Targeting thalamic circuits rescues motor and mood deficits in PD mice

Ying Zhang (), Dheeraj S. Roy (), Yi Zhu, Yefei Chen, Tomomi Aida, Yuanyuan Hou, Chenjie Shen, Nicholas E. Lea, Margaret E. Schroeder, Keith M. Skaggs, Heather A. Sullivan, Kyle B. Fischer, Edward M. Callaway, Ian R. Wickersham, Ji Dai, Xiao-Ming Li, Zhonghua Lu and Guoping Feng ()
Additional contact information
Ying Zhang: Massachusetts Institute of Technology
Dheeraj S. Roy: Broad Institute of MIT and Harvard
Yi Zhu: Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine
Yefei Chen: The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences
Tomomi Aida: Massachusetts Institute of Technology
Yuanyuan Hou: Massachusetts Institute of Technology
Chenjie Shen: Massachusetts Institute of Technology
Nicholas E. Lea: Massachusetts Institute of Technology
Margaret E. Schroeder: Massachusetts Institute of Technology
Keith M. Skaggs: Massachusetts Institute of Technology
Heather A. Sullivan: Massachusetts Institute of Technology
Kyle B. Fischer: Salk Institute for Biological Studies
Edward M. Callaway: Salk Institute for Biological Studies
Ian R. Wickersham: Massachusetts Institute of Technology
Ji Dai: The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences
Xiao-Ming Li: Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine
Zhonghua Lu: The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences
Guoping Feng: Massachusetts Institute of Technology

Nature, 2022, vol. 607, issue 7918, 321-329

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04806-x

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