The function of thalamic inhibition in auditory processing. Interactions between inhibitory and excitatory neurons along the auditory pathway shape how acoustic information is processed in the brain. The thalamic reticular nucleus (TRN) is the main source of inhibition in the thalamus; it sends dense inhibitory projections to thalamic nuclei including a key structure in the ascending auditory pathway, the medial geniculate body (MGB). MGB is comprised of excitatory thalamic relay cells that project to the auditory cortex (AC) wherein auditory information is then decoded. Additionally, the MGB relay cells send collaterals to TRN to provide feedback. Although TRN is necessary for transfer of important acoustic information to higher-order structures in the auditory pathway, TRN's function at the cellular level in remains poorly characterized. The goal of this proposal is to identify the function of different inhibitory neuronal subtypes in TRN in auditory processing. TRN is comprised entirely of GABAergic inhibitory neurons, of which the two dominant sub-classes are parvalbumin- (PV) and somatostatin- (SOM) positive neurons, with a subset of TRN neurons co-expressing both neurotransmitters. In AC, PV and SOM neurons differentially modulate frequency-dependent responses and differentially control adaptation in excitatory cortical neurons. However, to date, little is known of the function of these two inhibitory neuronal subtypes in the TRN. Moreover, their anatomical characterization remains limited. In this proposal, I will test the hypothesis that PV and SOM neurons in TRN target distinct sub-nuclei of the MGB, exhibit unique sound-response properties, and differentially modulate sound responses in MGB. To test this hypothesis, I will combine state- of-the-art anatomical tracing, optogenetic, and electrophysiological approaches. With novel tracing techniques, I will establish the anatomical connectivity between PV+ and SOM+ neurons of TRN and the MGB. Furthermore, I will use optogenetics and electrophysiological approaches to functionally characterize how PV and SOM neurons of TRN are modulating sound responses in the MGB. Combined, these results will reveal critically important information about the differential function of inhibitory neurons at the level of the auditory thalamus, an essential processing station in the auditory pathway.
The goal of the proposed research is to identify how circuit-level inhibitory mechanisms in the auditory thalamus shape sound responses prior to reaching higher-order cortical structures. Patients with hearing deficits, age-related hearing loss and communication deficits, exhibit disproportionate difficulty hearing in complex acoustic environments where inhibitory circuits are likely crucial. Identifying the function of specific inhibitory neuronal circuits in the auditory pathway and their relation to sound processing, is a prerequisite for the development of new and improvement of existing therapies for these large groups of patients.
