Daniel Stolzberg, Ph.D. - US grants

DESCRIPTION (provided by applicant): Summary Tinnitus is a disorder characterized by the perception of a phantom auditory sensation in the absence of an external source. Tinnitus affects approximately 14% of the population, and in approximately 1% of cases it is so severe that patients seek medical treatment. In the brain, the thalamus and cortex are intimately wired together into a reciprocal circuit;the thalamus targets the cortex, and the cortex targets the thalamus. It has been proposed that this recurrent circuit may be the substrate for a persistent miscommunication, resulting in abnormal activation of neighboring regions in the cortex resulting in the perception of a phantom sound. This theory, called "thalamocortical dysrhythmia" (TCD), has been applied to a spectrum of neurological disorders including tinnitus. In the auditory system, TCD is thought to result from the loss of input from the periphery, i.e. hearing loss, resulting in a functional switch of firing patterns of thalamocortical (TC) relay neurons from a tonic pattern to a bursting pattern with theta band rates (4-8 Hz). TC relay neurons rarely fire in a bursting pattern in the awake, conscious state. The presence of the thalamic bursting pattern during the wakeful state is abnormal and results in an abnormal pattern of cortical activity. One of the primary cortical targets of TC relay neurons are the horizontally projecting inhibitory interneurons which become less effective in maintaining normal inhibition of neighboring cortical regions when stimulated at theta band rates. This disinhibition of neighboring cortical regions permits aberrant neural activity at high rates, namely the gamma band (>30 Hz). In vitro studies have shown that stimulation of a cortical region at theta band rates and of a neighboring cortical region at gamma band rates, results in a confluence of cortical activity called the "edge-effect" and is thought to be related to perception of a phantom sound. The cortex also returns a signal back to the thalamus in such a way that it perpetuates the TC miscommunication. Although there is some evidence that the TCD theory may explain tinnitus in humans, these studies often lacked adequate controls to fully test the TCD theory. This investigation proposes to specifically test the TCD theory using a noise-induced model of tinnitus. The experiments will be performed in rats chronically implanted with thalamic and cortical microelectrodes. To accomplish this, recordings will be made from the auditory portion of the thalamus and cortex in awake-rats before and following intense noise-exposure. Since only a subset of rats will be expected to show behavioral evidence of tinnitus following the noise exposure, a critical comparison in this investigation will be between rats which have hearing loss and tinnitus versus rats which have hearing loss, but no tinnitus. The results of this investigation will provide a rigorous test of the TCD theory and the findings will have implications for our understanding of the mechanisms of tinnitus and lead to the development of pharmacologic or other therapies. PUBLIC HEALTH RELEVANCE: The goal of this project is to investigate and rigorously test a prominent the theory, Thalamocortical Dysrhymia (TCD), which predicts that tinnitus, is a symptom arising from the miscommunication between two important areas of the brain involved in hearing;the thalamus and cortex. To test this theory, recordings will be made of neural activity in the thalamus and cortex simultaneously of animals, before and following intense noise exposure. By comparing the neural activity from noise-exposed animals with and without tinnitus, I will be able to critically evaluate the TCD theory of tinnitus and increase our understanding how the phantom sound arises, persists, and may be treated.