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

Fan, Jiang-peng and Geng, Hui-zhen and Ji, Ya-wei and Jia, Tao and Treweek, Jennifer B. and Li, An-an and Zhou, Chun-yi and Gradinaru, Viviana and Xiao, Cheng (2021) Age-dependent alterations in key components of the nigrostriatal dopaminergic system and distinct motor phenotypes. Acta Pharmacologica Sinica . ISSN 1671-4083. doi:10.1038/s41401-021-00713-5. (In Press) https://resolver.caltech.edu/CaltechAUTHORS:20210709-224144084

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41401-021-00713-5DOIArticle
https://rdcu.be/cn43yPublisherFree ReadCube access
ORCID:
AuthorORCID
Gradinaru, Viviana0000-0001-5868-348X
Xiao, Cheng0000-0001-9649-7450
Additional Information:© The Author(s), under exclusive licence to CPS and SIMM 2021. Received 24 February 2021; Accepted 06 June 2021; Published 09 July 2021. 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). Author Contributions: 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. The authors declare no competing interests.
Group:Heritage Medical Research Institute
Funders:
Funding AgencyGrant Number
NIH1R01AG047664-01
NIH1U01NS090577
Heritage Medical Research InstituteUNSPECIFIED
Michael J. Fox Foundation11345
Alfred P. Sloan FoundationUNSPECIFIED
Human Frontier Science ProgramUNSPECIFIED
Xuzhou Medical UniversityUNSPECIFIED
National Natural Science Foundation of China81870891
National Natural Science Foundation of China82071231
National Natural Science Foundation of China81701100
National Natural Science Foundation of China81971038
Jiangsu Higher Education Institutions of China18KJA320009
Colvin FoundationUNSPECIFIED
Brain and Behavior Research FoundationUNSPECIFIED
Postgraduate Innovation Program in Jiangsu ProvinceKYCX20_2474
Postgraduate Innovation Program in Jiangsu ProvinceKYCX20_2478
Subject Keywords:aging; substantia nigra pars compacta; dopaminergic neurons; dopamine sensor; locomotion; coordination; rodent
DOI:10.1038/s41401-021-00713-5
Record Number:CaltechAUTHORS:20210709-224144084
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210709-224144084
Official Citation: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 (2021). https://doi.org/10.1038/s41401-021-00713-5
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109771
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 Jul 2021 23:01
Last Modified:09 Jul 2021 23:01

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