Abstract
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.
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Acknowledgements
This work was supported by grants to V.G.: NIH/NIA 1R01AG047664-01 (C.X. is a co-investigator); NIH BRAIN 1U01NS090577; Heritage Medical Research Institute; Michael J. Fox Foundation; Sloan Foundation; Human Frontiers in Science Program; grants to C.X.: Michael J. Fox Foundation (11345), Startup package in Xuzhou Medical University, National Natural Science Foundation of China (81870891, 82071231); and grants to C.Z.: Startup package in Xuzhou Medical University, National Natural Science Foundation of China (81701100, 81971038), Natural Science Foundation of the Jiangsu Higher Education Institutions of China (18KJA320009). J.B.T. acknowledges the Colvin Postdoctoral Fellowship and NARSAD Young Investigator award; Y.-W.J. and T.J. acknowledge the Postgraduate Innovation Program in Jiangsu Province (KYCX20_2474, KYCX20_2478).
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VG and CX designed the experiments. JPF, CX, and CZ performed electrophysiological recordings and imaging, and analyzed the data. JPF, CX, HZG, YWJ, JBT, and TJ acquired and analyzed the behavioral data. CX, CZ, VG, JBT, and AAL wrote the manuscript. All authors read and approved the final version of the manuscript. VG, CX, and CZ supervised the study.
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Fan, Jp., Geng, Hz., Ji, Yw. et al. Age-dependent alterations in key components of the nigrostriatal dopaminergic system and distinct motor phenotypes. Acta Pharmacol Sin 43, 862–875 (2022). https://doi.org/10.1038/s41401-021-00713-5
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DOI: https://doi.org/10.1038/s41401-021-00713-5
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