Long-range inhibitory neuron circuit organization and cortical function

长程抑制神经元回路组织和皮质功能

• 批准号: 10567648
• 负责人: Renata Batista-Brito
• 金额: $ 53.19万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567648
• 关键词: Affect; Animals; Area; Arousal; Axon; Behavioral; Brain; Brain imaging; Brain region; Cells; Cerebrum; Cognition; Communication; Data; Discrimination; Disease; Distant; Electroencephalography; Frequencies; Gene Expression; Generations; Genetic; Health; Human; Knowledge; Link; Measures; Mental Depression; Mental disorders; Minority; Mission; Monitor; Morphology; Mus; Neocortex; Neurons; Nitric Oxide Synthase Type I; Output; Pattern; Perception; Play; Positioning Attribute; Public Health; Pyramidal Cells; Reptiles; Research; Rest; Role; Schizophrenia; Sensory; Sleep; Slow-Wave Sleep; Somatostatin; Stimulus; Testing; United States National Institutes of Health; Visual; Visual Perception; Visual System; Visualization; Wakefulness; Work; area striata; autism spectrum disorder; cell type; extracellular; imaging modality; in vivo; inhibitory neuron; insight; millimeter; neocortical; nervous system disorder; neuronal circuitry; neuropsychiatric disorder; novel; operation; optogenetics; postsynaptic; preservation; presynaptic; rabies viral tracing; response; theories; tool

Project Summary Cortical activity is highly dependent on behavioral state of an animal with different states, such as sleep and wake, having profound impact on cognition and cortical processing. At the brain level, behavioral states (such as sleep and wakefulness) are associated with distinct patterns of cortical activity (or cortical states), that are well captured by oscillatory activity measured with EEG and/or LFP. Recent work shows that cortical states regulate processing of local neuronal information as well as the communication between brain areas, and despite this important function, relatively little is known about the circuits underlying these distinct states of network activity. Inhibitory neurons (INs), though they make up a minority of cells in the cortex, are well positioned to regulate cortical state. While the vast majority INs in the cortex project locally, there is a subtype of cortical IN that projects over a long distances in stark contrast to other INs. These cells arborize densely throughout the cortex, can span over different cortical regions, and are remarkably unique in terms of gene expression and morphology. Even though they constitute a very small portion of INs, they are evolutionarily conserved, suggesting that these cells play an important role in brain function. Their massive axonal arborization suggests that these cells can coordinate the activity of many downstream cells. Though this IN cell type is completely unique in its morphology and potential role in cortical circuits, we do not understand its function, though, I hypothesize it is crucial for regulating synchronized slow cortical rhythms. Here we will use new intersectional genetic tools in the mouse, to gain access to this distinct neuronal type and to interrogate the in vivo functional role of SST/nNOS INs in cortical circuits. The long projections and dense cortical arborizations of SST/nNOS cells make them a good candidate to synchronize activity across large areas. Furthermore, ex-vivo studies suggest that long-range inhibitory neurons are likely to be active during periods of highly synchronized brain of slow wave sleep (SWS). This state is characterized by a slow oscillation between UP and DOWN states that is tightly synchronized across millimeter distances in the cortex. While many believe transitions between UP and DOWN states arise solely from interactions between pyramidal cells, recent work suggests that an unknown mechanism exists to initiate the sharp and synchronous DOWN state transition across millimeter areas. I hypothesize that the activity pf SST/nNOS cells is critical for the generation of slow cortical rhythms and the transition from UP to DOWN states.

项目摘要 皮质活动高度依赖于具有不同状态的动物的行为状态，如睡眠和 觉醒，对认知和大脑皮层处理有深远影响。在大脑层面上，行为状态(如 睡眠和清醒)与皮质活动(或皮质状态)的不同模式有关，这是 通过EEG和/或LFP测量的振荡活动可以很好地捕捉到。最近的研究表明，大脑皮层状态 调节局部神经元信息的处理以及脑区之间的通信，尽管 这一重要功能对这些不同网络状态下的电路知之甚少 活动。抑制神经元(INS)虽然只占大脑皮层细胞的一小部分，但它们处于有利的位置 调节大脑皮层状态。虽然皮质中的绝大多数INS都是局部投射的，但大脑皮层IN有一种亚型 它的投射距离很远，与其他惯导系统形成鲜明对比。这些细胞密集地分布在整个 皮质，可以跨越不同的皮质区域，并且在基因表达和 形态学。尽管它们只占INS的很小一部分，但它们在进化上是保守的， 这表明这些细胞在大脑功能中发挥着重要作用。它们巨大的轴突分枝表明 这些细胞可以协调许多下游细胞的活动。尽管此IN单元格类型完全 其独特的形态和在皮质环路中的潜在作用，我们还不知道它的功能，尽管，我 假设它对调节同步的慢皮质节律是至关重要的。这里我们将使用新的交叉点 小鼠的遗传工具，以获得这种独特的神经元类型并询问体内的功能 SST/nNOS INS在皮质环路中的作用SST/nNOS的长投射和密集的皮质分支 细胞使它们成为同步大范围活动的一个很好的候选者。此外，体外研究 提示长距离抑制神经元可能在大脑高度同步化的时期活跃 慢波睡眠(SWS)这种状态的特征是上下两种状态之间的缓慢振荡，即 在大脑皮层的毫米距离内紧密同步。虽然许多人认为UP和UP之间的过渡 Down状态只出现在锥体细胞之间的相互作用中，最近的研究表明，一种未知的 存在启动跨毫米区域的锐化和同步向下状态转变的机制。我 假设SST/nNOS细胞的活动对慢皮质节律的产生至关重要，并且 从向上状态到向下状态的转换。