Crossmodal plasticity of adult corticothalamic circuits

About This Grant

PROJECT SUMMARY Sensory loss leads to widespread adaptation across the brain areas to enhance processing of the remaining senses as exemplified by enhanced auditory functions in blind individuals. Such crossmodal compensatory plasticity is not restricted to congenitally blind individuals but is also observed after late-onset vision loss. We previously found that visual deprivation initiated in adult mice leads to widespread synaptic and circuit-level plasticity in the auditory pathway: potentiation of feedforward inputs carrying auditory information in the primary auditory cortex (A1), including recovery of thalamocortical synaptic plasticity, functional refinement of local circuitry in A1, and disinhibition of the primary auditory thalamus. These changes correlated with a reduction in the sound detection threshold and sharper tuning of A1 layer 4 (L4) neurons as well as refinement of sound representation in A1 L2/3. Here, we propose to test the hypothesis that such widespread plasticity of the auditory system following visual deprivation is functionally coordinated by the plasticity of the corticothalamic (CT) circuit. There are largely three distinct CT circuits: (1) Lemniscal CT pathway mediated by A1 L6 neurotensin receptor 1 (Ntsr1)-positive neurons, which provide cortical feedback to the primary auditory thalamus (MGBv) and the inhibitory thalamic reticular (TRN) nucleus, (2) non-lemniscal CT pathway mediated by A1 L6b neurons (Cplx3 and Drb1a-positive), which project to higher order non-lemniscal thalamic nuclei, and (3) cortico-thalamo-cortical (CTC) pathway mediated by A1 L5 neurons (Rbp4-positive), which project to higher-order auditory cortical areas via the higher-order auditory thalamic nuclei. We aim to investigate how early- and late-onset visual deprivation alters the function of these CT circuits in adult mice (Aim 1), whether it affects CT circuit regulation of feedforward auditory pathways (Aim 2), and determine how it alters the sound encoding of CT neurons (Aim 3). We will utilize optogenetics to assess the plasticity of functional circuits, multi- photon Ca2+ imaging accompanied by auditory behavioral tasks to measure neural activity changes, and pharmacogenetics for testing neural circuit elements on in vivo function and behavior. Results from our work will provide mechanistic information on how the CT circuit mediates crossmodal compensatory plasticity in early- and late-onset blind models, which would benefit the development of potential therapeutics for improving sensory function.