Network modulators of auditory thalamocortical feedback inhibition - PROJECT SUMMARY/ABSTRACT Accurate coding and filtering of auditory information depends on the auditory thalamocortical circuit, dysfunction of which is linked to tinnitus and Autism Spectrum Disorder (ASD). Within this circuit, the thalamic reticular nucleus influences auditory thalamocortical neuron coding and activity to determine parameters of attention and stimulus selection, but an understanding of this circuit is incomplete. Clearly, thalamic and cortical afferents modulate the thalamic reticular nucleus, but other extrathalamocortical brain regions are also involved in shaping the sensory filtering properties of the TRN. We hypothesize that brain regions which integrate multi- modal sensory information to form internal predictions or determine emotional state are important for ‘tuning’ the filtering properties of TRN neurons through modulation of TRN activity, auditory coding, and sensory selection behaviors. Preliminary data indicate cerebellar output nuclei (sensorimotor predictions) and amygdala (emotion) directly project to the thalamic reticular nucleus – a brain region that inhibits sensory thalamic neurons to modulate stimulus coding, selection, and attention. This direct connection between cerebellum and thalamic reticular nucleus may be an important conduit for the relay of multi-modal sensory information and related predictions about surrounding events in time and space (e.g. changes in multiple acoustic stimuli sources, background noise, etc.). Likewise, a direct projection from the amygdala to the thalamic reticular nucleus may provide emotional context regulating selection of and attention to specific stimuli (e.g. heightened perception in stressful environments). While anatomical evidence for these connections is clear, the function of cerebellar and amygdala projections to thalamic reticular nucleus, cell type-specific circuitry, and subsequent influence on auditory thalamic neurons is widely unknown. To address this knowledge gap and develop a comprehensive model of this circuitry, we will perform whole cell recordings and immunohistochemistry/in situ hybridization on neurons in the thalamic reticular nucleus (Aim 1), cerebellar nuclei, and amygdala (Aim 2) that will identify the function of these pathways at a cellular level. Using an optogenetic approach, we will assess the neurotransmitter released by each projection (Aim 1) and the functional and molecular identity of neurons forming this projection in cerebellar nuclei and amygdala (Aim 2). These data will provide a foundation for identifying the functional impact of cerebellar and/or amygdala projections to the thalamic reticular nucleus regarding dynamics of this network, influence auditory processing in the thalamus, and involvement of these projections in stimulus selection and attention.
