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.

大脑皮层执行极其复杂功能的能力在于其复杂的神经回路 由大量的神经元组成。皮层神经元之间的突触相互作用最终表现出来 作为兴奋和抑制之间的相互作用，两种相反的力量共同协调 神经元活动的时空模式。因此，兴奋和抑制之间的关系（E-I 关系）是皮质神经元许多功能特性的基础，例如方向选择性 和视觉皮层神经元的对比反应功能。正确的 E-I 关系也很重要 许多神经发育和精神疾病中 E-I 关系改变的发现强调了这一点 失调。然而，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知之甚少。因此，本次活动的总体目标是 项目是确定单个神经元的活动和稳态突触可塑性如何调节 皮质兴奋、抑制和 E-I 关系。为此，我们使用正在发育的小鼠视觉皮层作为 模型系统和开发的分子方法来选择性地降低少数人的兴奋性 体内2/3层锥体神经元的细胞自主效应，这样我们就可以确定神经元的细胞自主效应 活动，同时最大限度地减少对整个电路的干扰。我们发现这些神经元抵消了 兴奋性和抑制性突触特定子集的稳态变化引起的活动扰动。这些 结果得出了一个中心假设，即稳态可塑性差异性地改变了突触的不同输入 单个皮层神经元调节其 E-I 关系，从而维持活动水平和 功能反应特性。我们建议将分子操作与光遗传学相结合， 生理学、成像和解剖学方法来系统地描绘体内平衡的变化 源自不同突触前神经元类型的不同突触（目标 1），以识别潜在的 输入特异性稳态可塑性的突触机制（目标 2），并确定这些机制的影响 突触变化对体内神经元视觉反应特性的影响（目标 3）。拟议的研究 连接从突触到电路到系统的三个层次的研究。本次活动的顺利完成 该项目将深入了解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。其结果也会对我们产生影响 了解可塑性机制如何帮助大脑应对一般扰动。