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.

项目概要 皮质活动高度依赖于不同状态的动物的行为状态，例如睡眠和 唤醒，对认知和皮质处理产生深远的影响。在大脑层面，行为状态（例如 正如睡眠和清醒）与不同的皮质活动模式（或皮质状态）相关，即 通过 EEG 和/或 LFP 测量的振荡活动可以很好地捕获。最近的工作表明，皮质状态 调节局部神经元信息的处理以及大脑区域之间的通信，尽管 对于这一重要功能，人们对这些不同网络状态背后的电路知之甚少 活动。抑制性神经元（IN）虽然只占皮层细胞的少数，但它们的位置很好 调节皮质状态。虽然皮质中的绝大多数 IN 在局部投射，但皮质 IN 有一种亚型 它的投射距离很远，与其他 IN 形成鲜明对比。这些细胞在整个细胞中密集地形成树状结构 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 IN 的一小部分，但它们在进化上是保守的， 表明这些细胞在大脑功能中发挥着重要作用。它们巨大的轴突树枝化表明 这些细胞可以协调许多下游细胞的活动。虽然这种 IN 细胞类型完全是 它的形态和在皮质回路中的潜在作用是独特的，但我们不了解它的功能，但我 假设它对于调节同步慢皮层节律至关重要。这里我们将使用新的交叉 小鼠中的遗传工具，以获得这种独特的神经元类型并询问体内功能 SST/nNOS IN 在皮质回路中的作用。 SST/nNOS 的长投影和密集的皮质树状结构 细胞使它们成为跨大区域同步活动的良好候选者。此外，离体研究 表明长程抑制神经元可能在大脑高度同步的时期活跃。 慢波睡眠（SWS）。该状态的特点是在 UP 和 DOWN 状态之间缓慢振荡，即 在皮层中毫米距离上紧密同步。虽然许多人认为 UP 和 DOWN 状态仅由锥体细胞之间的相互作用产生，最近的研究表明，一种未知的 存在机制来启动跨毫米区域的急剧且同步的向下状态转换。我 假设 SST/nNOS 细胞的活性对于慢皮质节律的产生和 从 UP 状态转换为 DOWN 状态。