PROJECT SUMMARY/ABSTRACT
Suprathreshold hearing disorders like hyperacusis are marked by dysfunction of fast-spiking Parvalbumin
positive interneuron (PVI) signaling and heightened cortical activity following peripheral sensorineural hearing
loss (SNHL). After cochlear injury, a rapid loss of interneuron-mediated inhibition in the auditory cortex occurs,
resulting in heightened spontaneous firing rates in cortical principal neurons, leading to hyper-synchrony and
hyper-responsiveness to sound.
The extent of PVI dysfunction can predict auditory plasticity and cortical response recovery after cochlear
damage. While many attribute PVI hypofunction solely to neuronal dysfunction, recent studies suggest non-
neural mechanisms may also play a role. Perineuronal nets (PNNs) are extracellular structures crucial for PVI
function, regulating synaptic inputs, neuronal activity, and intrinsic excitability. PNNs tighten around PVI during
development, limiting plasticity, but their disruption can reopen a plasticity window. Noise exposure degrades
PNNs and reduces PV expression in PVI, increasing cortical excitability akin to hyperacusis.
PNN degradation may result from noise-induced trauma to PVIs or an inflammatory response involving activated
microglia. Microglia, primarily associated with immune responses, also regulate homeostasis, synaptic
connectivity, and neural activity. In CNS diseases, activated microglia can have detrimental effects, such as
excessive synaptic pruning, neuroinflammation, and alterations in neuronal excitability. However, they can also
promote regeneration and cellular remodeling. The hypothesis underlying this research suggests that PNNs and
microglia play critical roles in PV hypofunction and may be early factors in central gain disorders. The study aims
to: 1) Investigate chronic PNN degradation in deafferented regions of the auditory cortex after cochlear SNHL,
alongside an increase in activated microglia. 2) Examine the impact of regional microglia elimination shortly
before SNHL on central gain and hyperacusis symptoms. 3) Explore targeted activation of PVI, potentially
normalizing PNN and microglia expression, and reversing loudness hyperacusis symptoms.
In summary, suprathreshold hearing disorders like hyperacusis are associated with PVI dysfunction leading to
cortical hyperexcitability following SNHL. PNNs and microglia are proposed as crucial contributors to PVI
hypofunction and central gain disorders, and this research aims to uncover their roles and potential therapeutic
avenues for restoring normal auditory function.