Divergent pallidal pathways underlying distinct Parkinsonian behavioral deficits

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...

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Published in:	Nature neuroscience Vol. 24; no. 4; pp. 504 - 515
Main Authors:	Lilascharoen, Varoth, Wang, Eric Hou-Jen, Do, Nam, Pate, Stefan Carl, Tran, Amanda Ngoc, Yoon, Christopher Dabin, Choi, Jun-Hyeok, Wang, Xiao-Yun, Pribiag, Horia, Park, Young-Gyun, Chung, Kwanghun, Lim, Byung Kook
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-04-2021 Nature Publishing Group
Subjects:	14/10 14/19 14/32 42/35 42/44 631/378/1689/1718 631/378/3920 9/74 Animal Genetics and Genomics Animals Basal ganglia Behavior Behavioral Sciences Biological Techniques Biomedical and Life Sciences Biomedicine Causes of Central nervous system diseases Circuits Cognition disorders Cognitive ability Complications and side effects Development and progression Divergence Female Functional morphology Gait Disorders, Neurologic - physiopathology Ganglia Globus pallidus Globus Pallidus - physiopathology Health aspects Learning Locomotion Male Mice Mice, Inbred C57BL Mice, Transgenic Motor task performance Movement disorders Neural circuitry Neural Pathways - physiopathology Neurobiology Neurodegenerative diseases Neurological research Neurons Neurons - physiology Neurosciences Parafascicular nucleus Parkinson's disease Parkinsonian Disorders - physiopathology Parvalbumin Parvalbumins Physiological aspects Populations Psychomotor disorders Reversal learning Reversal Learning - physiology Substantia nigra Substantia nigra pars reticulata Thalamus United States
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Summary:	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. The authors define two functionally distinct external globus pallidus basal ganglia pathways and their differential contributions to motor and cognitive Parkinsonian deficits in mice.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 V.L. and B.K.L. conceived and designed the study. V.L. performed all electrophysiological recordings. V.L., E.H.W., S.C.P. and A.N.T. performed stereotaxic surgery. V.L., C.D.Y. and E.H.W. performed behavioral experiments. V.L., S.C.P., A.N.T. and X.-Y.W. designed and generated viruses. V.L., J.H.C., N.D., S.C.P. and A.N.T. performed histology and immunohistochemistry. E.H.W. constructed the fiber photometry recording. V.L., S.C.P. and Y.-G.P. performed SHIELD-MAP tissue clearing and light-sheet imaging. Y.-G.P. and K.C. provided resources for SHIELD-MAP. H.P. assisted with the operant behavior experiment and in situ hybridization. V.L., E.H.W. and B.K.L. analyzed the data and interpreted the results. V.L., E.H.W. and B.K.L. wrote the manuscript with contributions from S.C.P. and A.N.T. Author contributions
ISSN:	1097-6256 1546-1726
DOI:	10.1038/s41593-021-00810-y