Project Grant K08DC022004

PLASTICITY OF AUDITORY CORTEX MICROGLIA AND PERINEURONAL NETS AFTER HEARING LOSS - 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.