Mechanisms and function of firing rate homeostasis in cortical circuits

皮质回路中放电率稳态的机制和功能

• 批准号: 9923773
• 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/9923773
• 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.

我的 NS 支持的研究项目的总体目标是了解 在体验过程中稳定中枢神经系统（CNS）微电路的功能- 依赖可塑性和学习。在过去约 20 年的国民服役支持中，我们发现并 表征了几种形式的稳态可塑性，包括突触缩放和内在 稳态可塑性，假设可以感知平均神经元活动的扰动， 然后双向调整突触和细胞特性，将活动保持在设定点内 范围。我们最近的工作重点是a）确定细胞和分子机制 这些可塑性的稳态形式，以增强我们的机械和功能 理解，并生成使我们能够选择性地阻止稳态可塑性的工具 体内； b) 确定神经元活动的哪些方面处于完整状态下的稳态控制之下 体内中枢神经系统回路。我们最近表明，新皮质锥体的平均放电率 自由行为动物的神经元在长时间后恢复到个体基线 对感觉驱动的扰动，强烈支持新皮质神经元的观点 体内平衡调节其围绕个体“发射率设定点”的平均发射。这样一个 理论上，过程对于防止电路低兴奋或高兴奋非常重要。 依赖经验的发展，以及短路积极反馈的性质 赫布可塑性规则会降低记忆保真度。我们现在拥有（或正在开发） 破坏体内稳态可塑性和放电率设定点的工具，使我们能够评估 这种中断对网络功能和内存存储的影响。我的国民服役的主要目标- 未来支持的研究计划是：1）确定如何建立活动设定点， 以及单个神经元如何具有与每个神经元有数量级不同的设定点 其他; 2）了解多种稳态机制如何相互配合 面对严重扰动时稳定网络活动； 3）测试角色 记忆编码和泛化中的突触缩放和内在稳态可塑性。 这些研究将对我们理解神经系统疾病产生重要影响 由异常的电路兴奋性（癫痫、自闭症谱系障碍）引起。他们可能 还为理解可能出现的创伤后应激障碍（PTSD）等疾病提供了新途径 来自厌恶学习期间的过度概括。