Biology subjects

Elkins, S.

Publications and source records attributed to Elkins, S..

3 recordsLinked to original sources

bioRxiv2025

Predicting cochlear synaptopathy in mice with varying degrees of outer hair cell dysfunction using auditory evoked potentials

Human temporal bones suggest a steady decline of cochlear synapses with age and greater synapse loss in adults with a history of military or occupational noise exposure. However, there is currently no validated method of diagnosing this type of cochlear deafferentation in living humans. Animal models indicate that cochlear synaptopathy is associated with reduced auditory brainstem response (ABR) wave 1 amplitude and envelope following response (EFR) magnitude for a sinusoidally amplitude modulated (SAM) tone. However, translating the SAM EFR to humans is complicated because it is difficult to obtain this measurement in humans using the same modulation frequency that showed the strongest relationship with synaptopathy in mice (1000 Hz). Computational modeling suggests that EFR magnitude measured with a rectangular amplitude modulated (RAM) tone may be a more sensitive measure of synaptopathy than the SAM EFR. In addition, because synaptopathy likely co-occurs with outer hair cell dysfunction, a diagnostic assay for synaptopathy needs to be robust even when auditory thresholds are abnormal. This study compared the relative ability of the ABR, SAM EFR, and RAM EFR to predict synapse numbers in mice with a large range of auditory thresholds and degrees of synaptopathy. The results indicate that the RAM EFR modulated at 1000 Hz is the single best predictor of synapse number when there is a broad loss of synapses across frequency, while combining RAM EFR and ABR further improves synapse prediction. In contrast, focal synaptopathy is best predicted by ABR wave 1 amplitude. Significance StatementThis study assessed the relative ability of two auditory evoked potentials to identify cochlear synaptopathy, a type of cochlear deafferentation that occurs with age and noise exposure, in mice. Performance of these measures in the presence of outer hair cell (OHC) damage was also evaluated because synaptopathy is expected to often co-occur with OHC dysfunction. Concrete recommendations of measurements to use for non-invasive diagnosis of synaptopathy in humans are provided. This represents a significant advance toward diagnosis of a condition that is thought to have a high prevalence in humans. The ability to identify individuals with cochlear synaptopathy is vital for furthering our understanding of how this auditory deficit impairs auditory perception and the future development of treatment options.

neuroscience↗

bioRxiv2023

The Na+ leak channel NALCN controls spontaneous activity and mediates synaptic modulation by α2-adrenergic receptors in auditory neurons

Cartwheel interneurons of the dorsal cochlear nucleus (DCN) potently suppress multisensory signals that converge with primary auditory afferent input, and thus regulate auditory processing. Noradrenergic fibers from locus coeruleus project to the DCN, and 2-adrenergic receptors inhibit spontaneous spike activity but simultaneously enhance synaptic strength in cartwheel cells, a dual effect leading to enhanced signal- to-noise for inhibition. However, the ionic mechanism of this striking modulation is unknown. We generated a glycinergic neuron-specific knockout of the Na+ leak channel NALCN, and found that its presence was required for spontaneous firing in cartwheel cells. Activation of 2-adrenergic receptors inhibited both NALCN and spike generation, and this modulation was absent in the NALCN knockout. Moreover, 2-dependent enhancement of synaptic strength was also absent in the knockout. GABAB receptors mediated inhibition through NALCN as well, acting on the same population of channels as 2 receptors, suggesting close apposition of both receptor subtypes with NALCN. Thus, multiple neuromodulatory systems determine the impact of synaptic inhibition by suppressing the excitatory leak channel, NALCN.

neuroscience↗

bioRxiv2019

Optimizing auditory brainstem response acquisition using interleaved frequencies

Auditory brainstem responses (ABRs) require averaging responses to hundreds or thousands of repetitions of a stimulus (e.g., tone pip) to obtain a measurable evoked response at the scalp. Fast repetition rates lead to changes in ABR amplitude and latency due to adaptation. To minimize the effect of adaptation, stimulus rates are sometimes as low as 10 to 13.3 stimuli per second, requiring long acquisition times. The trade-off between reducing acquisition time and minimizing the effect of adaptation on ABR responses is an especially important consideration for studies of cochlear synaptopathy, which use the amplitude of short latency responses (wave 1) to assess auditory nerve survival. It has been proposed that adaptation during ABR acquisition can be reduced by interleaving tones at different frequencies, rather than testing each frequency serially. With careful ordering of frequencies and levels in the stimulus train, adaptation in the auditory nerve can be minimized, thereby permitting an increase in the rate at which tone bursts are presented. However, widespread adoption of this stimulus design has been hindered by lack of available software. Here, we develop and validate an interleaved stimulus design to optimize the rate of ABR measurement while minimizing adaptation. We implement this method in an open-source data acquisition software tool that permits either serial or interleaved ABR measurements. The open-source software library, psiexperiment, is compatible with widely-used ABR hardware. Consistent with previous studies, careful design of an interleaved stimulus train can reduce ABR acquisition time by more than half, with minimal effect on ABR thresholds and wave 1 latency, while improving measures of wave 1 amplitude.

neuroscience↗