Mechanisms and function of firing rate homeostasis in cortical circuits

皮质回路放电率稳态的机制和功能

• 批准号: 10391451
• 负责人: GINA G TURRIGIANO
• 金额: $ 81.77万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391451
• 关键词: Animals; Back; Development; Disease; Epilepsy; Feedback; Goals; Homeostasis; Individual; Investigation; Learning; Memory; Molecular; Nature; Neuraxis; Neurons; Post-Traumatic Stress Disorders; Process; Property; Research Support; Role; Sensory; Synapses; Testing; Work; autism spectrum disorder; experience; hippocampal pyramidal neuron; in vivo; memory encoding; neocortical; nervous system disorder; prevent; programs; tool

The overall goal of my NS-supported research program is to understand the mechanisms that stabilize the function of central nervous system (CNS) microcircuits during experience- dependent plasticity and learning. Over the past ~20 years of NS support we discovered and characterized several forms of homeostatic plasticity, including synaptic scaling and intrinsic homeostatic plasticity, that are postulated to sense perturbations in mean neuronal activity, then bidirectionally adjust synaptic and cellular properties to keep activity within a set point range. Our recent work has focused on a) identifying the cellular and molecular mechanisms of these homeostatic forms of plasticity in order to bolster our mechanistic and functional understanding, and to generate tools that allow us to selectively block homeostatic plasticity in vivo; and b) to determine what aspect of neuronal activity is under homeostatic control in intact CNS circuits in vivo. We recently showed that the mean firing rates of neocortical pyramidal neurons in freely behaving animals return back to an individual baseline following prolonged perturbations to sensory drive, strongly supporting the idea that neocortical neurons homeostatically regulate their mean firing around an individual 'firing rate set point'. Such a process is theoretically important for preventing circuit hypo- or hyperexcitability during experience-dependent development, as well as to short-circuit the positive feedback nature of Hebbian plasticity rules that can degrade memory fidelity. We now have (or are developing) the tools to disrupt homeostatic plasticity and firing rate set points in vivo, allowing us to assess the impact of this disruption on network function and memory storage. The major goals of my NS- supported research program going forward are: 1) to determine how activity set points are built, and how individual neurons can have set points that are orders of magnitude different from each other; 2) to understand how multiple homeostatic mechanisms cooperate with each other to stabilize network activity in the face of profound perturbations; and 3) to test the role of synaptic scaling and intrinsic homeostatic plasticity in memory encoding and generalization. These studies will have important implications for our understanding of neurological disorders that arise from aberrant circuit excitability (epilepsy, autism-spectrum disorders). They may also provide a new avenue into understanding disorders such as PTSD that are likely to arise from excessive generalization during aversive learning.

我支持NS的研究计划的总体目标是了解这种机制 在体验期间稳定中枢神经系统（CNS）微电路的功能 - 依赖的可塑性和学习。在过去的大约20年的NS支持中，我们发现了 表征了几种形式的稳态可塑性，包括突触缩放和内在的 稳态可塑性被认为是在平均神经元活动中感知扰动的 然后双向调整突触和细胞特性，以保持活性在设定点之内 范围。我们最近的工作重点是a）识别细胞和分子机制 这些稳态形式的可塑性，以加强我们的机械和功能 理解并生成使我们能够选择性地阻断稳态可塑性的工具 体内b）确定神经元活动的哪个方面在完整的稳态控制下 CNS电路在体内。我们最近表明，新皮质金字塔的平均点火速率 延长后，自由表现的动物的神经元返回到单个基线 对感觉驱动的扰动，强烈支持新皮质神经元的观念 稳态调节其平均发射围绕单个“射击率设定点”。这样的 从理论上讲，过程对于防止电路过度或过度刺激性在理论上很重要 依赖经验的发展，以及为积极的反馈本质的缩短 Hebbian可塑性规则可以降低记忆保真度。我们现在已经（或正在开发） 破坏体内稳态可塑性和发射速率设定点的工具，使我们能够评估 这种中断对网络功能和内存存储的影响。我的NS的主要目标 未来支持的研究计划是：1）确定如何构建活动设定点， 以及单个神经元如何设定与每个神经元不同的数量级 其他; 2）了解多种稳态机制如何相互配合 面对深刻的扰动，稳定网络活动； 3）测试 记忆编码和概括中的突触缩放和内在稳态可塑性。 这些研究将对我们对神经系统疾病的理解具有重要意义 这是由异常电路的兴奋性（癫痫，自闭症谱系疾病）引起的。他们可能 还为理解可能出现的PTSD等疾病（例如PTSD）提供了新的途径 从厌恶学习过程中过度概括。