The Role of Long-Range Inhibitory Neurons in Cortical Circuits

长程抑制神经元在皮质回路中的作用

基本信息

批准号：
10434665
负责人：
Jacob Ratliff
金额：
$ 4.77万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434665
关键词：
Address Affect Animals Area Arousal Attention Axon Behavioral Brain Cell Shape Cells Cerebral cortex Code Cognition D Cells Data Electroencephalography Electrophysiology (science)Frequencies Gene Expression Gene Expression Profile Generations Genetic Impairment Interneurons Knowledge Light Locomotion Maintenance Measures Memory Mental disorders Microscopy Minority Modeling Morphology Mus Muscle Neocortex Neurons Nitric Oxide Synthase Type I Opsin Output Pattern Play Positioning Attribute Pyramidal Cells Recurrence Role Sensory Signal Transduction Sleep Slice Slow-Wave Sleep Somatostatin Specificity Synaptic plasticity Task Performances Test Result Testing Tissues Work area striata cell type excitatory neuron experimental study extracellular imaging modality in vivo inattention inhibitory neuron millimeter neocortical neuropsychiatric disorder optogenetics postsynaptic prevent response sensory input tool two photon microscopy two-photon

项目摘要

Project Summary Cortical activity changes dramatically upon changes in behavioral state of an animal with different behavioral states, such as sleep and wake, having profound impact on cortical processing. The circuitry responsible for sensing behavioral state and modifying cortical activity to generate cortical states remains unknown. However, inhibitory neurons (INs) have been recently implicated in this role. Interestingly, both dysregulation of behavioral states and disruptions in INs are hallmarks of major neuropsychiatric disorders. Here, I propose that a specific sub type of inhibitory neuron in the cortex plays a role in the generation of low-frequency oscillations, a hallmark of multiple cortical states. I propose that the long-range inhibitory neurons of the cortex play a crucial role in the generation of low-frequency oscillations. Long-range inhibitory neurons are highly distinct from other cell types in the cortex both in terms of their morphology and gene expression. While other INs in the cortex project locally, long-range inhibitory neurons project across many millimeters, in the mouse, and across cortical areas. Previous studies of the connectivity of these cells have been hampered by the necessity to slice tissue and fill cells to generate morphologies limiting our knowledge of these cells. In my first aim, I plan to address these issues using tissue clearing and light sheet microscopy to determine the postsynaptic areas targeted by these cells. I will compliment this with 2-photon recordings of the activity of these cells performed across behavioral states to determine the activity patterns affecting downstream areas. In my second aim, I will perform in vivo function characterizations of long-range inhibitory neurons using optogenetics and electrophysiology. Ex-vivo studies suggest that long-range inhibitory neurons are active during slow wave sleep, a period of low-frequency oscillations. I will perform in vivo extracellular electrophysiology while using optogenetic tools to manipulate the activity of long-range inhibitory neurons. I will use excitatory opsins with frequency modulated stimulation and an inhibitory opsin. I will measure the responses of single units and network oscillations to this stimulation. I will perform manipulations in long-range inhibitory neurons and other neuronal types to show specificity of results testing the hypothesis that these cells regulate the generation of low-frequency oscillations. Together these two aims provide the first in vivo characterizations of the activity of long-range inhibitory neurons. When completed, I will be able to relate the connectivity, morphology, and activity patterns of this cell type to understand the role of this cell type in cortical circuits.

项目概要具有不同行为状态的动物，皮质活动会随着行为状态的变化而发生显着变化，例如就像睡眠和清醒一样，对皮质处理产生深远的影响。负责感知行为状态的电路改变皮质活动以产生皮质状态仍然未知。然而，抑制性神经元（IN）已被最近又被卷入了这个角色。有趣的是，行为状态失调和 IN 紊乱都是标志主要神经精神疾病。在这里，我提出皮层中抑制性神经元的特定亚型发挥着作用低频振荡的产生是多种皮质状态的标志。我建议长程抑制皮层神经元在低频振荡的产生中起着至关重要的作用。长程抑制神经元在形态和结构上都与皮层中的其他细胞类型高度不同。基因表达。虽然皮层中的其他 IN 只投射到局部，但远程抑制神经元则投射到许多区域。毫米，在小鼠中，以及跨皮质区域。先前对这些细胞连接性的研究受到了阻碍由于需要切片组织和填充细胞以产生形态，限制了我们对这些细胞的了解。在我的第一个目标中，我计划使用组织透明化和光片显微镜来解决这些问题，以确定目标突触后区域由这些细胞。我将用 2 光子记录这些细胞在行为上的活动来对此表示称赞国家确定影响下游地区的活动模式。在我的第二个目标中，我将使用光遗传学和电生理学。离体研究表明，长程抑制神经元在慢波睡眠期间活跃，这是一个时期的低频振荡。我将在使用光遗传学工具的同时进行体内细胞外电生理学操纵远程抑制神经元的活动。我将使用具有调频刺激的兴奋性视蛋白和抑制性视蛋白。我将测量单个单元和网络振荡对这种刺激的响应。我会对远程抑制神经元和其他神经元类型进行操作，以显示测试结果的特异性假设这些细胞调节低频振荡的产生。这两个目标共同提供了远程抑制神经元活性的第一个体内特征。什么时候完成后，我将能够将这种细胞类型的连接性、形态和活动模式联系起来，以了解其作用皮质回路中的这种细胞类型。