Genetic and physiological dissection of the circuit mechanisms in the striatum

纹状体回路机制的遗传和生理解剖

基本信息

批准号：
8578545
负责人：
Tianyi Mao
金额：
$ 33.69万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8578545
关键词：
Address Algorithms Animal Behavior Area Axon Basal Ganglia Behavior Behavioral Benchmarking Brain Brain imaging Brain region Cell physiology Cells Cognitive Color Corpus striatum structure Cortical Column Data Set Defect Disease Dissection Drug Addiction Electric Stimulation Foundations Functional disorder Future Genetic Image Individual Knowledge Label Lasers Learning Light Maps Measures Mediating Methods Molecular Motor Movement Mus Neurons Obsessive-Compulsive Disorder Output Parkinson Disease Pathology Pathway interactions Pattern Physiological Physiology Play Population Preparation Process Property Research Resolution Role Scanning Slice Sorting - Cell Movement Source Specificity System Techniques Testing Thalamic structure Transgenic Mice Virus Diseases base cell type hippocampal pyramidal neuron infancy information processing innovation neuronal circuitry neuropsychiatry novel optogenetics postsynaptic presynaptic public health relevance segregation

项目摘要

DESCRIPTION (provided by applicant): The basal ganglia play essential roles in behavior, including movement control and learning. The striatum is the primary input station of the basal ganglia where it processes and sorts information from the cortical areas and the thalamus into downstream pathways. Defects in striatal function are responsible for the cognitive and behavioral deficits observed in neuropsychiatric disorders, including Parkinson's disease, obsessive-compulsive disorder, and drug addiction. Great strides have been made toward understanding striatal function at two levels. First, at the behavioral level, much has been learned about the crucial roles of the striatum in action selection and execution. Second, at the single cell level, the molecular and physiological properties of individual striatal neurons as wel as their overall roles in behaviors have been examined extensively. However, our understanding of the circuit mechanisms that bridge striatal behavioral functions and the cellular properties of individual striatal neurons remains in its infancy. The neuronal circuitry in other brain regions i often organized around functional subdivisions (e.g., cortical columns) and cell types (e.g., layer 5A and 5B cortical pyramidal neurons). Although the striatum has been grossly divided into three divisions according to their functions and it is known to consist of at least five major neuronal subtypes, its functional subdivision-dependent and cell-type- specific microcircuits are not fully understood. Herein, we propose to fill this gap by examining the striatal subdivision-dependent and cell-type-specific microcircuits in mice, a genetically tractable system required for unambiguously defining cell types. We will do so by investigating the organization of the thalamostriatal projections, which consist of one of the two major excitatory inputs to the striatum, at both anatomical and functional levels. We will use an innovative combination of anatomical tracing, imaging, genetic, optogenetic, and physiological approaches. We expect that our study will provide a complete functional thalamostriatal wiring diagram and uncover the principles behind how information from the thalamus is segregated into the downstream cell-type-specific and functional subdivision-specific circuits. Our acquired knowledge will synergize with current knowledge regarding the striatum at the levels of behavior and single-neuron properties to advance our understanding of how the striatum functions and how the thalamus contributes to the function of the basal ganglia as a source of upstream input. This knowledge will also pave the way for future studies of striatal function and pathology by providing a benchmark for circuit connectivity under normal conditions.

描述（由申请人提供）：基底神经节在行为中起着重要的作用，包括运动控制和学习。纹状体是基底神经节的主要输入站，在那里它处理并从皮质区域和丘脑分类信息到下游途径。纹状体功能的缺陷负责在神经精神疾病中观察到的认知和行为缺陷，包括帕金森氏病，强迫症和药物成瘾。在两个层面上了解纹状体功能方面已取得了长足的进步。首先，在行为层面上，关于纹状体在动作选择和执行中的关键作用已经有了很多了解。其次，在单细胞水平上，已经广泛研究了单个纹状体神经元作为其总体作用的单个纹状体神经元的分子和生理特性。但是，我们对桥接纹状体行为函数的电路机制和单个纹状体神经元的细胞特性仍然处于起步阶段。我经常在功能细分（例如皮层柱）和细胞类型（例如层，层）围绕其他大脑区域的神经元电路 5A和5B皮质锥体神经元）。尽管纹状体已根据其功能严重分为三个分裂，并且已知它至少由五个主要的神经元亚型组成，但其功能性细分依赖性和细胞类型的特定于特定于特定的微电路尚未完全了解。在本文中，我们建议通过检查小鼠中纹状体细分依赖性和细胞型特异性微电路的填补这一空白，这是一个明确定义细胞类型所需的遗传障碍系统。我们将通过调查丘脑纹状体预测的组织来做到这一点，该预测由解剖和功能水平的两个主要兴奋性输入之一组成。我们将使用解剖学追踪，成像，遗传，光遗传学和生理方法的创新组合。我们预计我们的研究将提供完整的功能性丘脑纹状体接线图，并揭示如何将来自丘脑的信息隔离到下游细胞型特异性和功能性细分特异性电路背后的原理。我们获得的知识将与当前有关行为和单神经元特性水平上纹状体的知识达成协议，以促进我们对纹状体功能的理解以及丘脑如何促进基底神经节作为上游输入来源的功能。这些知识还将通过在正常条件下为电路连接提供基准，为未来的纹状体功能和病理研究铺平道路。