Divergent pallidal pathways underlying distinct Parkinsonian behavioral deficits

Varoth Lilascharoen; Eric Hou Jen Wang; Nam Do; Stefan Carl Pate; Amanda Ngoc Tran; Christopher Dabin Yoon; Jun Hyeok Choi; Xiao Yun Wang; Horia Pribiag; Young Gyun Park; Kwanghun Chung; Byung Kook Lim

doi:10.1038/s41593-021-00810-y

Divergent pallidal pathways underlying distinct Parkinsonian behavioral deficits

Varoth Lilascharoen, Eric Hou Jen Wang, Nam Do, Stefan Carl Pate, Amanda Ngoc Tran, Christopher Dabin Yoon, Jun Hyeok Choi, Xiao Yun Wang, Horia Pribiag, Young Gyun Park, Kwanghun Chung, Byung Kook Lim

Yonsei Advanced Science Institute

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

Abstract

The basal ganglia regulate a wide range of behaviors, including motor control and cognitive functions, and are profoundly affected in Parkinson’s disease (PD). However, the functional organization of different basal ganglia nuclei has not been fully elucidated at the circuit level. In this study, we investigated the functional roles of distinct parvalbumin-expressing neuronal populations in the external globus pallidus (GPe-PV) and their contributions to different PD-related behaviors. We demonstrate that substantia nigra pars reticulata (SNr)-projecting GPe-PV neurons and parafascicular thalamus (PF)-projecting GPe-PV neurons are associated with locomotion and reversal learning, respectively. In a mouse model of PD, we found that selective manipulation of the SNr-projecting GPe-PV neurons alleviated locomotor deficit, whereas manipulation of the PF-projecting GPe-PV neurons rescued the impaired reversal learning. Our findings establish the behavioral importance of two distinct GPe-PV neuronal populations and, thereby, provide a new framework for understanding the circuit basis of different behavioral deficits in the Parkinsonian state.

Original language	English
Pages (from-to)	504-515
Number of pages	12
Journal	Nature Neuroscience
Volume	24
Issue number	4
DOIs	https://doi.org/10.1038/s41593-021-00810-y
Publication status	Published - 2021 Apr

Bibliographical note

Funding Information:
We thank D. Knowland and C. Santiago for their comments on the manuscript. S. Lilascharoen helped with quantification in Fig. 1 and with illustrations. We thank C. Gremel for essential comments on the reversal learning behavioral experiment. We thank the members of the Lim laboratory for support and discussions. V.L. was supported by the Anandamahidol Foundation Fellowship. This work was supported by grants from the National Institutes of Health (U01NS094342, R01DA049787, R01NS097772, R01MH108594 and U01MH114829).

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

All Science Journal Classification (ASJC) codes

Neuroscience(all)

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title = "Divergent pallidal pathways underlying distinct Parkinsonian behavioral deficits",

abstract = "The basal ganglia regulate a wide range of behaviors, including motor control and cognitive functions, and are profoundly affected in Parkinson{\textquoteright}s disease (PD). However, the functional organization of different basal ganglia nuclei has not been fully elucidated at the circuit level. In this study, we investigated the functional roles of distinct parvalbumin-expressing neuronal populations in the external globus pallidus (GPe-PV) and their contributions to different PD-related behaviors. We demonstrate that substantia nigra pars reticulata (SNr)-projecting GPe-PV neurons and parafascicular thalamus (PF)-projecting GPe-PV neurons are associated with locomotion and reversal learning, respectively. In a mouse model of PD, we found that selective manipulation of the SNr-projecting GPe-PV neurons alleviated locomotor deficit, whereas manipulation of the PF-projecting GPe-PV neurons rescued the impaired reversal learning. Our findings establish the behavioral importance of two distinct GPe-PV neuronal populations and, thereby, provide a new framework for understanding the circuit basis of different behavioral deficits in the Parkinsonian state.",

author = "Varoth Lilascharoen and Wang, {Eric Hou Jen} and Nam Do and Pate, {Stefan Carl} and Tran, {Amanda Ngoc} and Yoon, {Christopher Dabin} and Choi, {Jun Hyeok} and Wang, {Xiao Yun} and Horia Pribiag and Park, {Young Gyun} and Kwanghun Chung and Lim, {Byung Kook}",

note = "Funding Information: We thank D. Knowland and C. Santiago for their comments on the manuscript. S. Lilascharoen helped with quantification in Fig. 1 and with illustrations. We thank C. Gremel for essential comments on the reversal learning behavioral experiment. We thank the members of the Lim laboratory for support and discussions. V.L. was supported by the Anandamahidol Foundation Fellowship. This work was supported by grants from the National Institutes of Health (U01NS094342, R01DA049787, R01NS097772, R01MH108594 and U01MH114829). Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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AU - Choi, Jun Hyeok

AU - Wang, Xiao Yun

AU - Pribiag, Horia

AU - Park, Young Gyun

AU - Chung, Kwanghun

AU - Lim, Byung Kook

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N2 - The basal ganglia regulate a wide range of behaviors, including motor control and cognitive functions, and are profoundly affected in Parkinson’s disease (PD). However, the functional organization of different basal ganglia nuclei has not been fully elucidated at the circuit level. In this study, we investigated the functional roles of distinct parvalbumin-expressing neuronal populations in the external globus pallidus (GPe-PV) and their contributions to different PD-related behaviors. We demonstrate that substantia nigra pars reticulata (SNr)-projecting GPe-PV neurons and parafascicular thalamus (PF)-projecting GPe-PV neurons are associated with locomotion and reversal learning, respectively. In a mouse model of PD, we found that selective manipulation of the SNr-projecting GPe-PV neurons alleviated locomotor deficit, whereas manipulation of the PF-projecting GPe-PV neurons rescued the impaired reversal learning. Our findings establish the behavioral importance of two distinct GPe-PV neuronal populations and, thereby, provide a new framework for understanding the circuit basis of different behavioral deficits in the Parkinsonian state.

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Divergent pallidal pathways underlying distinct Parkinsonian behavioral deficits

Abstract

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