Mechanisms and Function of Firing Rate Homeostasis in Cortical Circuits

皮层回路放电率稳态的机制和功能

• 批准号: 10891888
• 负责人: GINA G TURRIGIANO
• 金额: $ 10.49万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10891888
• 关键词: Animals; Back; Central Nervous System; Development; Disease; Endowment; Epilepsy; Feedback; Goals; Homeostasis; Individual; Investigation; Learning; Memory; Molecular; Nature; Neocortex; 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

PROJECT SUMMARY 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 hyperexcitablity 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.

项目总结 我的NS支持的研究计划的总体目标是了解 在体验中稳定中枢神经系统(CNS)微回路的功能- 依赖可塑性和学习。在过去约20年的NS支持中，我们发现并 描述了几种形式的稳态可塑性，包括突触伸缩和内在可塑性 动态平衡可塑性，被认为是感觉平均神经元活动的扰动， 然后双向调整突触和细胞属性以将活动保持在设定点内 射程。我们最近的工作集中在a)确定细胞和分子机制 这些动态平衡的可塑性形式，以支持我们的机械和功能 理解，并产生工具，允许我们有选择地阻止体内平衡的可塑性 活体；以及b)确定在正常情况下，神经元活动的哪个方面处于动态平衡控制之下 活体内的中枢神经系统回路。我们最近发现，新皮质锥体的平均放电率 自由行为动物的神经元在延长时间后恢复到个人基线 对感觉驱动的扰动，有力地支持了新皮质神经元 自我恒定地将它们的平均射程调节在一个个体的“射速设定点”附近。这样的一个 从理论上讲，工艺对于防止电路过低或过兴奋是非常重要的 依赖经验的发展，以及短路的正反馈性质 可以降低记忆保真度的Hebbian可塑性规则。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 此中断对网络功能和内存存储的影响。我的NS的主要目标是- 未来支持的研究计划是：1)确定如何建立活动设置点， 以及单个神经元如何具有与每个神经元不同的数量级的设定点 其他；2)了解多种动态平衡机制如何相互协作 在面临深刻扰动的情况下稳定网络活动；以及3)测试 记忆编码和概括中的突触伸缩和内在内稳态可塑性。 这些研究将对我们理解神经系统疾病有重要意义。 由异常回路兴奋性(癫痫、自闭症谱系障碍)引起。他们可能会 也为理解可能出现的创伤后应激障碍等障碍提供了一种新的途径 避免在厌恶学习期间过度泛化。

项目成果

Strong Aversive Conditioning Triggers a Long-Lasting Generalized Aversion.

• DOI: 10.3389/fncel.2022.854315
• 发表时间: 2022
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Ramos R;Wu CH;Turrigiano GG
• 通讯作者: Turrigiano GG

CaMKIV Signaling Is Not Essential for the Maintenance of Intrinsic or Synaptic Properties in Mouse Visual Cortex.

CaMKIV 信号传导对于维持小鼠视觉皮层的内在或突触特性并不重要。

• DOI: 10.1523/eneuro.0135-21.2021
• 发表时间: 2021
• 期刊: eNeuro
• 影响因子: 3.4
• 作者: Trojanowski,NicholasF;Turrigiano,GinaG
• 通讯作者: Turrigiano,GinaG

Developmental Regulation of Homeostatic Plasticity in Mouse Primary Visual Cortex.

小鼠初级视觉皮层稳态可塑性的发育调节。

• DOI: 10.1523/jneurosci.1200-21.2021
• 发表时间: 2021
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Wen,Wei;Turrigiano,GinaG
• 通讯作者: Turrigiano,GinaG