The organism's behaviors are usually organized as action sequences. Sequence learning and execution serve as a wide range of abilities for the organism's survival and reproduction, from predating, mating to communicating. The basal ganglia have been suggested to be critically involved in learning and performance of action sequences. However, the molecular and circuit mechanisms underlying these processes remain largely uncovered. The current theory about basal ganglia function suggests that there are two major neural pathways, the striatonigral (direct) vs. striatopallidal (indirect) pathway, that workin an antagonistic manner to facilitate and inhibit movements respectively. Although this working hypothesis has been applied to basal ganglia function and related diseases for many years, this classic model has not been directly evaluated through experiments and thus it remains unclear if it's correct. The present project will systemically investigate the physiology and function of te striatonigral vs. striatopallidal subcircuit during learning and execution of action sequences. A combination of different techniques including operant conditioning, behavioral microstructure analysis, in vivo electrophysiology, genetic and optogenetic tools will be utilized to dissect the basal ganglia subcircuits in behaving mice. A novel action sequence training paradigm will be developed in mice and in vivo multiple-electrode neuronal recording will be performed during the performance of the task. Based on the analysis of behavioral microstructure, the sequence-related neuronal activity in the different nuclei of basal ganglia circuits will be established and compared. Cell types will be identified in vivo through optogenetic activation, followed by optogenetic manipulation experiments to define the cell-type and pathway- specific function of the striatonigral vs. striatopallidal subcircuit in sequence behavior. Together the project aims to physiologically and functionally revisit the classic working model of basal ganglia pathways.

Public Health Relevance

Basal ganglia dysfunction contributes to many neurological and psychiatric disorders from Parkinson's and Huntington's diseases to Obsessive-compulsive disorder. We are studying the physiology and function of direct vs. indirect pathway, whose imbalance is believed to be the major cause of many symptoms in these diseases. A detailed understanding of the functional organization of these two pathways will lead us to much more efficient interventions to treat and prevent these diseases in human.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Chen, Daofen
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Salk Institute for Biological Studies
La Jolla
United States
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