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

• 批准号: 9326354
• 负责人: Bernardo Rudy
• 金额: $ 136.55万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2019-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326354
• 关键词: Acetylcholine; Affective; Alleles; Animals; Anxiety; Anxiety Disorders; Attention; Autistic Disorder; Axon; Behavioral; Brain; Breeding; Cell physiology; Cells; Cerebral cortex; Classification; Collaborations; Communities; Complement; Complex; Development; Disease; Elements; Ensure; Epilepsy; Etiology; Foundations; Functional disorder; Funding; Ganglia; Genes; Genetic; Genotype; Glutamates; Goals; Grant; Human Resources; Injection of therapeutic agent; Injury; Interneurons; Knowledge; Label; Laboratories; Learning; Location; Logistics; Medical; Memory; Mental disorders; Microarray Analysis; Molecular; Mood Disorders; Motor Activity; Mus; Neurons; Neurosciences; Physiological; Population; Preparation; Prevalence; Process; Publications; Pyramidal Cells; Reagent; Reporting; Research Personnel; Research Project Grants; Resources; Role; Schizophrenia; Sensory; Serotonin; Signal Transduction; Somatosensory Cortex; Source; Structure; Synapses; Technology; Testing; Transgenic Mice; Transgenic Organisms; Viral Vector; Work; aged; blind; cholinergic; excitatory neuron; expectation; experience; experimental study; genome-wide analysis; hippocampal pyramidal neuron; improved; in vivo; information processing; insight; intersectionality; meetings; motor learning; neocortical; nervous system disorder; organizational structure; patch clamp; programs; receptor; recombinase; repaired; response; serotonin receptor; signal processing; success; synergism; tool; two-photon

The functions of the cerebral cortex depend on highly interconnected and dynamic microcircuits composed of two types of neurons, glutamatergic excitatory neurons that propagate the signals through the various stages of processing and GABAergic interneurons (INs) that regulate this information flow and sculpt cortical circuits. Signal processing in the cortex depends critically on the activity of these interneurons. This Program Project is focused on the characterization of a population of GABAergic INs whose size and breadth have been previously underestimated. These INs express the ionotropic serotonin receptor 5HT3a and largely originate during development from the caudal ganglionic eminence (CGE). Preliminary studies show that 5HT3aR INs represent about 30% of the total IN population in somatosensory cortex, and that they are concentrated in superficial layers, where they represent the largest IN population. This suggests that they are important in the processing of information in the associative layers of cortex. 5HT3aR INs are heterogeneous, but they are uniformly and potently modulated by serotonin and acetylcholine via ionotropic receptors. The Program Project will investigate the roles of cortical 5HT3aR INs on the development and function of the cerebral cortex. The PPG will consist of three research projects and two cores (an Administrative Core and a Molecular and Transgenic Core) to support the work of the three projects. Project I (by Gordon Fishell), will elucidate the mechanisms that determine the development of the 5HT3aR INs population. It will investigate the genetic program that governs the differentiation of 5HT3aR INs precursors, their connectivity throughout development and the role of activity on their maturation in the cortex. Project II (by Bernardo Rudy) will advance our understanding of the role of 5HT3aR INs in cortical function. Specifically, it will test the hypothesis that they are important in context-dependent sensory processing. It will investigate the functional connectivity of 5HT3aR INs, use photostimulation of channelrhodopsin-expressing cholinergic and serotonergic axons to investigate their modulation by these subcortical inputs and two photon targeted recordings in vivo to investigate the activity of 5HT3aR INs during different behavioral states and their response to motor activity and sensory stimulation. Project III (by Wen-Biao Gan) will investigate the location, structure and plasticity of the synapses 5HT3aR INs make on layer V pyramidal neurons and the role of these INs in regulating the activity and structural dynamics of pyramidal cells during learning and memory formation.

脑皮质的功能取决于由两种类型的神经元组成的高度相互连接和动态的微电路，谷氨酸能兴奋性神经元通过加工和GABAergic Interneurons（INS）传播信号，这些神经元传播信号，这些神经元（INS）调节了这些信息，并调节此信息流动和雕刻的Cortalical cocultical cipputtical循环。皮层中的信号处理取决于这些中间神经元的活性。该计划项目的重点是对以前低估的大小和广度的GABA能INS的表征。这些INS表达了离子性羟色胺受体5HT3A，并且在很大程度上起源于尾神经节隆起（CGE）的发育。初步研究表明，5HT3AR INS约占体感皮质总人口总数的30％，并且它们集中在浅层层中，它们代表人口最大。这表明它们在皮质关联层中的信息处理中很重要。 5HT3AR INS是异质的，但通过离子受体统一而有效地调节了5-羟色胺和乙酰胆碱。该计划项目将研究皮质5HT3AR INS在大脑皮层的发育和功能上的作用。 PPG将由三个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。项目I（由戈登·费舍尔（Gordon Fishell））将阐明决定5HT3AR INS人群发展的机制。它将调查控制5HT3AR前体分化的遗传程序，它们在整个发育过程中的连通性以及活动对皮质成熟的作用。项目II（伯纳多·鲁迪（Bernardo Rudy））将促进我们对5HT3AR INS在皮质功能中的作用的理解。具体而言，它将检验以下假设：它们在上下文依赖于情境的感觉处理中很重要。它将研究5HT3AR INS的功能连接性，使用表达胆碱能和血清素能轴突的光刺激，以研究这些皮层下输入和两个光子靶向记录的调节，以研究在不同的行为状态和对运动刺激的反应及其响应型和感觉刺激性和感官刺激性和感官刺激性和感官刺激性和感官刺激性和感觉刺激的活性。 III项目（由Wen-Biao Gan）将研究突触的位置，结构和可塑性5HT3AR INS在V层锥体神经元上进行，以及这些INS在调节学习和记忆形成过程中锥体细胞的活性和结构动力学中的作用。