Inhibitory and Disinhibitory VIP Interneuron-Mediated Circuits in Neocortex

摘要 GABA能抑制中间神经元(INS)是一组不同的神经元，在塑造 大脑皮层电路活动和信号处理的时空方面。此外，还会出现故障 这些神经元与许多疾病有关，从癫痫到精神分裂症，再到焦虑 精神障碍和自闭症。这个项目的重点是表达神经肽血管活性的GABA能INS。 肠肽(VIP)。VIP INS是皮质浅层的主要IN人群， 最近发现是皮质和丘脑皮质投射的主要靶点，以及胆碱能 调节自上而下或上下文感觉加工并主要针对抑制性生长抑素的投射 (SST)INS。基于这种连通性和对它们在多种类型体内活动模式的分析 这些研究表明，VIP INS介导了一种去抑制的典型环路，即 在大脑状态依赖的皮质功能控制中很重要。VIP INS牵涉到唤醒，注意， 感觉加工、突触可塑性和学习。此外，有几项研究表明VIP INS 在精神分裂症和与儿童癫痫相关的认知缺陷方面。最近的研究表明，VIP INS是多种多样的。我们表明，它们至少由三个不同的种群组成，具有不同的层状分布，如 以及不同的形态和潜在的不同的传入和传出连接，表明 对锥体神经元的抑制和去抑制作用。数据表明，要发现电路 血管活性肠肽调节特定皮质功能的机制及其引起的机制 疾病有必要了解VIP IN亚型的不同连接性和功能。这 应用程序使用最先进的电生理和光遗传学方法以及创新 识别和操纵亚型中特定VIP以了解其传出的交叉遗传策略 (目标1)和传入连接(目标2)。在目标3中，我们使用双光子钙成像，光发生和 清醒行为小鼠的药物遗传学操作以发现VIP in亚型如何调节效应 唤醒对皮质功能重组和感觉处理的影响。这些研究将推动我们的 了解血管活性肠肽IN的功能和感觉加工的自上而下调节机制。

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.