Neural Coding of Motor Sequences in the Basal Ganglia: Effects of Dopaminergic Modulation

Grant Type
Basic
Grant Year
2007-2008
Institution Location
MI
Institution Organization Name
University of Michigan
Investigators Name
Aldridge, J. Wayne, PhD

Tourette Syndrome (TS) is a disorder of neural circuits in the basal ganglia, a region of the brain involved in controlling movements. Our study is designed to test the idea that disrupted brain mechanisms that normally control sequences of movement underlie some of the problems observed in TS. Sequences of movement are crucial to nearly all behaviors. Each sequence requires the coordination of many skilled behavioral elements. Each motor element must be initiated in the proper order at the proper time. What would happen if a brain system controlling movement sequences went awry? We suspect that a disorder with the characteristics of TS might result from overactivity within a system controlling movement sequences. Our goal is to understand how information is encoded in brain systems that control movement sequences and what happens when those same brain systems malfunction. Such an understanding may help us learn how some current treatments alleviate the symptoms of TS, as well as spawn ideas for new treatments for the disorder. We will use rodent grooming as a model system to test these ideas. Grooming in rodents is composed of highly predictable sequences of movements. Importantly for a model of TS, rodent grooming depends strongly upon a functional basal ganglia dopamine system. Disorders of the basal ganglia dopamine system are thought in part to underlie the symptoms of TS. In TS one of the classes of dopamine receptors in the basal ganglia, the dopamine D1 receptors, is thought to be overly sensitive. The focus of our work will be to examine how acute or chronic over-stimulation of dopamine D1 receptors contributes changes in basal ganglia function in relation to repetition of sequential movements. We will also investigate how a drug used for the treatment of TS (haloperidol) influences this system. In previous work we have shown that when the D1 system is stimulated, grooming sequences in rodents become excessive. One could view the tics of Tourette Syndrome as excessive movement sequences similar to excessive grooming when under the influence of D1 drugs. In order to test these ideas, we will administer to rats a drug that stimulates dopamine D1 receptors. We will then analyze the pattern of electrical activity in individual neurons of the substantia nigra, which is an important part of the basal ganglia system controlling movement sequences. We suspect that D1 receptor stimulation, which causes excessive repetition of grooming sequences, will disrupt the pattern of activity in these neurons. Furthermore, we anticipate that haloperidol will cause the neurons to revert to their normal behavior along with a return to normal levels of movement sequences. In order to better understand long-term changes in the basal ganglia, we will then repeat the experiment, but this time in rats that have undergone chronic stimulation of D1 receptors. We suspect that chronic activation of D1 receptors will cause D1 receptor sensitization, that is, a long term change in the sensitivity of the D1 system. This change may cause a permanent change in excessive grooming and we expect to identify permanent changes in neural activity, too. These findings could lead to a better understanding of how dopamine receptors modulate neural function and repetitive movements and may also support the implementation of excessive repetition of the sequential grooming as an animal model for the complex motor tics observed in TS. We hope that this work might provide a useful model of the long term changes in brain systems of TS in a way that may lead to better treatments. Wayne J. Aldridge, Ph.D., Jennifer Taylor, Ph.D., Andrew Klein, B.S. University ofMichiganMedical School Ann Arbor, MI Award: $73,240 In Memory of Henrietta Leonard, M.D. A compassionate physician and leader in research into the association of Tourette Syndrome and Obsessive Compulsive Disorder. Tourette Association of America Inc. – Research Grant Award 2007-2008