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

大脑皮层执行难以置信的复杂功能的能力存在于其复杂的神经回路中 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为 作为兴奋和抑制之间的相互作用，两种相反的力量一起工作，以协调 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）对于皮层神经元的许多功能特性（如方向选择性）是基础性的 和视皮层神经元的对比度反应功能。正确的E-I关系的重要性也是 在许多神经发育和精神疾病中， 紊乱然而，E-I关系的调节以及改变E-I关系对植物生长发育的影响还有待进一步研究。 皮质神经元的功能反应特性仍然知之甚少。因此，这一总体目标 该项目旨在确定单个神经元的活动和稳态突触可塑性如何调节 皮层兴奋、抑制和E-I关系。为此，我们使用发育中的小鼠视觉皮层作为 一个模型系统，并开发了分子方法来选择性地降低少数人的兴奋性， 在体内的2/3层锥体神经元，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的特定子集的稳态变化引起的活动扰动。这些 结果导致了一个中心假设，即稳态可塑性差异地改变了不同的突触输入， 单个皮层神经元调节它们的E-I关系，从而维持活动水平， 功能反应特性。我们建议将联合收割机分子操作与光遗传学结合起来， 生理学、成像和解剖学方法，系统地描绘了 不同的突触起源于不同的突触前神经元类型（目的1），以确定潜在的 突触机制的输入特异性稳态可塑性（目的2），并确定这些影响 体内神经元视觉反应特性的突触变化（目的3）。拟议研究 连接了从突触到电路再到系统的三个层次的研究。成功完成本 该项目将提供有关稳态突触可塑性在调节E-I关系中的作用的见解， 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。

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.