The tics in Tourette’s Syndrome (TS) are often performed in response to unbidden, irrepressible urges or sensations. Our research will focus on a part of the brain called the Nucleus Accumbens (NAcc) that may contribute to these unwanted sensation-action sequences. Neurons in the NAcc increase their activity when stimulated by sensory cues in the environment. Two pieces of evidence suggest that the increased firing rate of these neurons could play a role in generating the symptoms of TS. First, NAcc neuron firing is sensitive to dopamine, a neurotransmitter that appears to be released in unusually high amounts in the NAcc in people with TS. Second, when NAcc neurons increase firing in response to cues, the activity may promote the execution of a motor response – making these neurons very important for the performance of sensation-action sequences. Given this evidence, we hypothesize that unusually high levels of NAcc dopamine release may make NAcc neurons overexcitable, so that they increase their firing and promote the performance of sensation-action sequences even when the sensations are unimportant and the actions are unwanted. To test this theory, we will measure NAcc neurons firing in rats that have been trained to perform specific movements in response to specific auditory cues. We will look for neurons that increase their firing in response to the cues, and (using a motion tracking system) we will determine whether these increases also correspond to the subsequent motor response made by the rat. Next, we will treat the rats with a drug (amphetamine), that increases dopamine levels in the NAcc and measure whether this treatment potentiates the cue- and motor-related firing of NAcc neurons. These experiments have the potential to show how NAcc neurons and NAcc dopamine contribute to the generation of tics in TS, and may help explain why these tics have both sensory and motor features. Vincent B. McGinty, Ph.D. Albert Einstein College of Medicine, Bronx, NY Award: $40,000 (Fellowship) Commentary: The changes that occur in the brain that lead to tics remain unknown. Dr. McGinty has put forward the idea that nerve cell activity in a part of the brain called the Nucleus Accumbens is responsible for generating the symptoms of the disorder. Specifically, it is believed that these nerve cells form an important link between tics and the unusual sensations that often precede tics (premonitory sensations). In this grant, Dr. McGinty will test his theory by determining whether environmental cues may trigger activity in the nerve cells of the Nucleus Accumbens that generate movements in the body. He will also determine whether the activity of these nerve cells is sensitive to dopamine, a brain chemical thought to be involved in TS. These studies will help to show us what parts of the brain are involved in generating the symptoms of TS. Tourette Association of America Inc. – Research Grant Award 2009-2010