Synaptic and cellular mechanisms of neuronal synchronization

神经元同步的突触和细胞机制

• 批准号: 10192023
• 负责人: Simon Chamberland
• 金额: $ 12.26万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192023
• 关键词: Action Potentials; Acute; Animals; Architecture; Attention; Award; Behavior; Brain; Brain region; Cells; Complex; Data; Disinhibition; Electrophysiology (science); Environment; Epilepsy; Experimental Designs; Fire - disasters; Frequencies; Goals; Hippocampus (Brain); In Vitro; Individual; Inferior; Interneurons; Interruption; Intervention; Investigation; Knowledge; Lead; Lifting; Light; Location; Longitudinal Studies; Maintenance; Measurable; Measures; Membrane Potentials; Memory; Mentorship; Motivation; Motor; Neurons; Neurosciences; New York; Parvalbumins; Pathologic; Pattern; Phase; Physiological; Population; Population Heterogeneity; Preparation; Property; Pyramidal Cells; Recruitment Activity; Research; Rewards; Role; Schizophrenia; Slice; Speed; Synapses; Synaptic Transmission; System; Time; Training; Universities; Whole-Cell Recordings; Work; anatomical tracing; autism spectrum disorder; base; career; cognitive function; comparative; excitatory neuron; genetic approach; hippocampal pyramidal neuron; in vivo; inhibitory neuron; medical schools; memory retrieval; millisecond; nervous system disorder; optogenetics; preservation; recruit; skills; spatial memory; synaptic inhibition; way finding

Project Summary/Abstract Neuronal activity must be precisely coordinated to provide an accurate representation of our environment, a feature exemplified by the electrical patterns measured in the brain during spatial navigation and memory retrieval. While the activity of individual neurons is tuned to specific features such as physical location or speed, simultaneous observations at the network level reveals electrical oscillations reflecting the coordinated activity of thousands of neurons. Therefore, a central goal of neuroscience is to understand how network activity emerges from the interactions between individual neurons. The neuronal architecture is relatively well-conserved across multiple brain regions: a population of highly heterogenous inhibitory interneurons (INs) with dense connectivity control a large population of excitatory neurons. Thus, the mechanisms controlling INs themselves are poised to have a dramatic impact on network activity. Previous studies support the existence of small populations of INs that selectively synapse onto other INs. These relatively sparse INs operate disinhibitory networks that could have a profound impact on network activity. Here, I investigate how coordinated activity emerges from neuronal interactions by investigating how disinhibition controls hippocampal circuits. In Aim 1, I will dissect a disinhibitory circuits controlling parvalbumin-expressing (PV) INs, a class of neurons controlling the firing of pyramidal cells. My preliminary results show that an overlooked class of INs known as backprojecting (BP) INs hierarchically control PV-INs. I devised an intersectional genetic strategy to specifically access BP-INs and establish their role in the network. Under Aim 2, I will explore how disinhibition maintains temporal neuronal sequences, a hallmark feature of coordinated neuronal activity during network oscillations. I will focus on when and how BP-INs are recruited during network oscillations and on the downstream effects of their activity by working in vitro. Under Aim 3, I will reconstruct the impact of disinhibitory neurons on hippocampal network dynamics. I will determine the necessity and the sufficiency of BP-INs in controlling hippocampal network oscillations at different phases. Overall, this research will shed light on the physiological functions of disinhibition, a well-conserved, but generally understudied circuit feature. During the K99 phase of the award, I will benefit from the mentorship of Drs. Tsien and Buzsáki at New York University Grossman School of Medicine to obtain additional training in system neuroscience. The training plan proposed will equip me with the necessary research and professional skills to start an independent career at the intersection between cellular and system neuroscience in the R00 phase. This work is further motivated by observations that dysregulation in neuronal coordination can lead to neurological disorders such as autism spectrum disorders and epilepsies. In the long term, studying how inhibitory neurons and disinhibition control neuronal network activity will provide a better understanding of these pathological conditions.

项目总结/摘要 神经元活动必须精确协调，以提供对我们环境的准确表示， 在空间导航和记忆过程中测量大脑中的电模式所例示的特征 检索虽然单个神经元的活动会根据物理位置或速度等特定特征进行调整， 在网络水平上的同步观测揭示了反映协调活动的电振荡 of thousands数千of neurons神经元.因此，神经科学的一个中心目标是了解网络活动如何 是由单个神经元之间的相互作用产生的。神经元结构相对保守 跨多个大脑区域：一群高度异质性的抑制性中间神经元（IN）， 连接控制着大量的兴奋性神经元。因此，控制IN本身的机制 将对网络活动产生巨大影响。以前的研究支持存在小的 选择性地与其他神经元形成突触的神经元群。这些相对稀疏的神经元发挥去抑制作用 这些网络可能对网络活动产生深远影响。在这里，我调查了协调的活动 通过研究去抑制如何控制海马回路，从神经元的相互作用中产生。在目标1中， 将解剖一个去抑制电路控制小清蛋白表达（PV）的神经元，一类神经元控制的神经元， 锥体细胞的放电我的初步结果表明，一类被忽视的IN（称为反向投影） (BP)IN分级控制PV-IN。我设计了一种交叉遗传策略来专门访问BP-IN 并在网络中建立自己的角色。在目标2下，我将探讨去抑制如何维持颞叶神经元 序列，在网络振荡期间协调神经元活动的标志性特征。我会集中在什么时候 以及BP-IN如何在网络振荡期间被招募，以及它们活动的下游效应， 在试管中工作在目标3下，我将重建去抑制神经元对海马网络的影响 动力学本研究将确定BP-INs控制海马网络的必要性和充分性 不同阶段的振荡。总的来说，这项研究将揭示去抑制的生理功能， 这是一种保存完好但研究不足的电路特征。在K99阶段，我将受益于 来自纽约大学格罗斯曼医学院的钱博士和布扎基博士的指导， 系统神经科学的额外培训。建议的培训计划将使我具备必要的研究能力 和专业技能，在蜂窝和系统之间的交叉点开始独立的职业生涯 R 00阶段的神经科学。这项工作的进一步动机是观察到神经元的调节障碍， 协调可能导致神经系统疾病，如自闭症谱系障碍和癫痫。从长远 长期以来，研究抑制性神经元和去抑制性神经元如何控制神经元网络活动将提供更好的 了解这些病理状况。