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"Reduced acoustic sensory reactivity after mild traumatic brain injury: Startling implications for brainstem inflammation"

by
Swamini Sinha
MD/Ph.D. Program
B.A. 2008, Rutgers University



Thesis Advisor: Kevin Pang, Ph.D.
Professor
Department of Neurology and Neurosciences

Friday, October 31, 2014
9:00 A.M., Cancer Center, H-1196


Abstract

Nearly 75% of all traumatic brain injuries occurring annually in the U.S. are classified as mild (mTBI). Patients with mTBI – trauma that results in a disruption of neurological function in the absence of gross brain damage – may present with a constellation of both acute and chronic symptoms, which are primarily evaluated based on self-report.
A closer look at the symptoms of mTBI reveals that a majority of symptoms may reflect abnormal brainstem function. The brainstem modulates consciousness, sleep, and many physiological homeostatic mechanisms. Alterations to brainstem function are evident in symptoms of mTBI: acute loss of consciousness at the time of the insult, as well as chronic symptoms such as nausea, vomiting, sleep disturbances.
The focus of this thesis is to understand brainstem dysfunction in a rodent model of mTBI, specifically by examining the acoustic startle reflex (ASR). The ASR is a non-invasive, translational test that quantifies a subject’s motor response to a brief yet sharp acoustic stimulus. The neural circuitry is well defined and conserved across mammalian species, and requires the caudal pons (PnC). Moderate/severe TBI produces a suppression of the ASR in humans as well as rodent models. However, the effects of mTBI on ASR are not well established.
The main purpose of this thesis was to explore the effects of mTBI on the acoustic startle response, in order to gain a better understanding of brainstem pathology and dysfunction after mild brain injury. Using fluid percussion injury in rodents, startle suppression after mTBI were characterized up to three weeks post-injury. These effects were replicated and extended to understand the effect of an even milder brain injury on the ASR. Next, an examination of whether the startle suppression after mTBI could be explained by injury-induced inflammation in the brainstem was conducted in two parts: molecular and cellular markers of inflammation were quantified in the PnC (the essential relay of the startle circuit), and an examination of whether treatment with an anti-inflammatory agent reversed the effect of mTBI on ASR was conducted.
The studies presented here demonstrate that mTBI produces a persistent suppression of the acoustic startle reflex. Additionally, mTBI produces an inflammatory cascade in the brainstem, with latent neurodegeneration. Acute inhibition of NFêB prevents the ASR suppression after mTBI. These results suggest the susceptibility of the brainstem to mTBI, and implicate the acoustic startle reflex as a functional measure of brainstem inflammation.


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