GABA and NPY Signaling Interact to Shape Inhibition in the Auditory Tectothalamic Pathway - Abstract Inhibition critically shapes auditory signal processing, impacting nearly every aspect of hearing. In the inferior colliculus (IC), inhibition shapes how neurons respond to auditory cues that are essential for speech and vocalization processing, including frequency tuning curves and directional selectivity for frequency modulated (FM) sweeps. In addition, diminished synaptic inhibition is a critical feature in age-related hearing loss. The IC is considered the hub of the central auditory pathway, and despite the crucial role of inhibition in the IC, the cellular mechanisms underlying GABAergic inhibition remain largely unknown. This gap in our understanding exists because it has been proven difficult to identify distinct GABAergic neuron types in the IC. We recently overcame this problem by identifying Neuropeptide Y (NPY) expression as a marker for a novel class of inhibitory principal neurons in the IC. NPY neurons are GABAergic, have a stellate morphology and project to the auditory thalamus (MG). In addition, we found that NPY signaling dampens the excitability of a large family of IC glutamatergic neurons that express the NPY Y1 receptor (Y1R). In this proposal, I will investigate the mechanisms underlying NPY signaling in the IC and how the co-release of NPY and GABA affects auditory processing in vivo. The overall objective of this research is to determine how NPY and GABA signaling from a defined class of IC GABAergic neurons influence Y1R neurons to shape frequency tuning and FM sweep direction selectivity in the auditory tectothalamic pathway. I will further determine whether augmenting NPY signaling improves features of auditory processing in the IC and MG that are disrupted in a mouse model of aging. To pursue these objectives, I will use in vitro and in vivo electrophysiology, combined with pharmacology, chemogenetics and optogenetics. Aim 1 will be accomplished during the K99 phase. I will combine in vitro electrophysiology with pharmacology and optogenetic circuit mapping to determine how GABA and NPY signaling interact to modulate excitability in the IC. Aim 2 will be performed during the K99 phase. I will make in vivo recordings in the IC-MG pathway while using pharmacology, chemogenetics and optogenetics to modulate NPY and GABAergic signaling. This aim will determine how NPY signaling shapes the tonal receptive fields and FM sweep direction selectivity of neurons in the IC and MG. In Aim 3, during the R00 phase, I will combine the skills I have learned during the K99 phase with my background in electrophysiology and viral tract tracing to investigate how NPY and Y1R neurons interact to shape postsynaptic activity in the MG. I will further determine how excitatory-inhibitory interactions in this circuit are affected in a mouse model of aging. This research will provide a mechanistic understanding of how a distinct subtype of GABAergic neuron interacts with neuropeptide signaling in the IC to shape auditory computations in the tectothalamic pathway.
