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，例如睡眠和睡眠。 唤醒，对认知和皮层处理有深远的影响。在大脑层面，行为状态（如 睡眠和清醒）与不同的皮质活动模式（或皮质状态）有关， 通过EEG和/或LFP测量的振荡活动很好地捕获。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下的电路知之甚少 活动抑制性神经元（INs），虽然它们在皮层中占少数，但它们处于良好的位置， 调节皮质状态。虽然皮质中的绝大多数神经元在局部投射，但皮质神经元中有一种亚型 与其他神经元形成鲜明对比的是，这些细胞在整个神经元中密集分布。 皮质，可以跨越不同的皮质区域，并且在基因表达方面非常独特， 形态学尽管它们只占IN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起着重要作用。它们大量的轴突分支表明 这些细胞可以协调许多下游细胞的活动。尽管这种IN细胞类型完全 虽然它的形态和在皮层回路中的潜在作用是独一无二的，但我们还不了解它的功能， 假设它对于调节同步缓慢皮质节律至关重要。在这里，我们将使用新的交叉 在小鼠中的遗传工具，以获得这种独特的神经元类型，并询问体内功能 SST/nNOS INs在皮层回路中的作用。SST/nNOS的长投射和密集的皮质分支 细胞使它们成为在大面积上同步活动的良好候选者。此外，离体研究 这表明，长距离抑制神经元可能是活跃的高度同步的大脑期间， 慢波睡眠（SWS）。该状态的特征在于UP和DOWN状态之间的缓慢振荡， 大脑皮层中的毫米距离上的紧密同步虽然许多人认为， DOWN状态只产生于锥体细胞之间的相互作用，最近的研究表明， 存在一种机制来启动跨越毫米级区域的急剧和同步的向下状态转换。我 假设SST/nNOS细胞的活性对于缓慢皮质节律的产生是至关重要的， 从UP状态转换到DOWN状态。