Regulation of inhibitory interneuron development

抑制性中间神经元发育的调节

基本信息

批准号：
9762394
负责人：
Janghoo Lim
金额：
$ 25.13万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762394
关键词：
Adult Affect Anatomy Animal Model Behavioral Biochemical Biological Assay Biological Process Brain Brain Diseases Cell Count Cell Proliferation Complex Corpus striatum structure Data Defect Development Embryo Embryonic Development Equilibrium Foundations Functional disorder Future Ganglia Generations Goals Histologic Homologous Gene Human Impairment Interneuron function Interneurons Knockout Mice Knowledge Lateral Lead Link Maintenance Medial Mental Depression Mental disorders Molecular Molecular Analysis Molecular and Cellular Biology Mus Neurodevelopmental Disorder Neurologic Neurons Output Pathogenesis Pathway interactions Pattern Play Process Production Prosencephalon Protein-Serine-Threonine Kinases Regulation Regulatory Pathway Research Resolution Role Schizophrenia Signal Pathway Stem cells Testing Tissues Treatment Efficacy autism spectrum disorder base cell growth effective therapy excitatory neuron improved in vivo inhibitory neuron insight nemo-like kinase nerve stem cell neural circuit neurodevelopment neurogenesis neuron development neuropsychiatric disorder neuropsychiatry neuroregulation novel recombinase-mediated cassette exchange subventricular zone

项目摘要

The human brain consists of over one hundred billion neurons assembled into functional neural circuits, which underlie all sophisticated brain functions. A precise balance between neuronal excitation and inhibition is required for proper brain function, and the imbalance between them leads to various types of behavioral and neurological problems including many complex brain disorders, such as schizophrenia, depression, and autism. Regulatory mechanisms for excitatory and inhibitory neuron formation have been studied in great detail, but those mechanisms regulating inhibitory interneurons are still being elucidated. The overarching goal of this project is to better understand the regulatory pathways underlying inhibitory interneuron formation with the hope that such insight will lead to the better understanding of complex brain disorders and the development of effective therapeutics. In order to reach this goal, we began by identifying factors that could potentially affect the development of the embryonic ganglionic eminences (GE), a ventral forebrain region where inhibitory interneurons are born. We rationalized that such factors should be expressed in the GE and regulate signaling pathways essential for controlling neurogenesis. Our initial studies reveal that Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, satisfies these criteria. We have found that Nlk (mouse homologue of NLK) is specifically expressed in different regions of the GE, and loss of Nlk in mice causes a dramatic increase in the proliferation of neural progenitor cells and impairment of their differentiation into mature inhibitory interneurons. Based on these preliminary studies, we hypothesize that Nlk plays a fundamental role in the development of inhibitory interneurons. To investigate this idea, we propose the following two major aims. In Aim 1, we will determine the role of Nlk in the control of neural progenitor cell proliferation in the mouse GE. We will investigate specifically when, and how, Nlk influences progenitor cell number in specific regions of the GE. In Aim 2, we will examine if Nlk is required for the proper differentiation and maintenance of specific subtypes of inhibitory interneurons in the cortex and striatum during embryonic and adult stages. We believe that the knowledge gained from the studies proposed in this application will fundamentally advance our understanding of the regulatory mechanisms of normal inhibitory interneuron formation, and thus provide insights into the relevance of this important process to understanding the pathogenesis of complex brain disorders.

人类大脑由超过 1000 亿个神经元组成，这些神经元组装成功能性神经回路，神经兴奋和抑制之间的精确平衡是所有复杂大脑功能的基础。大脑正常功能所必需的，而它们之间的不平衡会导致各种类型的行为和行为神经系统问题，包括许多复杂的脑部疾病，例如精神分裂症、抑郁症和自闭症的兴奋性和抑制性神经元形成的调节机制已得到广泛研究。细节，但那些调节抑制性中间神经元的机制仍在阐明中。该项目的目的是更好地了解抑制性中间神经元形成的调控途径希望这种见解能够更好地理解复杂的大脑疾病和发展为了实现这一目标，我们通过识别可能影响的因素来实现素食。胚胎神经节隆起（GE）的发育，这是一个腹侧前脑区域，其中抑制我们认为这些因子应该在 GE 中表达并调节信号传导。我们的初步研究表明，Nemo 样激酶 (NLK) 是一种控制神经发生所必需的途径。进化上保守的丝氨酸/苏氨酸激酶，满足这些标准，我们发现 Nlk（小鼠。 NLK 的同源物）在 GE 的不同区域特异性表达，小鼠中 Nlk 的缺失会导致神经祖细胞增殖急剧增加，并损害其分化为神经祖细胞的能力。基于这些初步研究，我们利用了 Nlk 的作用。为了研究这个想法，我们提出了抑制性中间神经元发育中的基本作用。在目标 1 中，我们将确定 Nlk 在神经祖细胞控制中的作用。小鼠 GE 中的增殖。我们将具体研究 Nlk 何时以及如何影响祖细胞。在目标 2 中，我们将检查 Nlk 是否是胚胎和成年阶段皮质和纹状体中抑制性中间神经元特定亚型的必要条件。中提出的研究该应用将从根本上增进我们对正常抑制性中间神经元形成的调节机制的理解，从而深入了解这一重要过程与理解复杂脑部疾病发病机制的相关性。