Targeting thalamic circuits rescues motor and mood deficits in PD mice
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nihms-1829821.pdf
Description
Accepted version
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7.03 MB
Format
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Author(s)
Zhang, Ying
Roy, Dheeraj S
Zhu, Yi
Chen, Yefei
Aida, Tomomi
Hou, Yuanyuan
Shen, Chenjie
Lea, Nicholas E
Schroeder, Margaret E
Skaggs, Keith M
Date Issued
2022
Journal
Nature
Publisher
Springer Science and Business Media LLC
Citation
Zhang, Ying, Roy, Dheeraj S, Zhu, Yi, Chen, Yefei, Aida, Tomomi et al. 2022. "Targeting thalamic circuits rescues motor and mood deficits in PD mice." Nature, 607 (7918).
Version
Author's final manuscript
Abstract
Although bradykinesia, tremor and rigidity are the hallmark motor defects in patients with Parkinson's disease (PD), patients also experience motor learning impairments and non-motor symptoms such as depression1. The neural circuit basis for these different symptoms of PD are not well understood. Although current treatments are effective for locomotion deficits in PD2,3, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking4-6. Here we found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN) and nucleus accumbens (NAc). Whereas PF→CPu and PF→STN circuits are critical for locomotion and motor learning, respectively, inhibition of the PF→NAc circuit induced a depression-like state. Whereas chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation (LTP) at PF→STN synapses restored motor learning behaviour in an acute mouse model of PD. Furthermore, activation of NAc-projecting PF neurons rescued depression-like phenotypes. Further, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1038/S41586-022-04806-X
