Richard J. Salvi, Ph.D. - US grants

Acoustic trauma causes numerous distortions in hearing such as poor frequency resolution, tinnitus, abnormal temporal processing, loudness recruitment and poor speech discrimination. The range of hearing disorders suggests that the underlying pattern of neural is altered significantly. The goal of this project is document the changes that occur in the discharge patterns of single units in the auditory periphery during noise-induced hearing loss and to relate these changes to the audiological disorders and underlying cochlear pathologies. This project has four separate, but related goals: (1) Recent studies suggest that the breakdown in auditory temporal summation may be partially due to changes in the central auditory pathway. One possibility is that acoustic trauma may alter the properties of certain cells in the cochlear nucleus that are known to exhibit temporal summation. Thus, a goal of the project is to determine if acoustic trauma alters the temporal response characteristics of these cells. (2) Listeners with permanent hearing loss often have prolonged forward masking functions. One underlying neural mechanism for this may be a prolongation in the recovery from short-term neural adaptation. This issue will be examined by measuring the time-course of recovery from short-term adaptation in auditory nerve fibers from animals with noise-induced permanent threshold shift. (3) Hearing-impaired listeners also show a reduced ability to detect the sinusoidal amplitude fluctuations in noise. To investigate the underlying neural basis for this temporal resolution, the response patterns of single auditory nerve fibers to sinusoidally amplitude modulated noise will be compared in normal and hearing-impaired listeners. (4) Finally, the loss of tuning, two-tone suppression and lateral inhibition that occurs in single neurons from noise-exposed ears could significantly alter their input/output functions to broadband signals. Therefore, we plan to use broadband noise and determine how acoustic trauma alters the discharge rate-intensity functions of units in the auditory nerve and cochlear nucleus. Ultimately, we will attempt to relate the neural firing patterns seen in units from noise-exposed animals to the underlying cochlear histopathologies as well as to the psychophysical changes that occur in the noise-exposed animals. These results should help to establish a clearer understanding of the anatomical and physiological basis of the audiological symptoms of noise-induced hearing loss. This may potentially lead to better management and treatment of the hearing-impaired listener.

Salicylates are the most widely used drugs in the United States. If taken in high doses, salicylates can cause a number of severe auditory side effects, the most common of which are temporary hearing loss and tinnitus. It has generally been assumed that the auditory effects of salicylates such as aspirin are temporary. However, recent results indicate that aspirin can cause an increase in the magnitude of hearing loss (TTS) induced by a given noise exposure and prolong the time needed for recovery. Given that industrial and recreational noise exposure is the most common cause of hearing loss in the adult population, it is important to know whether individuals taking salicylates are at increased risk for developing permanent hearing loss from noise exposure. Our primary goal is to determine if salicylates will increase the magnitude of hearing loss and hair cell loss induced by a well-defined noise exposure. A second goal is to determine what effects salicylates have on suprathreshold measures of hearing, specifically, temporal resolution (forward masking) and frequency selectivity (tuning curves). The results of this study have important implications for understanding how a drug that presumably produces only temporary hearing loss interacts with intense noises that can produce either temporary or permanent hearing loss. Furthermore, the results have important implications for developing occupational noise standards for industry.

noise biological effect; aspirin; ototoxin; noise induced deafness; hearing disorders; drug adverse effect; tinnitus; stimulus /response; ear hair cell; auditory discrimination; dosage; auditory stimulus; auditory threshold shift; sequential perception; evoked potentials; perceptual maskings; sound frequency; histology; chinchilla; hearing tests;

In mammals, loss of hair cells in the cochlea is permanent. When noise trauma or ototoxic produce cell loss, the anatomical and functional changes remain for life. By contrast, avian cochlear hair cells along with support cells and the tectorial membrane have been shown to regenerate. While this is an finding with potentially major importance, the awareness that the phenomenon is more complicated initial impression has been growing with recent observations that the number of cochlear ganglion cell decrease hair cell regeneration, and that the functional capacity of the auditory system may not fully recover even though nearly all of the hair cells have regenerated. These findings has given special impetus to determining the functional and morphological condition at different levels in the avian auditory system which regenerated hair cells. In the present project, we will approach this issue from the joint perspectives of behavioral audiometry, electrophysiology, and anatomy in the chicken after acoustic overstimulation. The ultimate criterion for assessing the full extent of functional recovery is the functioning of the whole tasks with auditory cues, which behavioral psychoacoustic attempts to evaluate. We will measure pure tone thresholds, psychophysical tuning curves and gap detection after hair cells and support cells have been damaged and allowed to regenerate. All information reaching the higher levels of the auditory system must ass through the cochlear ganglion, and cells in the cochlear ganglion are most intimately related to the cochlear hair cells. For this reason, whole nerve potentials and single unit recordings from cochlear ganglion neuron will be studied to examine the functional status of regenerated hair cells and auditory nerve. Some will be physiologically characterized and retrogradely labeled in order to determine which hair cells innervate along the basilar papilla. Anatomical evaluation of cochlea, cochlear ganglion and cochlear n will help to relate any functional defect to residual structural changes. Finally, the expression of the gi associated protein GAP-43 and the incorporation of bromodeoxyuridine (BrdU), a marker for cell proliferation, will be studied to evaluate the possibility of neural plasticity in the cochlear ganglion and cochlear nucleus associated with hair cell regeneration.

The primary goal of this project is to determine how the central auditory system reorganizes functionally and structurally as a result of temporary or permanent injury to the cochlea. The first objective of the project will determine how the discharge patterns of single neurons in the cochlear nucleus (CN) and central nucleus of the inferior colliculus (ICC) are altered by acoustic overstimulation that causes temporary threshold shift (TTS) or permanent threshold shift (PTS). A second objective of the project will determine if there is any evidence of axonal sprouting, as reflected in GAP-43 immunohistochemistry, in the CN or IC as a result of chronic cochlear lesions. The project aims to answer the following questions. How is the tonotopic organization of the CN and ICC altered by PTS and cochlear lesions. Is the tonotopic map reorganized or is there a "silent region' in the ICC or CN corresponding to the region of cochlear damage? How are the excitatory and inhibitory response areas of units in the CN and ICC altered by TTS and PTS. Is there a change in the best frequency or width of the excitatory or inhibitory response areas when either the excitatory or inhibitory response area is selectively damaged or inactivated? Does the saturation firing rate and the dynamic range of a unit increase or decrease when the injury is confined to either the excitatory or inhibitory response area? Are the functional changes in the CN and ICC related to the pattern of cell damage in the cochlea or the compound action potential threshold shift? Do cochlear lesions give rise to increased levels of GAP-43 immunostaining, indicative of axonal sprouting, in the CN or ICC? Is the spatial distribution of GAP-43 immunostaining within the ICC or CN related to the location of the cochlear lesion? The results of the project should provide new insights regarding the structural and functional plasticity of the central auditory pathway following chronic or acute injury to the periphery. Moreover, the data may provide a clearer understanding of the neural mechanisms underlying many of the symptoms of sensorineural hearing loss such as loudness recruitment, tinnitus, poor speech discrimination and diplacuis. Finally, the functional changes may provide new information related to the underlying neural circuits present in the ICC and CN.

The goal of the proposal is to organize an international symposium to synthesize and review the findings and issues related to neural plasticity, reorganization and sensory cell regeneration in the auditory system. The proposed symposium will be organized in conjunction with Dr. Vittorio Colletti (University of Verona, Italy) who will solicit financial support for approximately half the conference from European organizations. The conference will focus on three important areas of research which represent key elements in National Strategic Plan for Research at NIDCD. The three topics are: (1) hair cell regeneration (2) the reorganization of the central auditory pathway following damage to the auditory periphery and (3) the "toughening" of the auditory system that occurs with repeated exposures to noise exposure. These three topics focus on the ability of the auditory system to respond to stress and trauma and compensate for damage to the peripheral auditory system. The goal of the symposium is to provide a comprehensive, up to date review of advances made in each of these areas, to elucidate the basic underlying mechanisms involved and to discuss the interrelationship of the findings and their clinical implications. The three day conference will consist of a series of lectures and poster sessions. The conference will take place near Trento, Italy in September, 1993. Conference participants will submit chapters synthesizing the progress and advances made in their area of expertise. The chapters will be edited and published as a book so that the proceedings of the symposium can be made widely available to a scientists, clinicians, administrators and student in the field.

The primary goal of this project is to determine how the central auditory system reorganizes functionally and structurally as a result of temporary or permanent injury to the cochlea. The first objective of the project will determine how the discharge patterns of single neurons in the cochlear nucleus (CN) and central nucleus of the inferior colliculus (ICC) are altered by acoustic overstimulation that causes temporary threshold shift (TTS) or permanent threshold shift (PTS). A second objective of the project will determine if there is any evidence of axonal sprouting, as reflected in GAP-43 immunohistochemistry, in the CN or IC as a result of chronic cochlear lesions. The project aims to answer the following questions. How is the tonotopic organization of the CN and ICC altered by PTS and cochlear lesions. Is the tonotopic map reorganized or is there a "silent region' in the ICC or CN corresponding to the region of cochlear damage? How are the excitatory and inhibitory response areas of units in the CN and ICC altered by TTS and PTS. Is there a change in the best frequency or width of the excitatory or inhibitory response areas when either the excitatory or inhibitory response area is selectively damaged or inactivated? Does the saturation firing rate and the dynamic range of a unit increase or decrease when the injury is confined to either the excitatory or inhibitory response area? Are the functional changes in the CN and ICC related to the pattern of cell damage in the cochlea or the compound action potential threshold shift? Do cochlear lesions give rise to increased levels of GAP-43 immunostaining, indicative of axonal sprouting, in the CN or ICC? Is the spatial distribution of GAP-43 immunostaining within the ICC or CN related to the location of the cochlear lesion? The results of the project should provide new insights regarding the structural and functional plasticity of the central auditory pathway following chronic or acute injury to the periphery. Moreover, the data may provide a clearer understanding of the neural mechanisms underlying many of the symptoms of sensorineural hearing loss such as loudness recruitment, tinnitus, poor speech discrimination and diplacuis. Finally, the functional changes may provide new information related to the underlying neural circuits present in the ICC and CN.

The hair cells and supporting elements in the avian ear can regenerate after being damaged by ototoxic drugs or acoustic overstimulation resulting in the partial, or in some cases, complete recovery of hearing. However, relatively little is known about the biological mechanisms that regulate or limit the recovery of auditory function at the level of the cochlea. The overall goal of this project is to determine what functional deficits are present in the neural output of the cochlea when the hair cells, tectorial membrane or afferent dendrites are damaged and then to determine how quickly and to what extent these neurophysiological deficits recover as these anatomical structures regenerate or are repaired. Three different agents will be used to selectively damage different cochlea structure; kanamycin selectively destroys all the hair cells; intense acoustic stimulation selectively destroys only short hair cells and associated tectorial membrane; kainic acid selectively destroys the afferent dendrites. The destruction and regeneration of these structures will be assessed by light, fluorescence and transmission electron microscopy. The functional deficits and recovery process will primarily be assessed by recording from and then labeling single cochlea ganglion neurons. The proposed experiments will answer the following questions. What functional deficits are associated with the permanent loss of short hair cells? Does the cochlear frequency-place map change when short hair cells are missing or when the short and tall hair cells regenerate? What neurophysiological deficits are present in cochlear ganglion neurons that innervate regenerated hair cells: How long does it take for the cochlear afferent dendrites to become functionally mature in the presence of intact hair cells? Do the kanamycin and kainic acid treatments reduce the number of cochlear ganglion neurons? The results of these studies will provide new insights into the mechanisms that lead to the partial or complete recovery of auditory function when the hair cells and supporting elements in the inner ear regenerate.

The mammalian inner ear contains two types of sensory cells, inner hair cells (IHCs) and outer hair cells (OHCs). A great deal is known about the deleterious effects that OHC damage has on auditory function; however, almost nothing is known about the functional deficits that are associated with IHC damage. We have developed a preparation in which it is possible to use carboplatin, an anti-neoplastic agent, to selectively destroy the IHCs in the chinchilla while retaining a functionally intact population of OHCs. We will use this preparation to determine how IHC damage affects the discharge patterns of single auditory nerve fibers and how the selective loss of IHCs and type I afferent neurons affects behavioral measures of hearing. The specific questions that will be addressed are: (1) Do the spontaneous discharge rates, driven discharge rates and the adaptation and recovery of discharge rate eventually recover to their normal levels following carboplatin treatment? (2) Is the elevation of threshold in auditory nerve fibers linked to stereocilia damage on IHCs? (3) Does partial IHC loss alter behavioral thresholds? (4) Does partial IHC loss lead to abnormal intensity discrimination? (5) Does partial IHC loss lead to abnormal frequency distribution? (6) Does partial IHC loss lead to abnormal temporal resolution? The proposed experiments have the potential to clarify the functional role of IHCs at the level of the cochlea and to increase our understanding of how IHC damage alters our ability to hear critical features of acoustic stimuli.

This Program Project consists of four integrated projects that explore the mechanisms, functional consequences, and prevention of cochlear damage/hearing loss induced by ototoxic drugs and acoustic over- stimulation. In addition to its basic scientific merit, the project has clinical implications with regard to acquired hearing loss (HL) in humans. The clinical motivations for Projects 1 and 2 are (a) a growing awareness that inner hair cell (IHC) loss may underlie many of the perceptual difficulties experienced by people with acquired HL, and (b) a lack of clinical tools for assessing IHC loss. Clinical motivations for Projects 3 and 4 include observations that (a) susceptibility to HL varies tremendously among individuals, and (b) identification of the factors that contribute to susceptibility may be crucial for preventing acquired HL in the future. All four projects utilize the chinchilla, a mammal whose hearing capabilities are similar to humans. Project 1 examines anatomical, physiological, and behavioral changes associated with selected IHC lesions produced by carboplatin, an anti-cancer drug. Project 2 uses auditory evoked potentials to examine functional changes along the auditory neuroaxis associated with permanent IHC loss from carboplatin and transient cochlear deafferentation by kainic acid, a glutamate analog. Project 3 explores acoustic and biochemical methods of protecting the cochlea from hearing loss induced by acoustic over-stimulation and carboplatin. Project 4 focuses on potential protective effects on lateral and medial olivocochlear efferent fibers on hair cell loss and hearing loss induced by carboplatin, aminoglycosides, kainic acid and acoustic over-stimulation. Overlapping themes among the projects include consequences of IHC loss, central nervous system reorganization, mechanisms of ototoxic damage, and strategies for protecting the inner ear from damage.

[unreadable] DESCRIPTION (provided by applicant): The inner hair cells (IHC) and type-I auditory nerve fibers are thought to provide the only pathway through which auditory information is conveyed to the central auditory system; however, little is known about the deficits in hearing and central auditory function that are associated with damage that is exclusively confined to the IHC/type-I neurons. In the chinchilla, it is possible to selectively destroy a subset of IHC/type-I neurons along the entire length of the cochlea with an anticancer drug. This type of lesion creates a situation in which the central auditory system receives only a small percentage of its normal neural input. What types of hearing deficits are associated with an IHC/type-I lesion? The current proposal will determine directly address this question by measuring five different aspects of hearing: (1) thresholds for hearing long and short duration tones in quiet; this will assess the sensitivity of the system and temporal integration, (2) threshold for detection of tones in broadband noise; this will test the width of the internal auditory filters and the sensitivity of the detector mechanism, (3) masking patterns for narrow band noise; this assess the spread of masking to low and high frequencies, (4) intensity discrimination and frequency discrimination, and (5) modulation thresholds for detection sinusoid ally amplitude modulated noise, a comprehensive measure of temporal resolution. The project will also record the local field potentials from the inferior colliculus and auditory cortex to look at the neural correlates of threshold, increases in intensity, the detection of tones in noise and narrow band noise masking patterns. The changes in hearing function and neural activity will be correlated to the degree of damage to the IHC/type-I neuron. The results of the study could have important implications for developing clinical tests to detect IHC/type-I damage in patients and for understanding auditory neuropathy, a clinical entity thought to involve pathologies of the IHCs or auditory nerve. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The overall goals of this project are to (A) obtain behavioral estimates of tinnitus induced by salicylate or noise exposure, (B) identify the changes in neural activity associated with salicylate or noise-induced tinnitus using MicroPET imaging and electrophysiological recordings and (C) determine if the behavioral, metabolic and neural manifestations of tinnitus can be suppressed by NS1883, a potassium channel agonist that appears to suppress salicylate-induced tinnitus. Spontaneous and sound evoked neural activity will be assessed in the auditory cortex and inferior colliculus of awake animals using 16-channel electrode arrays. MicroPET imaging combined with FDG tracer will be used to identify regions in the auditory pathway that show a significant change in metabolic activity during tinnitus. In Aim 1, the onset, recovery and pitch of tinnitus will be measured following treatment with a high dose of salicylate. Behavioral measures of tinnitus will be correlated with changes in metabolic activity and neural activity. We will determine if NS1883 can suppress the behavioral, neural and metabolic changes associated with salicylate-induced tinnitus. In Aim 2, the onset, time course and pitch of tinnitus will be assessed after high level noise exposure. Behavioral measures of noise-induced tinnitus will be correlated with changes in metabolic activity and neural activity. We will determine if NS1883 can suppress the behavioral, neural and metabolic changes associated with noise-induced tinnitus. This project will be the first to use MicroPET imaging to identify changes in metabolic activity in animal models of tinnitus. The project will significantly advance our understanding of the metabolic and neural changes in the auditory pathway that are associated with tinnitus, and will evaluate the effectiveness of a new potassium channel agonist in suppressing salicylate and noise-induced tinnitus. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The overall goals of this project are to (1) obtain behavioral estimates of tinnitus induced by salicylate and acoustic overstimulation and measure the time course and the pitch of the tinnitus in individual animals, (2) identify the changes in neural activity (single unit activity, local field potentials) in the auditory cortex of awake rats using16 channel recording electrodes and (3) determine how the time course and pattern of neural activity correlate with behavioral measures of the pitch and time course of tinnitus, (4) determine if the behavioral and neurophysiological measures of salicylate induced tinnitus and noise-induced tinnitus can be suppressed by NS1883, a potassium channel agonist that has shown promise in suppressing salicylate-induced tinnitus. Two behavioral techniques, SIPAC and GPIAS, will be used to independently confirm the time course and pitch of the tinnitus. Spontaneous and sound evoked neural activity will be assessed in awake animals using chronically implanted 16-channel electrode arrays. The project will significantly advance our understanding of the time course and pitch of noise and drug induced tinnitus in an animal model, aid in identifying the key neurophysiological changes in the auditory cortex that are associated with tinnitus, and evaluate the effectiveness of a potassium channel agonist in suppressing salicylate and noise-induced tinnitus. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Blast wave explosions are a major cause of hearing loss among military personnel, but blasts can also induce traumatic brain injury and impair memory. In preliminary experiments, we have shown that exposure to blast waves and continuous noise not only damaged the inner ear, but caused cell death in the hippocampus, suppressed neurogenesis and impaired memory function. The goals of this project are to: (1) Assess the amount of functional hearing impairment and cochlear damage (necrosis and apoptosis) that results from blast wave vs. continuous noise exposures. (2) Determine the extent to which D-methionine, an anti-antioxidant and apoptotic agent, can protect against blast wave induced hearing impairment and cochlear pathology. (3) Determine the extent to which blast wave exposure disrupts memory function and induces cell death and suppresses neurogenesis in the hippocampus. (4) Determine if D-methionine can protect against blast wave induced memory impairments, prevent hippocampal cell death and restore hippocampal neurogenesis. These studies will provide new mechanistic insights on the role of necrosis and apoptosis in blast and noise induced injury to the inner ear and hippocampus and whether antioxidant, anti-apoptotic drug therapy can prevent or ameliorate blast wave injury to the inner ear and hippocampus.

? DESCRIPTION (provided by applicant): Hearing loss from intense noise exposure and ototoxic drugs greatly reduces the neural output of the cochlea. Despite a reduced cochlear output, neural activity in the central auditory pathway often becomes hyperactive at suprathreshold intensities indicative of Enhanced Central Gain. Enhanced Central Gain is believed to be responsible for hyperacusis, a condition in which listeners experience everyday sounds as unbearably loud or even painful. The goals of this project are: (1) Determine if Enhanced Central Gain is responsible for the temporal and spectral features of hyperacusis, (2) Determine how the acoustic environment (sound enrichment/deprivation) modulates hyperacusis/loudness growth and Central Gain and (3) Determine how serotonin and GABA agonists/antagonists affect hyperacusis and Central Gain. The proposed studies will increase our understanding of the neural mechanisms of hyperacusis and test the efficacy of pharmacological agents to treat hyperacusis.

? DESCRIPTION (provided by applicant): Intense noise exposure and ototoxic drugs cause hearing loss and reduce the neural output of the cochlea. Paradoxically, cochlear damage often enhances neural activity in the central auditory pathway at suprathreshold intensities. This compensatory increase in the central auditory pathway is referred to as Enhanced Central Gain. Enhanced Central Gain is believed to be responsible for hyperacusis (loudness intolerance) and tinnitus, two debilitating conditions that afflict millions of Americans. The goal of this project s to experimentally test the Central Gain model to determine if it can account for hyperacusis and tinnitus induced by ototoxic drugs or intense noise exposure. To accomplish this, we will determine if the temporal and spectral properties of noise-induced or drug-induced hyperacusis match time course and spectral features of the electrophysiological metric of increased central gain in auditory cortex (AC), medial geniculate body (MGB), lateral amygdala and inferior colliculus (IC). We will also determine if the time course of noise-induced or drug- induced tinnitus is correlated with the time course and spectral features of hyperacusis and increased central gain in the AC, MGB, LA or IC. Since hyperexcitability disorders can be controlled by drugs that regulate potassium channel permeability, we will test the hypothesis that potassium channel modulators can suppress noise- or drug-induced hyperacusis and enhanced central gain. The proposed studies are designed to increase our understanding of the neural mechanisms of hyperacusis and tinnitus and test the efficacy of novel pharmacological agents to treat these two debilitating disorders.

PROJECT SUMMARY A fundamental goal of hearing research and auditory neuroscience is to understand the causes and consequences of hearing loss and to use this knowledge to mitigate hearing disorders. One of the premier venues for promoting scientific progress toward this goal is the series of International Hearing Loss Conference (IHLC). In 2019, IHLC will take place on May 5-9 in Niagara-on-the-Lake, Ontario, Canada. This will be the 4th IHLC. The first three conferences also took place in the Niagara region, on the US side of The Falls. IHLC is the only multi-day meeting that focuses exclusively on the causes and consequences of hearing loss. Further, because IHLC takes place in a relatively cloistered setting, it maximizes formal and informal scientific discourse in a collegial atmosphere. Aim #1 is to bring together auditory scientists to exchange ideas, methods, and concepts on hearing loss. The goal of the 2019 meeting is to promote our understanding of six specific areas of related to hearing loss: hidden hearing loss, tinnitus, hyperacusis, central gain, neuroplasticity, and impaired auditory processing. In particular, the organizers of IHLC are interested in attracting scientists that (1) employ methodologies and conceptual/theoretical paradigms that are often novel to studies of hearing loss; and (2) whose research focuses on studying the consequences of hearing loss through a synthesis of both human and animal research. Aim #2. To facilitate meaningful and educational interactions between junior and senior auditory neuroscientists during the program and to broaden the pipeline for women and minority scientists in auditory research. ?Early Investigator Talks? give a cadre of students and post- doctoral fellows the opportunity to advertise their posters as a short oral presentation. Select speaker slots will be reserved for junior faculty members and post-doctoral fellows. Further, we will award a number of travel grants for graduate students and post-doctoral fellows that offset the cost of attending IHLC to significantly increase the footprint of trainees at the 2019 IHLC. IHLC is extremely relevant to the scientific mission of the NIDCD. This conference supports the NIDCD mission in three ways. First, the program brings together successful junior and established investigators who represent a substantial component of NIDCD-sponsored programs to foster new ideas in hearing research. Second, the conference provides a superb environment in which to educate and engage students and junior faculty in our field. Third, the program features numerous presentations on clinically relevant research into temporary and permanent hearing loss, vulnerability to acoustic noise, tinnitus, and cognitive and psychological factors influencing hearing (attention, tinnitus).

Abstract Converging evidence from human and animal studies have identified cellular and molecular disruptions that are central to the pathophysiology of autism spectrum disorders (ASD). Connecting this molecular pathology to behavioral phenotypes in ASD has been limited by our understanding of how these disruptions manifest at the neural circuit level, which in turn has impeded development of ASD therapies. Aberrant sensory processing is a key diagnostic criterion for ASD that is likely related to fundamental circuit deficits underlying more complex but less accessible features of the disorder, such as communicative impairment and abnormal social behavior. Sensory hypersensitivity, particularly in the auditory realm, also profoundly impacts the quality of life for autistic individuals and is associated with self-harm and aggression. Thus, determining the nature of aberrant sound perception in ASD is a tractable model for identifying core circuit and system level alterations in ASD that also has direct clinical implications for unique aspects of the disorder. We have developed novel behavioral paradigms to measure loudness growth and sound intolerance in rodents. Using these tools, we found 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. Here we propose to combine these novel behavioral assays with high-density in vivo electrophysiological recordings and local pharmacological manipulation of multiple brain areas to determine how altered auditory network activity gives rise to aberrant sound perception in Fmr1 KO animals. In addition, we will test several distinct pharmacological therapies aimed at reversing these sensory disturbances. 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.