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Defining cell types that control action selection and execution

定义控制动作选择和执行的单元类型

基本信息

批准号：
10406120
负责人：
Evan Harriman Feinberg
金额：
$ 3.51万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406120
关键词：
Address Anatomy Animals Axon Bar Codes Basal Ganglia Behavior Behavior Control Behavior monitoring Behavioral Brain Calcium Cell Nucleus Data Etiology Future Gene Expression Genetic Genetic Identity Genetic Transcription Globus Pallidus Huntington Disease Image Impairment Ion Channel Knowledge Label Lateral Lead Logic Mediating Modeling Modernization Molecular Monitor Morphology Neurons Neurosciences Neurotransmitter Receptor Output Parkinson Disease Pathway interactions Performance Pharmacology Phase Physiological Portraits Property RNA Reporting Route Schizophrenia Shapes Signal Transduction Speed Structure Substantia nigra structure Testing Textbooks Translating addiction base cell type inhibitory neuron molecular marker novel novel strategies parent grant predictive modeling receptor expression relating to nervous system selective expression single cell sequencing single-cell RNA sequencing superior colliculus Corpora quadrigemina tool two-photon

项目摘要

PROJECT SUMMARY/ABSTRACT A fundamental task of the brain is to choose what to do next, and an impaired ability to select appropriate behaviors and repress inappropriate actions is thought to underlie conditions including schizophrenia, addiction, and Huntington's disease. How the brain weighs available actions to choose and execute the most adaptive is not understood. In the canonical model, effector structures such as the superior colliculus (SC) are constantly poised to generate behaviors, but are repressed by tonically active GABAergic neurons of the basal ganglia (BG) output nuclei substantia nigra pars reticulata (SNr) and internal globus pallidus; before an action, the specific subset of BG output neurons inhibiting that action pause firing to “release” its effector pathway. However, several studies have revealed that SNr harbors multiple GABAergic inhibitory cell types of which some are only phasically active, and both tonic and phasic inhibitory SNr neurons can converge on the same target neurons in structures such as SC. These cell types are intermingled in SNr, which has hindered efforts to apply the genetic tools of modern neuroscience to decipher how their convergent phasic and tonic inhibitory signals influence downstream neural processing to control behavioral choice and execution. To surmount this obstacle, my lab has developed approaches to selectively express genetic tools in either phasic or tonic SNr neurons. Here I propose to apply our approach to reveal how phasic and tonic inhibitory BG subtypes coordinate behavior. First, we will test the hypothesis that phasic SNr neurons encode both behavioral choice and execution by recording their activity during behavior. Second, we will test the hypothesis that phasic inhibitory neurons shape both choice and execution of the chosen behavior using targeted manipulations. Third, to understand the transcriptional basis of physiologic differences between these phasic and tonic types, we will define the genetic identities of both using a novel barcoding approach in single-cell sequencing. Collectively, these studies will provide a comprehensive portrait of how phasic and tonic inhibitory BG cell types coordinate behavioral choice and execution. The findings from these studies may help us to understand the etiology of and lead to new treatments for conditions including addiction, schizophrenia, Parkinson's, and Huntington's disease.

项目总结/文摘