Activity-Dependent Mechanisms Regulating Synaptic Excitation and Inhibition in Neural Circuits

调节神经回路中突触兴奋和抑制的活动依赖性机制

• 批准号: 10170437
• 负责人: Mingshan Xue
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-16 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170437
• 关键词: Anatomy; Biological Models; Brain; Brain Diseases; Cells; Cerebral cortex; Complex; Coupled; Development; Electrophysiology (science); Etiology; Excitatory Synapse; Frequencies; Functional Imaging; Functional disorder; Goals; Homeostasis; Human; Impairment; Individual; Inhibitory Synapse; Investigation; Knowledge; Long-Term Potentiation; Maintenance; Mental Depression; Mental disorders; Methods; Modification; Molecular; Mus; Muscarinic Acetylcholine Receptor; Neurodevelopmental Disorder; Neurons; Outcome; Parvalbumins; Pharmacology; Physiology; Property; Proteins; Recovery; Regulation; Research; Role; Sensory; Specificity; Stimulus; Synapses; Synaptic plasticity; System; Testing; Time; Vision; Visual; Visual Cortex; Work; flexibility; hippocampal pyramidal neuron; improved; in vivo; insight; inward rectifier potassium channel; nervous system disorder; neural circuit; neuronal patterning; optogenetics; orientation selectivity; overexpression; postsynaptic; preservation; presynaptic; response; spatiotemporal

The ability of the cerebral cortex to perform incredibly complex functions resides in its intricate neural circuits composed of a vast number of neurons. The synaptic interactions among cortical neurons ultimately manifest as the interplay between excitation and inhibition, two opposing forces that work together to orchestrate the spatiotemporal patterns of neuronal activity. Hence, the relationship between excitation and inhibition (E-I relationship) is fundamental to many functional properties of cortical neurons such as the orientation selectivity and contrast response function of visual cortical neurons. The importance of proper E-I relationship is also underscored by the discovery of altered E-I relationship in many neurodevelopmental and psychiatric disorders. However, the regulation of E-I relationship and the impacts of altering this relationship on the functional response properties of cortical neurons remain poorly understood. Thus, the overall goal of this project is to determine how the activity of individual neurons and homeostatic synaptic plasticity regulate cortical excitation, inhibition, and E-I relationship. To this end, we used the developing mouse visual cortex as a model system and developed molecular approaches to selectively reduce the excitability of a small number of layer 2/3 pyramidal neurons in vivo, such that we can determine the cell-autonomous effect of neuronal activity while minimizing the perturbation to the whole circuit. We found that these neurons counteract the activity perturbation by homeostatic changes at a specific subset of excitatory and inhibitory synapses. These results led to the central hypothesis that homeostatic plasticity differentially modifies distinct synaptic inputs of individual cortical neurons to regulate their E-I relationship, thereby maintaining the activity levels and functional response properties. We propose to combine molecular manipulations with optogenetic, physiological, imaging, and anatomical methods to systematically delineate the homeostatic changes at different synapses originating from distinct presynaptic neuronal types (Aim 1), to identify the underlying synaptic mechanisms of input-specific homeostatic plasticity (Aim 2), and to determine the impact of these synaptic changes on the visual response properties of neurons in vivo (Aim 3). The proposed research connects three levels of investigations from synapse to circuit to system. The successful completion of this project will provide insights into the role of homeostatic synaptic plasticity in regulating E-I relationship and functional response properties of cortical neurons. The outcomes will also have an impact on our understanding of how plasticity mechanisms help the brain cope with perturbations in general.

大脑皮层执行令人难以置信的复杂功能的能力在于其复杂的神经回路 由大量神经元组成。皮质神经元之间的突触相互作用最终表现出来 作为激发和抑制之间的相互作用，两个共同努力来编排的对立力量 神经元活性的时空模式。因此，激发与抑制之间的关系（E-I 关系）是皮质神经元的许多功能特性，例如方向选择性 视觉皮质神经元的对比反应函数。适当的E-I关系的重要性也是 在许多神经发育和精神病学中发现改变的E-I关系的强调 疾病。但是，E-I关系的调节以及改变这种关系对 皮质神经元的功能反应特性仍然很了解。因此，总体目标 项目将确定单个神经元和稳态突触可塑性的活性如何调节 皮质激发，抑制和E-I关系。为此，我们将开发的鼠标Visual Cortex用作 模型系统和开发的分子方法，可选择性地降低少量的兴奋性 体内2/3层锥体神经元 在最小化整个电路的扰动的同时，活动。我们发现这些神经元可以抵消 在兴奋性和抑制性突触的特定子集中，通过稳态变化的活性扰动。这些 结果导致了一个中心假设，即体内可塑性差异地修饰了不同的突触输入 单个皮质神经元调节其E-I关系，从而维持活动水平和 功能响应属性。我们建议将分子操作与光遗传学， 生理，成像和解剖方法系统地描述了稳态变化 不同的突触来自不同的突触前神经元类型（AIM 1），以识别基础 输入特异性稳态可塑性的突触机制（AIM 2），并确定这些影响 神经元在体内的视觉响应特性的突触变化（AIM 3）。拟议的研究 连接从突触到电路到系统的三个级别的调查。成功完成 项目将提供有关稳态突触可塑性在调节E-I关系和 皮质神经元的功能反应特性。结果也将对我们的 了解可塑性机制如何帮助大脑应对一般的扰动。