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

大脑皮层执行令人难以置信的复杂功能的能力存在于其复杂的神经回路中 由大量神经元组成的。皮质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，两种相反的力量共同协调 神经元活动的时空模式。因此，激发和抑制之间的关系(E-I 关系)是皮层神经元许多功能特性的基础，例如定向选择性 以及视皮层神经元的对比反应函数。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患者中发现E-I关系改变突出了这一点 精神错乱。然而，E-I关系的调节以及这种关系的改变对 大脑皮层神经元的功能反应特性仍然知之甚少。因此，这一计划的总体目标是 项目是确定单个神经元的活动和稳态突触可塑性是如何调节的 大脑皮层兴奋、抑制和E-I关系。为此，我们使用发育中的小鼠视皮层作为 一种模型系统和发展的选择性降低少量兴奋性的分子方法 2/3层锥体神经元，以便我们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扰动。我们发现，这些神经元能中和 兴奋性和抑制性突触的特定子集上的自稳变化引起的活动扰动。这些 结果导致了中心假说，即内稳态可塑性以不同的方式改变了不同的突触输入 单个皮质神经元调节其E-I关系，从而维持活动水平和 功能反应特性。我们建议将分子操作与光遗传相结合， 生理、影像和解剖学方法系统地描绘人体内环境平衡的变化 来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 输入特异性内稳态可塑性的突触机制(目标2)，并确定这些机制的影响 神经元视反应特性中突触的变化(目标3)。拟议的研究 连接了从突触到电路再到系统的三个层次的研究。成功地完成这项工作 该项目将提供对动态平衡突触可塑性在调节E-I关系和 大脑皮层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总体上的干扰。

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.