Maladaptive cortico-amygdalar plasticity after noise-induced hearing loss

At the level of the auditory cortex (ACtx) neural representations of acoustic sound properties are modulated by
extra-acoustic influences arising from other sensory modalities, internal state variables, past memories, and
future predictions. Our effortless perceptual fusion of acoustic and extra-acoustic features likely reflects the
dense bi-directional connectivity of the ACtx with higher-order cortical areas, the basal ganglia, the amygdala,
and the subcortical auditory pathway. However, the multi-dimensional fusion of physical, emotional, and
cognitive variables in sound perception is also vulnerable to neurodegenerative processes in the cochlea and
brain linked to aging and noise exposure. For example, hearing disorders such as tinnitus and hyperacusis can
be triggered by sensorineural degeneration in the cochlea, but the perceptual experience of these disorders
often features extra-acoustic complaints featuring a generalized aversion, irritation, and discomfort to sound.
This proposal will provide advanced mentored training to the Candidate focused on a research strategy with
three Specific Aims. Aim 1 (K99) will leverage the unique strengths of two-photon calcium imaging to perform
chronic tracking of genetically targeted ACtx neural ensembles before and after noise-induced high-frequency
sensorineural hearing loss (SNHL). By separately recording from distinct cardinal classes of long-range ACtx
projection neurons, we will test the hypothesis that corticoamygdalar (CAmy) neurons – more than inter-
hemispheric or corticothalamic neurons – develop the strongest hyperactivity, hyper-responsivity, and hyper-
synchrony after SNHL. Experiments in Aim 2 (R00) will leverage fiber-based bulk calcium recordings within the
amygdala to contrast varying degrees of auditory hyper-responsivity in thalamo-amygdalar and CAMy afferent
inputs after SNHL. We will then use single-unit recordings and optogenetics to test the hypothesis that neural
hyperactivity, hyper-responsivity, and hyper-synchrony within the lateral and basolateral amygdala after SNHL
can be largely reversed by optogenetic silencing of CAmy synaptic inputs. Aim 3 (R00) will expand these
concepts to the behavioral domain by demonstrating poorly discriminative non-extinguishing auditory threat
memories observed in mice with SNHL are causally linked to CAmy hyperactivity, such that directly causing
CAmy hyperactivity in mice with normal hearing produces the over-generalized threat memory phenotype while
silencing CAmy hyperactivity in mice with SNHL reinstates normal discriminative threat memory recall. Overall,
the research and training plan will provide a bridge to an independent research career investigating the affective
dimensions of hearing loss, with the ultimate goal of identifying therapeutic targets for common sensory disorders
that have no widely effective therapies.

Grant Number: 1K99DC022957-01
NIH Institute/Center: NIH
Principal Investigator: Bishara Awwad