Inhibitory and Disinhibitory VIP Interneuron-Mediated Circuits in Neocortex

新皮质中抑制和去抑制 VIP 中间神经元介导的回路

• 批准号: 10719028
• 负责人: Bernardo Rudy
• 金额: $ 64.84万
• 依托单位: NEW YORK UNIVERSITY SCHOOL 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: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719028
• 关键词: Anxiety Disorders; Area; Arousal; Attention; Axon; Behavioral; Brain; Cerebral cortex; Cognition; Cognitive deficits; Data; Disease; Disinhibition; Electrophysiology (science); Epilepsy; Feedback; Functional disorder; Genetic; Glutamates; Goals; Head; Image; Interneuron function; Interneurons; Knowledge; Learning; Light; Location; Mediating; Methods; Morphology; Motor; Mus; Neocortex; Neurons; Neuropeptides; Output; Pattern; Perception; Pharmacogenetics; Population; Population Heterogeneity; Process; Property; Psychological reinforcement; Reagent; Regulation; Research Project Grants; Rett Syndrome; Role; Schizophrenia; Sensory; Signal Transduction; Slice; Somatostatin; Source; Structure; Synaptic plasticity; Testing; Transgenic Mice; Vasoactive Intestinal Peptide; Work; area striata; autism spectrum disorder; awake; basal forebrain; childhood epilepsy; cholinergic; cognitive function; experimental study; genetic approach; hippocampal pyramidal neuron; human disease; imaging modality; in vivo; innovation; neocortical; novel; optogenetics; postsynaptic; recruit; response; restraint; sensory cortex; sensory integration; signal processing; spatiotemporal; two-photon; visual control

Summary GABAergic inhibitory interneurons (INs) are a diverse group of neurons with critical roles in sculpting the spatiotemporal aspects of circuit activity and signal processing in the cerebral cortex. Moreover, malfunction of these neurons has been implicated in a number of diseases ranging from epilepsy to schizophrenia, anxiety disorders and autism. This project is focused on the GABAergic INs that express the neuropeptide vasoactive intestinal peptide (VIP). VIP INs are the main IN population in the superficial layers of the cortex, and were recently found to be major targets of cotico-cortical and thalamocortical projections, as well as cholinergic projections, that mediate top-down or contextual sensory processing and to mainly target inhibitory somatostatin (SST) INs. Based on this connectivity and the analysis of their patterns of in vivo activity in multiple types of sensory cortices, these studies have suggested that VIP INs mediate a disinhibitory canonical circuit that is important in brain state-dependent control of cortical function. VIP INs have been implicated in arousal, attention, sensory processing and synaptic plasticity and learning. Furthermore, several studies have implicated VIP INs in schizophrenia and in the cognitive deficits associated with childhood epilepsy. Recent work shows that VIP INs are diverse. We show they consist of at least three distinct populations with different laminar distribution, as well as different morphology and potentially different afferent and efferent connectivity, suggesting distinct inhibitory and disinhibitory actions on pyramidal neurons. The data implies that to discover the circuit mechanisms by which VIP INs regulate specific cortical functions and the mechanisms by which they cause disease it is necessary to understand the differential connectivity and function of VIP IN subtypes. This application uses state-of-the-art electrophysiological and optogenetic methods as well as innovative intersectional genetic strategies to identify and manipulate specific VIP IN subtypes to understand their efferent (Aim 1) and afferent connectivity (Aim 2). In Aim 3 we use 2-photon Ca2+ imaging, optogenetic and pharmacogenetic manipulations in awake behaving mice to discover how VIP IN subtypes regulate the effects of arousal on cortical functional reorganization and sensory processing. These studies will advance our understanding of VIP IN function and the mechanisms of top down modulation of sensory processing.

概括 GABA能抑制性中间神经元（INS）是一组不同的神经元，在雕刻中具有关键作用 大脑皮层中电路活性和信号处理的时空方面。而且，故障 这些神经元与从癫痫到精神分裂症，焦虑的多种疾病有关 疾病和自闭症。该项目的重点是表达神经肽血管活性的GABA能INS 肠肽（VIP）。 VIP INS是皮质表面层中的主要人口，并且是 最近发现是Cotico-Cortical和丘脑皮质投影的主要靶标，以及胆碱能 预测，介导自上而下或上下文感官处理，主要针对抑制性生长抑素 （SST）ins。基于这种连通性及其对多种类型的体内活性模式的分析 感觉皮层，这些研究表明，VIP INS介导一个抑制性的规范电路 对于大脑状态依赖性皮质功能的控制很重要。 VIP INS与唤醒，注意力相关， 感觉处理和突触可塑性和学习。此外，几项研究暗示了VIP INS 在精神分裂症和与儿童癫痫相关的认知缺陷中。最近的工作表明VIP INS是多样的。我们表明它们由至少三个不同的人群组成，具有不同的层流分布，如 以及不同的形态和潜在的传入和传出连接性，表明不同 对锥体神经元的抑制和抑制作用。数据意味着要发现电路 VIP通过调节特定皮质功能及其引起的机制的机制 疾病有必要了解VIP在亚型中的差异连通性和功能。这 应用使用最先进的电生理和光学遗传学方法以及创新 识别和操纵亚型的特定VIP以了解其发出的交叉遗传策略 （AIM 1）和传入连接性（AIM 2）。在AIM 3中，我们使用2光子Ca2+成像，光遗传学和 醒着的行为小鼠的药物遗传操作，以发现亚型中的VIP如何调节效果 在皮质功能重组和感觉处理上的唤醒。这些研究将推动我们的 了解VIP的功能和感觉处理的自上而下调制的机制。