Synaptic and cellular mechanisms of neuronal synchronization

神经元同步的突触和细胞机制

• 批准号: 10415155
• 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/10415155
• 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.

项目摘要/摘要 神经元活动必须精确协调以提供我们环境的准确表示，a 在空间导航和记忆过程中大脑中测得的电气模式的特征例证 检索。虽然单个神经元的活动被调整为特定特征，例如物理位置或速度，但 网络级别的简单观察结果揭示了反映协调活动的电振荡 成千上万的神经元。因此，神经科学的核心目标是了解网络活动如何 来自单个神经元之间的相互作用。神经元结构相对良好 在多个大脑区域中 连通性控制大量兴奋性神经元。那，控制自己的机制 被中毒以对网络活动产生巨大影响。以前的研究支持小的存在 选择性突触到其他INS的INS群体。这些相对稀疏的INS操作 可能会对网络活动产生深远影响的网络。在这里，我研究了如何协调活动 通过研究抑制如何控制海马电路，从神经元相互作用中出现。在AIM 1中，我 将剖析控制表达Parvalbumin（PV）INS的抑制电路，一类控制的神经元 锥体细胞发射。我的初步结果表明，一类被忽略的INS类称为背面 （bp）INS层次控制PV-INS。我设计了一个交叉遗传策略来专门访问BP-INS 并确定其在网络中的作用。在AIM 2下，我将探讨如何维持临时神经元 序列是网络振荡过程中协调神经元活动的标志性特征。我会专注于何时 以及如何在网络振荡期间招募BP-INS以及通过其活动的下游影响 体外工作。在AIM 3下，我将重建抑制性神经元对海马网络的影响 动力学。我将确定在控制海马网络中BP-IN的必要和充分性 在不同阶段的振荡。总体而言，这项研究将阐明抑制的身体功能， 保存良好但通常理解的电路功能。在奖项的K99阶段，我将受益 来自博士的精神。纽约大学格罗斯曼医学院的Tsien和Buzsáki获得 系统神经科学的额外培训。提出的培训计划将使我能够接受必要的研究 和专业技能，在蜂窝和系统之间的交集开始独立职业 R00阶段的神经科学。观察到神经元失调的观察进一步激发了这项工作 协调可以导致神经系统疾病，例如自闭症谱系障碍和癫痫病。长时间 术语，研究抑制性神经元和抑制​​性控制神经元网络活动将如何提供更好的 了解这些病理状况。