Thursday, November 21, 2024
11/21/2024
Project Summary Functional diversity of Type I spiral ganglion neurons (SGNs) in the cochlea is a fundamental feature of mammalian auditory circuits thought to support the wide dynamic range of sound intensity coding. They were classified recently into three molecularly distinct subtypes (Ia, Ib, Ic). Based on their synapse morphology and location around the inner hair cell (IHC) circumference, these molecular classes correspond to SGN subgroups with high, medium and low spontaneous firing rates (SR), respectively, defined previously. Selective loss of Ic contribution to sound encoding is thought to underlie deterioration of hearing, particularly in noisy conditions, after acoustic overexposure or due to old age. A thorough understanding of the mechanisms shaping SGN identities is crucial for re-establishing the afferent response diversity needed for normal hearing. SGN heterogeneity emerges through at least two major splits in their differentiation trajectory during embryogenesis. The first one involves maintenance of the transcription factor Runx1 to Ib/Ic precursors and repression in SGNs that become Ia, while Ib and Ic SGNs segregate further in a subsequent split. Final SGN subtype proportions are then set postnatally in an activity-dependent manner; in mice lacking glutamatergic transmission from IHCs to SGNs (Vglut3-/-), most develop as Ia. Runx1 is necessary embryonically and must also be maintained postnatally to avoid a similar overproduction of Ia SGNs. Here we further characterize the regulatory logic of SGN diversification in mice using single-cell genomic approaches. In Aim 1, we investigate mechanisms underlying the first bifurcation of SGN subtype identities featuring downregulation of Runx1 in a subset of neurons. In Aim 2, we study how heterogeneity in SGN spontaneous activity relates to their transcriptomic identities and explore whether Ia SGNs can be converted back to Ib/Ic. In Aim 3, we map the gene regulatory landscape supporting plasticity and stability of SGN identities by performing single-cell multiomic profiling of SGNs. Together, these studies will advance our understanding of how SGN molecular identities emerge, remain plastic, and ultimately become stabilized, thereby offering a powerful platform to explore the possibility of interconversion of SGN identities. These goals are highly relevant for addressing hearing health-related challenges such as synaptopathy, SGN degeneration, and genetic hearing loss.
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