous firing in dSNc and vSNc DA neurons and depolarization-evoked firing in dSNc DA neurons showed inverse V-shaped changes with age. But depolarization-evoked firing in vSNc DA neurons increased with age. In the dorsal striatum, dopamine release declined with age. In locomotor tests, 12-month-old rodents showed hyperactive exploration, relative to 6- and 24-month-old rodents. Additionally, aged rodents showed significant deficits in coordination. Elevating dopamine levels with a dopamine transporter inhibitor improved both locomotion and coordination. Therefore, key components in the nigrostriatal DA system exhibit distinct aging patterns and may contribute to age-related alterations in locomotion and coordination.
Keywords: aging; substantia nigra pars compacta; dopaminergic neurons; dopamine sensor; locomotion; coordination; rodent

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