Biology subjects

White, P. M.

Publications and source records attributed to White, P. M..

3 recordsLinked to original sources

bioRxiv2025

Expression of the naked mole-rat transgene for Has2 improved health span in C57Bl/6 mice, but it did not attenuate age-related hearing loss.

The naked mole-rat (NMR) is renowned for being the longest-lived rodent, with a maximum lifespan of over 40 years. This exceptional longevity has been attributed to increased cytoprotective signaling, which has been partially ascribed to a major component of the NMRs extracellular matrix hyaluronan (HA), which has an unusually large molecular mass in this species. The HA molecular mass in the NMR is five to six times greater than in mice and humans. Mice expressing the transgene for NMR HA synthase 2 (nmrHas2), which is the enzyme that produces very high molecular mass HA (vHMM-HA), had improved health outcomes at an advanced age, such as improved mobility, grip strength, and reduced inflammation. Calorie restriction (CR) similarly improves healthspan in mice, and CR has also been shown to attenuate age-related hearing loss (AHL). Specifically, CR mitigates the effects of a single-nucleotide polymorphism (SNP) in the cadherin 23 (Cdh23) gene, which encodes a protein required for the stability of stereocilia on cochlear hair cells in mice and humans. Therefore, we hypothesized that AHL would be attenuated in nmrHas2+ mice. We performed auditory brainstem response testing on 3-month and 12-month-old mice with (nmrHas2+) and without (nmrHas2-) the NMR transgene. We observed AHL at 12 months of age in both nmrHas2+ and nmrHas2-mice, and AHL was not attenuated by nmrHas2 expression. This suggests that the cytoprotective effects of vHMM-HA work through a different pathway from CR, at least with respect to the inner ear.

neuroscience↗

bioRxiv2020

Endogenous SIRT3 activity is dispensable for normal hearing recovery after noise exposure in young adult mice

Occupational noise-induced hearing loss (NIHL) affects millions of people worldwide and presents a large social and personal burden. Some genetic variants in the mitochondrial oxidative stress response correlate strongly with susceptibility to NIHL in both humans and mice. Here we test the hypothesis that SIRT3, a regulator of the mitochondrial oxidative stress response, is required in mice for endogenous recovery of auditory thresholds after a sub-traumatic noise exposure. We expose homozygous Sirt3-KO mice and their wild-type littermates to a noise dose that confers a temporary threshold shift, but is not sufficient to permanently reduce cochlear function, compromise cell survival, or damage synaptic structures. We find no difference in hearing function after recovery from noise exposure between the two genotypes, when measured by either auditory brainstem response (ABR) or distortion product otoacoustic emissions (DPOAE). We show that SIRT3-specific immunoreactivity is present in outer hair cells, around the post-synaptic regions of inner hair cells, and faintly within inner hair cells. Nonetheless, outer hair cells and auditory synapses show no increase in loss after noise exposure in the homozygous Sirt3-KO mouse. These data show that SIRT3-dependent processes are not necessary for endogenous hearing recovery after a single, sub-traumatic noise exposure. They demonstrate the existence of cellular mechanisms of cochlear homeostasis in addition to the mitochondrial oxidative stress response. We also present a novel statistical analysis for identifying differences between peak 1 amplitude progressions in ABR waveforms.

neuroscience↗

bioRxiv2019

Partial Hearing Restoration after ERBB2 Induction in Deafened Adult Mice

Noise-induced hearing loss (NIHL) affects over ten million adults in the United States, and has no biological treatment. We hypothesized that activation of signaling from ERBB2 receptors in cochlear supporting cells could mitigate cochlear damage. We adopted a new timeline for assessing mitigation that parallels hearing recovery from damage in avians. We drove expression of a constitutively active variant of ERBB2 (CA-ERBB2) in cochlear supporting cells three days after permanent noise damage in young adult mice. Between 100-200 supporting cells in the apical cochlea expressed a lineage marker, indicating competence to express CA-ERBB2. Hearing thresholds were assessed with auditory brainstem response tests, and hearing recovery was assessed over a ninety-day period. Mice harboring CA-ERBB2 capability had similar hearing thresholds to control littermates prior to noise exposure, immediately after, and 30-days after. Sixty and ninety days after noise exposure, CA-ERBB2+ mice demonstrated a partial but significant reversal of NIHL threshold shifts at one in five frequencies tested, which was in the region of CA-ERBB2 expression. We evaluated inner and outer hair cell (IHC and OHC) survival, synaptic preservation, stereociliary morphology, and IHC cytoskeletal alterations with histological techniques. Improved IHC and OHC survival were observed in the basal cochlea. No differences were seen in synaptic numbers or IHC cytoskeletal alterations, but more stereocilia may have been preserved. These data indicate, for the first time, that ERBB2 signaling in supporting cells can promote hair cell survival and partial functional recovery, and that permanent threshold shifts from noise may be partially reversed in mice.

neuroscience↗