# Mechanisms of Loudness Intolerance in a Rat Model of Fragile X

> **NIH NIH R21** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2021 · $199,375

## Abstract

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.

## Key facts

- **NIH application ID:** 10133603
- **Project number:** 5R21DC017813-02
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** RICHARD J SALVI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $199,375
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133603

## Citation

> US National Institutes of Health, RePORTER application 10133603, Mechanisms of Loudness Intolerance in a Rat Model of Fragile X (5R21DC017813-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10133603. Licensed CC0.

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