Synaptic and cellular mechanisms of neuronal synchronization

项目摘要/摘要 神经元的活动必须精确地协调，才能准确地代表我们的环境 以在空间导航和记忆过程中在大脑中测量的电模式为例的特征 取回。虽然单个神经元的活动是根据特定的特征进行调整的，比如物理位置或速度， 在网络水平上的同步观测揭示了反映协调活动的电振荡 数以千计的神经元。因此，神经科学的一个中心目标是了解网络活动是如何 来自单个神经元之间的相互作用。神经元的结构相对保守。 跨多个脑区：一群高度异质的抑制性中间神经元(INS) 连接性控制着大量的兴奋性神经元。因此，控制INS本身的机制 都将对网络活动产生巨大影响。以前的研究支持小的存在 选择性地与其他INS突触的INS群体。这些相对稀疏的INS不起抑制作用 可能对网络活动产生深远影响的网络。在这里，我调查了协调活动是如何 通过研究去抑制如何控制海马体电路，从神经元的相互作用中浮现出来。在目标1中，我 将剖析控制小白蛋白表达(PV)INS的去抑制电路，这是一类控制 锥体细胞的放电。我的初步结果显示，一类被忽视的惯导系统被称为反投影 (BP)INS分层控制PV-INS。我设计了一种跨部门遗传策略，专门访问BP-INS 并确立他们在网络中的角色。在目标2中，我将探索去抑制如何维持颞叶神经元 序列，这是网络振荡期间协调神经元活动的一个标志特征。我将重点关注什么时候 以及BP-IN是如何在网络振荡期间招募的，以及它们的活动的下游影响 在体外工作。在目标3下，我将重建去抑制性神经元对海马网的影响 动力学。我将确定BP-INS在控制海马网中的必要性和充分性 不同阶段的振荡。总体而言，这项研究将阐明去抑制的生理功能， 一种保守但普遍未被研究的电路特性。在K99颁奖阶段，我将受益于 从纽约大学格罗斯曼医学院钱存训和布萨基博士的指导下获得 系统神经科学方面的额外培训。建议的培训计划将使我具备必要的研究能力。 和专业技能，在蜂窝和系统的交叉点开始独立的职业生涯 处于R00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失调 协调可能会导致神经障碍，如自闭症谱系障碍和癫痫。在漫长的岁月里 因此，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 对这些病理情况的理解。

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.