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

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...

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Published in:Acta pharmacologica Sinica 2022-04, Vol.43 (4), p.862-875
Main Authors: Fan, Jiang-peng, Geng, Hui-zhen, Ji, Ya-wei, Jia, Tao, Treweek, Jennifer B., Li, An-an, Zhou, Chun-yi, Gradinaru, Viviana, Xiao, Cheng
Format: Article
Language:English
Subjects:
Age
Aging
Biomedical and Life Sciences
Biomedicine
Caudate-putamen
Corpus Striatum
Depolarization
Dopamine
Dopamine receptors
Dopamine transporter
Dopaminergic Neurons
Humans
Immunology
Internal Medicine
Locomotion
Medical Microbiology
Motor task performance
Neostriatum
Neurons
Pars Compacta
Pharmacology/Toxicology
Phenotype
Phenotypes
Substantia nigra
Substantia Nigra - physiology
Vaccine
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Summary: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.
ISSN:1671-4083
1745-7254
DOI:10.1038/s41401-021-00713-5