Through NIDCD funding (R21DC013172) we showed that noise-induced temporary damage to the auditory
dendrites is more severe when the exposure occurs at night compared to the day. Preliminary data strongly
suggest that circulating glucocorticoids, which peak at nighttime in mice, are responsible for the greater
sensitivity to night noise trauma. In absence of circulating glucocorticoids (by adrenalectomy), mice exposed to
night noise show complete recovery of their auditory brainstem thresholds, and have their synaptic ribbons
protected. RNAseq data show that inflammatory pathways rise at nighttime in the cochlea, and this is
abolished in adrenalectomised mice, suggesting that inflammatory response could underlie the greater
vulnerability of the auditory synapse. The RNAseq identified 7211 genes in the cochlea that have circadian
expression and 65% of these genes show maximal expression at night-time. Since it is not standard practice in
the auditory field to collect samples at different time points throughout the day a full understanding of gene
regulation during the day and the night in the cochlea is lacking. Our laboratory is currently addressing this
challenge with the following aims:
Specific Aim 1: To identify glucocorticoid-dependent inflammatory signals that display circadian
patterns and are triggered by day or night noise trauma in the cochlea. Hypothesis: GCs modulate
inflammatory signals in a circadian manner causing a greater inflammatory response to night noise trauma
compared to the day.
Specific Aim 2: To determine whether Bmal1 in the cochlea regulates the GC-dependent inflammatory
signals in response to day or night noise trauma. Hypothesis: In the cochlea, the core clock protein Bmal1
regulates the circadian cytokine release in response to noise and causing synaptopathy.
Specific Aim 3: To develop new pharmacological treatments targeting the circadian machinery to
protect from inflammatory-triggered noise-induced synaptopathy. Hypothesis: Inhibition of the clock at
nighttime can prevent night noise-induced synaptopathy via the inhibition of inflammatory responses.
This project will clarify how circadian and glucocorticoid-dependent inflammatory signals cause cochlear
synaptopathy after temporary noise trauma. A battery of functional methods (auditory electrophysiology, noise
trauma), quantitative morphological methods (cochleograms, spiral ganglion neuron counts, pre/post synaptic
counts) and molecular methods (genetic mouse models, RNA seq) will be used. Ultimately, novel drugs that
will modulate circadian rhythms could emerge to prevent and treat from noise-induced synaptopathy. Our
results will introduce a new concept to the auditory field, namely, chronopharmacology, where optimal efficacy
of drug treatment depends on the time of administration. The novel theoretical concept of this proposal is
that the optimal function of the auditory system requires periods of activity followed by rest that is
tightly regulated by clock genes. As simple and obvious as this may sound, this concept has neither
been previously explored in the context of noise trauma nor treatment strategies.