The primary auditory cortex (A1) generates extensive descending projections to a variety of subcortical structures, including the striatum and the inferior colliculus (IC). These so-called corticofugal projections originate from excitatory pyramidal neurons located mostly in layer 5 of the cortex. Despite their widespread influence, little is known about the functional contributions of these neurons to the processing of auditory sensory information. An important issue to address is whether or not these descending projections arise from a common population of cortical neurons or from relatively separate, target-specific subpopulations. Previous studies suggest that, while collateralization to multiple targets exists, many corticofugal neurons may innervate a single target. This is important as physiological properties may vary, even among commingled neurons within a layer, depending on their specific long-range targeting profile. This raises the possibility that the auditory corticofugal system may consist of several functionally distinct, projection-specific subpopulations. To access these neurons and characterize their anatomical and physiological properties, an adeno-associated viral (AAV) based strategy will be used to retrogradely label neurons with a specified subcortical target. Using paired injections of AAV-Cre and a Cre-dependent virus expressing GFP in mice, Aim 1 will systematically examine the laminar origin, morphology, and extent of collateralization for all corticofugal populations in A1. This will provie a comprehensive characterization of auditory corticofugal projection neurons, and the results of this study may help clarify the degree to which these innervate single or multiple subcortical targets.
Aim 2, will employ a Cre-dependent channelrhodopsin 2 (ChR2) expressing virus to tag and optogenetically identify retrogradely labeled neurons in A1 that project to either IC or striatum. Under the guidance of Dr. Li Zhang, I will learn to perform high quality, in vivo loose-patch recordings from these neurons in awake mice during the presentation of auditory stimuli. These studies will directly reveal the spectral and temporal response properties for each of these two target-defined projection populations, and they may provide evidence for or against the functional specialization of neurons based on their subcortical target. In pursuit of these aims, the proposed training complements my strong anatomical background with the ability to investigate the functional properties of specific classes of neurons using sophisticated optogenetic and electrophysiological methods. The mentorship, guidance, and technical expertise I will acquire under this training grant will contribute greatly to my overall goal of becoming a Principal Investigator studying the function of neural circuits in the brain.
The auditory cortex has the capacity to modify and relay incoming sensory information via extensive corticofugal projections to the striatum, thalamus, and early auditory processing centers. The goal of this study is to characterize the degree to which these descending projections share a common functional role, or rather arise from independent groups of neurons that have specialized roles in the regulation of specific subcortical targets. The proposed studies will generate new insights for our understanding of the normal physiology and organization of the auditory system, which may provide a means for identifying circuit components that may go awry in psychiatric and neurological disorders.
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