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

• 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
• 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

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.

项目摘要 随着行为状态不同的动物行为状态的变化，皮质活动发生了巨大变化，例如 作为睡眠和唤醒，对皮质加工产生深远影响。负责传感行为状态的电路 修改皮质活性以产生皮质态仍然未知。但是，抑制性神经元（INS）已经 最近与这个角色有关。有趣的是，行为状态的失调和INS中的干扰都是标志 主要的神经精神疾病。在这里，我建议皮质中的特定亚类抑制神经元起作用 在低频振荡的产生中，这是多种皮质状态的标志。我建议远程抑制 皮质的神经元在低频振荡的产生中起着至关重要的作用。 远程抑制性神经元与皮质中的其他细胞类型高度不同，无论是在其形态上和 基因表达。而在本地皮质项目中的其他INS，但许多人跨越远程抑制性神经元项目 毫米，小鼠和跨皮质区域。这些细胞连通性的先前研究已受到阻碍 由于有必要切片组织并填充细胞以产生形态，从而限制了我们对这些细胞的了解。在我的第一个目标中 我计划使用组织清除和轻度显微镜解决这些问题，以确定针对的突触后区域 通过这些细胞。我将以两光子的录音来称赞这些细胞在行为上执行的活性 国家确定影响下游区域的活动模式。 在第二个目标中，我将使用光遗传学和 电生理学。前病毒研究表明，在慢波睡眠期间，远距离抑制性神经元活跃，一个时期 低频振荡。我将在使用光遗传学工具时进行体内细胞外电生理学 操纵远距离抑制神经元的活性。我将使用具有频率调节刺激的兴奋性蛋白 和抑制性蛋白。我将测量单个单元和网络振荡对此刺激的响应。我会 在远程抑制性神经元和其他神经元类型中进行操纵，以显示结果的特异性 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，我将能够关联此细胞类型的连通性，形态和活动模式，以了解角色 这种细胞类型的皮质电路。