Inhibitory and Disinhibitory VIP Interneuron-Mediated Circuits in Neocortex

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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.