R01DC022254

CORTICAL MECHANISMS OF INNATE FREQUENCY DISCRIMINATION - ABSTRACT THROUGHOUT EVOLUTION, THE ABILITY TO DISTINGUISH ACOUSTIC FREQUENCIES FROM EACH OTHER AND FROM THE SURROUNDING AUDITORY ENVIRONMENT HAS BEEN ESSENTIAL FOR SURVIVAL. IN HUMANS, THIS ABILITY REMAINS FUNDAMENTAL TO EVERYDAY HEARING, LINGUISTICS, AND MUSICALITY, YET THE NEURAL AND MOLECULAR MECHANISMS UNDERLYING FREQUENCY DISCRIMINATION ARE NOT WELL UNDERSTOOD. GABAERGIC INTERNEURONS (INS) IN THE AUDITORY CORTEX (ACX) HAVE BEEN IMPLICATED AS THE CELLULAR LOCI UNDERLYING BEHAVIORS THAT RELY ON FREQUENCY-DISCRIMINATION ABILITIES. THIS NOTION HAS BEEN CONFIRMED BY THE RECENT DISCOVERY THAT HYPEREXCITABILITY OF GABAERGIC INS IN THE ACX CAUSES FREQUENCY- DISCRIMINATION HYPERACUITY IN MODELS OF WILLIAMS-BEUREN SYNDROME (WBS), A NEURODEVELOPMENTAL DISORDER ASSOCIATED WITH COGNITIVE AND LEARNING IMPAIRMENTS THAT SPARES OR ENHANCES AUDITORY FUNCTIONS. WE RECENTLY SHOWED THAT MOUSE MODELS OF WBS HAVE INNATELY SUPERIOR FREQUENCY-DISCRIMINATION ACUITY THAT RESULTS FROM HYPEREXCITABLE GABAERGIC INS IN THE ACX. AMONG THE WBS GENES, GTF2IRD1 IS THE ONLY ONE WHOSE HAPLOINSUFFICIENCY REPLICATES WBS PHENOTYPES BY DOWNREGULATING VASOACTIVE INTESTINAL POLYPEPTIDE RECEPTOR 1 (VIPR1). VIPR1 DEFICIENCY CAUSES HYPEREXCITABILITY OF GABAERGIC INS IN THE ACX AND IMPROVES FREQUENCY- DISCRIMINATION ABILITIES. PRELIMINARY DATA INDICATED THAT VIPR1 ACTS THROUGH VOLTAGE-GATED CALCIUM CHANNELS (VGCCS), BUT THE IDENTITY OF SPECIFIC VGCCS IS UNKNOWN. VIPR1 OVEREXPRESSION IN THOSE CELLS REVERSES THE CELLULAR AND BEHAVIORAL PHENOTYPES OF WBS MICE. THIS FINDING INDICATES THAT THE VIPR1-DEPENDENT MECHANISM IN CORTICAL INS UNDERLIES THE MECHANISM OF SUPERIOR FREQUENCY-DISCRIMINATION ACUITY IN WBS MICE. FURTHERMORE, THIS MECHANISM IMPROVES FREQUENCY-CODING CAPABILITIES IN THE ACX, AS EVIDENCED BY 2-PHOTON IMAGING OF NEURONAL ENSEMBLE ACTIVITIES IN AWAKE MICE. WE SURMISED THAT WE COULD EMPLOY THE REVERSE-TRANSLATIONAL APPROACH BY USING THESE FINDINGS IN A DISEASE MODEL TO GAIN INSIGHTS INTO THE NORMAL PHYSIOLOGY OF FREQUENCY DISCRIMINATION BY FOCUSING ON VIPR1 SIGNALING IN CORTICAL INS. THEREFORE, WE PROPOSE THE FOLLOWING HYPOTHESIS: VIPR1 SIGNALING IN A CERTAIN SUBTYPE OF GABAERGIC INS (PV+, SOM+, OR VIP+) IN THE ACX UNDERLIES FREQUENCY- DISCRIMINATION ABILITIES AND FREQUENCY CODING THROUGH BIDIRECTIONAL TUNING OF IN EXCITABILITY VIA VGCCS. TO TEST THIS HYPOTHESIS, WE PROPOSE 3 SPECIFIC AIMS: IN AIM 1, WE WILL IDENTIFY THE SUBTYPE OF CORTICAL GABAERGIC INS IN WHICH VIPR1 SIGNALING REGULATES FREQUENCY DISCRIMINATION. IN AIM 2, WE WILL ELUCIDATE THE MECHANISTIC LINK BETWEEN VIPR1 SIGNALING AND IN HYPEREXCITABILITY IN THE ACX BY IDENTIFYING THE VGCC INVOLVED. IN AIM 3, WE WILL DETERMINE HOW VIPR1 SIGNALING AFFECTS FREQUENCY CODING IN THE ACX. THE RESULTS OF THESE EXPERIMENTS WILL SUBSTANTIALLY ADVANCE OUR KNOWLEDGE ABOUT THE CORTICAL MECHANISM OF FREQUENCY DISCRIMINATION.

St. Jude Children's Research Hospital

TO INVESTIGATE SOLUTIONS TO PROBLEMS DIRECTLY RELEVANT TO INDIVIDUALS WITH DEAFNESS OR DISORDERS OF HUMAN COMMUNICATION IN THE AREAS OF HEARING, BALANCE, SMELL, TASTE, VOICE, SPEECH, AND LANGUAGE. THE NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS (NIDCD) SUPPORTS RESEARCH AND RESEARCH TRAINING, INCLUDING INVESTIGATION INTO THE ETIOLOGY, PATHOLOGY, DETECTION, TREATMENT, AND PREVENTION OF DISORDERS OF HEARING AND OTHER COMMUNICATION PROCESSES, PRIMARILY THROUGH THE SUPPORT OF BASIC AND APPLIED RESEARCH IN ANATOMY, AUDIOLOGY, BIOCHEMISTRY, BIOENGINEERING, EPIDEMIOLOGY, GENETICS, IMMUNOLOGY, MICROBIOLOGY, MOLECULAR BIOLOGY, THE NEUROSCIENCES, OTOLARYNGOLOGY, PSYCHOLOGY, PHARMACOLOGY, PHYSIOLOGY, PSYCHOPHYSICS, SPEECH-LANGUAGE PATHOLOGY, AND OTHER SCIENTIFIC DISCIPLINES. THE NIDCD SUPPORTS: (1) RESEARCH INTO THE EVALUATION OF TECHNIQUES AND DEVICES USED IN DIAGNOSIS, TREATMENT, REHABILITATION, AND PREVENTION OF DISORDERS OF HEARING AND OTHER COMMUNICATION PROCESSES, (2) RESEARCH INTO PREVENTION AND EARLY DETECTION AND DIAGNOSIS OF HEARING LOSS AND SPEECH, VOICE, AND LANGUAGE DISORDERS AND RESEARCH INTO PREVENTING THE EFFECTS OF SUCH DISORDERS BY MEANS OF APPROPRIATE REFERRAL AND REHABILITATION, (3) RESEARCH INTO THE DETECTION, TREATMENT, AND PREVENTION OF DISORDERS OF HEARING AND OTHER COMMUNICATION PROCESSES IN THE ELDERLY POPULATION AND ITS REHABILITATION TO ENSURE CONTINUED EFFECTIVE COMMUNICATION SKILLS, AND (4) RESEARCH TO EXPAND KNOWLEDGE OF THE EFFECTS OF ENVIRONMENTAL AGENTS THAT INFLUENCE HEARING OR OTHER COMMUNICATION PROCESSES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENCOURAGE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.173 - Research Related to Deafness and Communication Disorders

National Institute on Deafness and Other Communication Disorders (NIDCD) [HHS - NIH]

Memphis, Tennessee 38105 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)