Wednesday, April 30, 2025
4/30/2025
Top-down modulation of the dorsal cochlear nucleus - PROJECT SUMMARY An animal’s survival depends on their accurate perception of biologically relevant sounds in a complex hearing environment that is awash with background noise. Top-down contextual information modulates the processing of bottom-up sensory signals at multiple levels of the auditory pathway to improve hearing accuracy, but the neural mechanisms underlying this essential function remain unclear, especially at the earliest processing level in central auditory system. Here we examine the role of the massive top-down projection from the inferior colliculus (IC) to the dorsal cochlear nucleus (DCN). Our overarching hypothesis is that top-down signals that encode contextual information are conveyed to DCN by descending IC projections to guide context-dependent filtering. The proposed project will reveal the circuit mechanisms of top-down modulation at the first level of auditory processing in the central nervous system. This work could provide insight into ways to improve auditory perception when bottom-up signals are degraded due to hearing loss, as well auditory processing disorders for which top-down modulation has been implicated. Early filtering that is guided by top-down modulation is a general principle in sensory systems. Establishing how neural circuits implement context-dependent filtering has been difficult, due in part to a lack of in vivo phenomenological studies being combined with circuit-level analysis. We will examine the neural mechanisms underlying top-down modulation of the DCN by utilizing a powerful combination of (1) neural circuit analysis using projection-specific retrograde tracing, (2) in vitro acute brain slice electrophysiology in transgenic mice, and (3) cutting-edge in vivo electrophysiology and optogenetics in awake mice. Aim 1 tests the hypothesis that DCN-projecting IC neurons are a subtype of small cells in the central nucleus, by retrogradely labeling them and targeting them for direct electrophysiological and anatomical analyses. Aim 2 tests how descending IC projections are processed by specific cells and microcircuits in DCN. We recently discovered a pathway, through excitatory interneurons called unipolar brush cells, that could preserve the descending tonotopic signals and extend their neural representation. This aim will test the hypothesis that unipolar brush cells amplify signals to principal cells in DCN. Aim 3 tests how descending IC projections shape auditory responses of DCN principal neurons in awake mice. We will use optogenetic inhibition of DCN-projecting IC neurons to test their role in spontaneous firing rates, frequency response properties, temporal response properties, and tone-in-noise detection thresholds. Successful completion of this project will establish how top-down projections from IC modulate auditory responses in the first level of auditory processing in the brain and will reveal the circuit mechanisms that contribute to accurate auditory processing in complex sound environments.
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