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Principal Investigator: Benjamin D Auerbach
Organization: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
Fiscal Year: 2024
Award: $138,690
Funding agency: National Institute on Deafness and Other Communication Disorders
PROJECT SUMMARY
Sensory hypersensitivity, particularly in the auditory realm, is one of the most common and debilitating
features of autism spectrum disorders (ASD). Not only is auditory hypersensitivity a core deficit and important
clinical problem in ASD, but it likely contributes to and reflects fundamental brain pathology that will extend to
more complex but less accessible features of autism, such as communication impairment and abnormal social
interaction. Thus, determining the nature of aberrant sound perception in ASD is a tractable model for
identifying core cellular and circuit alterations in ASD that also has direct clinical implications for unique
aspects of the disorder. I have developed novel behavioral paradigms to measure loudness growth and sound
intolerance in rodents. Using these tools, I determined that a well-validated rat model of Fragile X Syndrome
(FX), one of the leading inherited causes of ASD, exhibits exaggerated loudness perception and extreme
sound avoidance behavior, consistent with auditory hypersensitivity observed in a majority of FX individuals.
This proposal will combine these novel behavioral assays with high-density in vivo multi-electrode, ex vivo
whole-cell electrophysiological recordings, and novel cell-type specific chemogenetic manipulations to
determine how altered auditory network activity gives rise to aberrant sound perception and loudness
intolerance in Fmr1 KO animals. The results from these aims will: (1) offer insight into clinically relevant
features of FX and other autism-related disorders; (2) uncover fundamental neural disruptions at the core of
ASD pathophysiology; and (3) provide a novel platform for screening potential therapies for FX and ASD.
The proposed research is both a logical extension and novel direction from my previous work in
neurodevelopmental disorders and the mechanisms of experience-dependent plasticity. With the guidance of
my mentor, co-mentors and collaborator, I will develop the experimental and intellectual tools for dissecting the
neural circuits involved the dynamic encoding of sensory information, and how these processes may be
disturbed in neurological disorders like autism and hyperacusis. The technical and professional training I would
receive here will be instrumental towards my ultimate goal of establishing an independent academic laboratory
where I can combine the above techniques to study how experience shapes functional brain circuits at multiple
levels of analysis, using the auditory system as a model that is also associated with direct clinical implications.
Terms: <4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><ASD><Allergy><Aminalon><Aminalone><Animals><Area><Auditory><Auditory Cortex><Auditory Perception><Auditory area><Auditory system><Autism><Autistic Disorder><Automobile Driving><Behavioral><Behavioral Assay><Behavioral Paradigm><Brain><Brain Nervous System><Brain Pathology><Brain region><Causality><Cell Body><Cells><Chronic><Clampings><Clinical><Closure by clamp><Common Rat Strains><Communication Disorders><Communication impairment><Communicative Disorders><Complex><Connector Neuron><Disease><Disorder><Dysfunction><Early Infantile Autism><Electrodes><Electrophysiology><Electrophysiology (science)><Encephalon><Equilibrium><Escalante syndrome><Etiology><Exhibits><Fragile X><Fragile X Syndrome><Functional disorder><Funding><GABA><Generalized Growth><Genetic><Genetic Enhancement><Goals><Growth><Hearing Loss><Hereditary><Hyperactivity><Hyperacusia><Hyperacusis><Hypersensitivity><Hypoacuses><Hypoacusis><Impairment><Individual><Infantile Autism><Inherited><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Ion Channel><Ionic Channels><Kanner's Syndrome><Laboratories><Loudness><Loudness Perception><Loudness Perception Disturbances><Loudness Recruitment><Martin-Bell Syndrome><Martin-Bell-Renpenning syndrome><Measures><Membrane Channels><Mentors><Modeling><Nature><Nerve Cells><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neurocyte><Neurodevelopmental Disorder><Neurologic Disorders><Neurological Development Disorder><Neurological Disorders><Neurons><Neurophysiology / Electrophysiology><Pathology><Perception><Physiopathology><Population><Position><Positioning Attribute><Postdoc><Postdoctoral Fellow><Preparation><Prevalence><Process><Rat><Rats Mammals><Rattus><Renpenning syndrome 2><Research><Research Associate><Rodent><Rodentia><Rodents Mammals><Role><Sensory><Sensory impairment><Severities><Shapes><Slice><Social Interaction><Symptoms><Synapses><Synaptic><System><Techniques><Testing><Thalamic structure><Thalamus><Tissue Growth><Training><Viral><Work><X-linked mental deficiency-megalotestes syndrome><X-linked mental retardation with fragile X syndrome><X-linked mental retardation-fragile site 1 syndrome><autism attributes><autism indicator><autism model><autism spectral disorder><autism spectrum disorder><autism spectrum disorder features><autism spectrum disorder indicator><autism spectrum disorder symptoms><autism symptomology><autism symptoms><autism-fragile X (AFRAX) syndrome><autism-like symptoms><autism-related attributes><autistic features><autistic spectrum disorder><autistic symptoms><autistic traits><autistic-like symptoms><avoidance behavior><awake><balance><balance function><behavior phenotype><behavioral phenotyping><causation><cell type><clinical relevance><clinical translation><clinically relevant><clinically translatable><decreased loudness tolerance><density><disease causation><driving><dysfunctional hearing><electrophysiological><excitatory neuron><experience><fra(X) syndrome><fra(X)(28) syndrome><fra(X)(q27) syndrome><fra(X)(q27-28) syndrome><fragile X-mental retardation syndrome><fragile Xq syndrome><fragile site mental retardation 1><gamma-Aminobutyric Acid><gene manipulation><genetic approach><genetic manipulation><genetic strategy><genetically manipulate><genetically perturb><hearing challenged><hearing defect><hearing deficient><hearing deficit><hearing difficulty><hearing dysfunction><hearing impairment><hearing perception><in vivo><inhibitory neuron><insight><loudness intolerance><macro-orchidism-marker X (MOMX) syndrome><macro-orchidism-marker X syndrome><mar(X) syndrome><marker X syndrome><mental retardation-macroorchidism syndrome><model of autism spectrum disorder><neural><neural circuit><neural circuitry><neurocircuitry><neurodevelopmental disease><neurological disease><neuronal><neuronal excitability><neurophysiological><neurophysiology><noise sensitivity><novel><ontogeny><patch clamp><pathophysiology><post-doc><post-doctoral><post-doctoral trainee><preparations><programs><research associates><response><screening><screenings><social role><sound><sound perception><synapse><synapse function><synaptic circuit><synaptic circuitry><synaptic function><thalamic><tool><voltage clamp><γ-Aminobutyric Acid>