Targeting thalamic circuits rescues motor and mood deficits in PD mice

Article

关键词: LONG-TERM POTENTIATION;    NICOTINIC ACETYLCHOLINE-RECEPTORS;    SUBTHALAMIC NUCLEUS;    NITRIC-OXIDE;    RAT;    ACTIVATION;    AGONIST;    NEURONS;    PROJECTIONS;    RESPONSES;   

DOI  :  10.1038/s41586-022-04806-x

来源: SCIE

【 摘 要 】

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 depression(1). 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 lacking(4-6). 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.

【 授权许可】

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