Inhibitory and Disinhibitory VIP Interneuron-Mediated Circuits in Neocortex

总结 GABA能抑制性中间神经元（INs）是一组不同的神经元，在塑造神经元的功能中起关键作用。 大脑皮层中电路活动和信号处理的时空方面。此外， 这些神经元与许多疾病有关，从癫痫到精神分裂症， 失调和自闭症。本项目的重点是GABA能神经内表达的神经肽血管活性 肠肽（VIP）。VIP IN是皮质浅层的主要IN群体， 最近发现是cotico-cortex和thalamocortical投射的主要目标，以及胆碱能 投射，介导自上而下或上下文感觉处理，主要针对抑制性生长抑素 (SST)基于这种连接性和对它们在多种类型的细胞中的体内活性模式的分析， 这些研究表明，VIP INs介导了一种去抑制的典型回路， 在大脑状态依赖的皮层功能控制中很重要。VIP IN与唤醒注意力 感觉处理和突触可塑性以及学习。此外，一些研究表明VIP IN 精神分裂症和与儿童癫痫相关的认知缺陷。最近的研究表明， IN是不同的。我们发现它们至少由三个不同的种群组成，具有不同的层流分布， 以及不同的形态和潜在的不同传入和传出连接，表明不同的 对锥体神经元的抑制和去抑制作用。数据表明要发现电路 VIP INs调节特定皮质功能的机制以及它们引起 因此，有必要了解VIP IN亚型的差异连接性和功能。这 应用程序使用最先进的电生理学和光遗传学方法以及创新的 交叉遗传策略，以识别和操纵特定的VIP IN亚型，以了解它们的传出 (Aim 1）和传入连接（目标2）。在目标3中，我们使用双光子Ca 2+成像，光遗传学和 在清醒行为小鼠中进行药物遗传学操作，以发现VIP IN亚型如何调节效应 对皮层功能重组和感觉处理的影响。这些研究将推动我们的 了解VIP IN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.