Development and Function of 5HT3aR-Expressing Cortical GABAergic Interneurons

表达 5HT3aR 的皮质 GABA 能中间神经元的发育和功能

基本信息

批准号：
10550163
负责人：
Bernardo Rudy
金额：
$ 149.32万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10550163
关键词：
Acceleration Adult Advisory Committees Anxiety Disorders Architecture Auditory Auditory Perception Auditory area Behavior Behavioral Brain Cells Cerebral cortex Collaborations Communication Coupled Cues Development Disease Ensure Epilepsy Family Fostering Funding Generations Genetic Genetic Techniques Genomics Glutamates Goals Human Resources Interneuron function Interneurons Leadership Learning Mediating Mentors Molecular Mus Neocortex Neurons Output Perception Population Positioning Attribute Prevalence Process Publications Reagent Recording of previous events Regulation Research Research Personnel Research Project Grants Resource Sharing Role Schedule Schizophrenia Sensory Signal Transduction Somatosensory Cortex Structure Time Transgenic Mice Transgenic Organisms Viral Vector Virus Work auditory processing autism spectrum disorder awake cell type cholinergic cognitive function data sharing excitatory neuron human disease information processing innovation meetings neocortical neuroregulation novel postnatal postnatal development programs sensory stimulus signal processing success synergism vector web site

Acceleration Adult Advisory Committees Anxiety Disorders Architecture Auditory Auditory Perception Auditory area Behavior Behavioral Brain Cells Cerebral cortex Collaborations Communication Coupled Cues Development Disease Ensure Epilepsy Family Fostering Funding Generations Genetic Genetic Techniques Genomics Glutamates Goals Human Resources Interneuron function Interneurons Leadership Learning Mediating Mentors Molecular Mus Neocortex Neurons Output Perception Population Positioning Attribute Prevalence Process Publications Reagent Recording of previous events Regulation Research Research Personnel Research Project Grants Resource Sharing Role Schedule Schizophrenia Sensory Signal Transduction Somatosensory Cortex Structure Time Transgenic Mice Transgenic Organisms Viral Vector Virus Work auditory processing autism spectrum disorder awake cell type cholinergic cognitive function data sharing excitatory neuron human disease information processing innovation meetings neocortical neuroregulation novel postnatal postnatal development programs sensory stimulus signal processing success synergism vector web site

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项目摘要

The functions of the cerebral cortex rely upon highly interconnected and dynamic microcircuits composed of two types of neurons: glutamatergic excitatory neurons that propagate signals through the various stages of processing, and GABAergic interneurons that regulate this information flow and sculpt cortical circuit dynamics. Signal processing in the cortex critically depends on the activity of specific interneuron subtypes. While the PV and SST interneuron populations have been well studied, this Program Project is focused on the 5HT3aR family of GABAergic interneurons whose prevalence, breadth and contributions to cortical function have been previously underestimated. 5HT3aR interneurons represent about 30% of the total interneuron population in the neocortex and are concentrated within the superficial associative layers, where they comprise the majority of interneurons. During development, 5HT3aR interneurons originate from the caudal ganglionic eminence (CGE), become positioned within the cortex late during the first postnatal week and contribute to both the function and plasticity of the cortex thereafter. Here we will investigate the roles of cortical 5HT3aR interneurons during development, as well as their function and plasticity within the somatosensory and auditory cortices. The Program Project will consist of three interrelated research projects and two cores (an Administrative Core and a Molecular and Transgenic Core) to support the work of the three projects. A focus of all three projects will be neocortical layer 1 (L1), the main cortical layer receiving contextual information. All neurons in L1 are interneurons of the 5HT3aR family. Project 1 (by Gordon Fishell), will elucidate the mechanisms that determine the development of the 5HT3aR interneuron population. It will investigate the genetic program that governs the differentiation of 5HT3aR interneuron precursors, their connectivity throughout development and the role of activity (with a particular focus on L-type Ca++ signaling) on their maturation in the cortex. Project 2 (by Bernardo Rudy) will advance our understanding of the role of 5HT3aR interneurons in cortical function by focusing on the interneuron subtypes that we have identified in L1 during the previous funding period. Specifically, Project 2 will investigate their input and output connectivity and their contributions to context-dependent sensory processing. Project 3 (by Robert Froemke) will examine the contributions of the same populations to both auditory processing and plasticity. This project will examine the role of L1 5HT3aR interneurons in awake behaving mice in an auditory recognition task and determine the requirement of cholinergic neuromodulation for this process. Together these projects will provide a comprehensive assessment of the 5HT3aR populations’ development, plasticity and function.

大脑皮质的功能依赖于由两种类型的神经元组成的高度相互联系和动态的微电路：谷氨酸能兴奋的神经元通过处理的各个阶段传播信号的神经元，以及gabaergic Interneurons，这些神经元和gabaergic Interneurons调节了这些信息流动和雕刻的皮质电路动态。皮质中的信号处理严重取决于特定的内神经元亚型的活性。尽管PV和SST中间神经元的种群已经进行了很好的研究，但该程序项目却集中在5HT3AR的GABA能中间神经元家族上，其患病率，广度和对皮质功能的贡献先前已被低估了。 5HT3AR中间神经元约占新皮层中总神经元种群的30％，并集中在浅表联想层中，其中大部分是中间神经元。在开发过程中，5HT3AR中间神经元源自尾神经节杰出（CGE），在产后的第一个周后期位于皮质中，并在此后有助于皮质的功能和可塑性。在这里，我们将研究皮质5HT3AR在发育过程中的作用，以及它们在体感和听觉皮层中的功能和可塑性。该计划项目将由三个相互关联的研究项目和两个核心（一个行政核心和一个分子和转基因核心）组成，以支持这三个项目的工作。这三个项目的重点将是新皮层第1层（L1），这是接收上下文信息的主要皮层层。 L1中的所有神经元都是5HT3AR家族的中间神经元。项目1（戈登·费舍尔（Gordon Fishell））将阐明决定5HT3AR间神经元人口发展的机制。它将研究控制5HT3AR间神经元前体分化的遗传程序，通过发育的连通性以及活动的作用（特别关注L型Ca ++信号传导）在皮质中成熟。项目2（由伯纳多·鲁迪（Bernardo Rudy）撰写）将通过关注我们在上一个资金期间在L1中确定的中间神经元亚型来提高我们对5HT3AR中间神经元在皮质功能中的作用的理解。具体而言，项目2将研究其输入和输出连接及其对上下文相关的感觉处理的贡献。项目3（由罗伯特·弗洛姆克（Robert Fromek）撰写）将研究同一人群对听觉处理和可塑性的贡献。该项目将检查L1 5HT3AR中间神经元在听觉识别任务中醒着的行为小鼠中的作用，并确定胆碱能神经调节对此过程的需求。这些项目将共同对5HT3AR人群的发展，可塑性和功能进行全面评估。