Experience-dependent flexibility in a molecularly diverse central-to-peripheral auditory feedback system

Abstract

Brainstem olivocochlear neurons (OCNs) modulate the earliest stages of auditory processing through feedback projections to the cochlea and have been shown to influence hearing and protect the ear from sound-induced damage. Here, we used single-nucleus sequencing, anatomical reconstructions, and electrophysiology to characterize murine OCNs during postnatal development, in mature animals, and after sound exposure. We identified markers for known medial (MOC) and lateral (LOC) OCN subtypes, and show that they express distinct cohorts of physiologically relevant genes that change over development. In addition, we discovered a neuropeptide-enriched LOC subtype that produces Neuropeptide Y along with other neurotransmitters. Throughout the cochlea, both LOC subtypes extend arborizations over wide frequency domains. Moreover, LOC neuropeptide expression is strongly upregulated days after acoustic trauma, potentially providing a sustained protective signal to the cochlea. OCNs are therefore poised to have diffuse, dynamic effects on early auditory processing over timescales ranging from milliseconds to days.

Lateral olivocochlear neurons modulate cochlear responses to noise exposure

“…The finding that LOCs-but not MOCs-exhibited changes in expression of neural signaling molecules following NE (Figs. 1E, S1D-F), combined with prior findings of long-lasting changes in protein expression of such molecules (5,15,33), suggested a distinct role for LOCs in modulating cochlear properties following NE. To test how LOCs affect auditory function after NE, we developed an intersectional genetic approach to selectively access LOCs bilaterally, without impacting MOCs or other cells in the auditory brainstem.…”

“…However, this binary classification scheme belies a more nuanced reality: as with cellular subtypes identified elsewhere in the brain (65)(66)(67)(68), LOC subtypes appear to exist along a spatially defined continuum, with a gradient of gene expression blending LOC2s into LOC1s along the medial-lateral axis of the LSO (5). We have previously shown that this gradient persists at the protein level after NE, even as the fraction of peptide-expressing LOCs increases (5). Determining the gene-regulatory programs that establish this expression gradient and examining how these programs are altered by LOC activity constitutes a rich avenue for future study.…”

“…Moreover, exposure to noise can induce changes in the expression profile of LOC signaling molecules that persist for days to weeks (5,15,33). These findings raise the possibility that LOCs influence cochlear function in multiple ways that can change in response to auditory experience.…”

“…OCNs consist of two major cell types: lateral olivocochlear neurons (LOCs) densely innervate Type I SGN peripheral fibers and medial olivocochlear neurons (MOCs) innervate outer hair cells (OHCs), with sparse collaterals onto SGN peripheral processes (Fig. 1A) (4)(5)(6)(7)(8). In response to sound, MOCs rapidly and dynamically tune OHC control over cochlear sensitivity (9)(10)(11)(12)(13).…”

Fast inhibition slows and desynchronizes mouse auditory efferent neuron activity

“…For inhibition, there may be an additional direct projection from the CN 85 , but poly-synaptic inputs are likely because of the ~3-4 ms delay between first and second clusters of IPSCs in most recordings. Potential polysynaptic inhibitory inputs from auditory neurons include the LNTB 86,87 , the superior peri-olivary nucleus (SPON) 88,89 , other inhibitory neurons in the VNTB 90 , or the MOC neurons themselves, which are cholinergic but likely also GABAergic [91][92][93] .…”