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DELINEATING CELL-SPECIFIC OUTPUT PATHWAYS OF THE GPe THAT SUPPORT LONG-LASTING BEHAVIORAL RECOVERY IN DOPAMINE DEPLETED MICE

描绘支持多巴胺耗尽小鼠长期行为恢复的 GPe 细胞特异性输出途径

基本信息

批准号：
10317096
负责人：
Aryn Hilary Gittis
金额：
$ 38.81万
依托单位：
CARNEGIE-MELLON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317096
关键词：
Address Affect American Anatomy Anxiety Axon BRAIN initiative Basal Ganglia Behavior Behavioral Brain Cell Nucleus Cell physiology Cells Complement Corpus striatum structure Coupled Data Diffuse Disease Dopamine Electrophysiology (science)Environment Food Functional disorder Funding Genetic Globus Pallidus Goals Heterogeneity Homeobox Hour Intervention Knowledge Lead Location Maps Mediating Methodology Modeling Motor Movement Mus Nature Neurodegenerative Disorders Neurologic Neurons Opsin Output Parkinson Disease Parvalbumins Pathologic Pathway interactions Pattern Play Population Positioning Attribute Property Recovery Research Personnel Resources Rest Rodent Role Site Social Interaction Structure of subthalamic nucleus Substantia nigra structure Techniques Testing Therapeutic Therapeutic Intervention Transgenic Mice Viral Work base cell type experimental study improved in vivo insight motor disorder motor symptom nervous system disorder neural circuit optogenetics restoration tool treatment strategy

项目摘要

Abstract A major challenge in the treatment of neurological diseases is the elaborate and diffuse nature of neural circuits, where physically proximal neurons are engaged in functionally different pathways. The ability to target neurons based on function, rather than location, is critical to improving treatments for disease. In Parkinson’s disease, improved treatments have been driven by the discovery of cell type diversity in the striatum, providing access to functionally opposing circuits: the direct and indirect pathways. However, with the exception of neuronal diversity in the striatum, all other downstream nuclei in the basal ganglia are depicted as homogeneous relay nuclei, an oversimplification whose limits are increasingly apparent as techniques to study circuit function become more sophisticated. Recently, my lab has pioneered the use of transgenic mouse lines to subdivide neurons in the external globus pallidus (GPe) into subpopulations that differ in anatomy and electrophysiological properties. Leveraging tools to optogenetically manipulate these genetic subpopulations, we are now in position to discover their contributions to behavior. In preliminary studies, we found that optogenetic interventions targeted to particular subpopulations in the GPe (but not global stimulation of the entire nucleus) could restore motor function in dopamine depleted mice and the effects persisted for hours after stimulation. This finding challenges long-standing models of circuit organization in the basal ganglia and has relevance for PD, where current interventions provide only transient relief of motor symptoms that rapidly return once stimulation stops. Experiments in this proposal will identify which neuronal subpopulations in the GPe are required to induce long-lasting motor rescue (Aim 1) and will elucidate the pathways through which they mediate their effects (Aim 2). Aim 1, will use optogenetics and in vivo recordings to assess the impact of modulating genetically-defined neuronal subpopulations on local circuit dynamics in the GPe and their effects on behavior. Specifically, we will test the hypothesis that recovered movements following optogenetic stimulation are goal-directed and restore the ability of mice to seek out food, social interactions, and avoid anxiety-provoking environments. In Aim 2, we will use in vivo recordings, coupled with viral-assisted circuit mapping, to elucidate the pathways through which neuronal subpopulations in the GPe exert their prokinetic effects on movement. Our preliminary data suggest that therapeutic interventions share a common mechanism of reversing pathological firing patterns in the substantia nigra reticulata (SNr), the primary basal ganglia output nucleus in rodents. Our proposed experiments will determine whether this effect is mediated by direct projections of GPe neurons to the SNr, or whether it is mediated through a disynaptic pathway involving the subthalamic nucleus (STN). Combined, results from these studies will elucidate the pathways and circuit mechanisms responsible for long-lasting motor rescue in dopamine depleted mice and will revise long-standing models of indirect pathway dysfunction in disease.

文摘