Anatomical Correlates of Tourette Syndrome: Interactions Among ‘Estrogenergic’, Dopaminergic, and Prefrontal Cortex-Basal Ganglia Circuitries in the Rodent and Primate Brain

Grant Type
Grant Year
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Institution Organization Name
Yale University
Investigators Name
Jakab, Robert, PhD

My goal is to explore neural connections which mediate the symptoms of Tourette Syndrome (TS). Changes in sex steroid levels and the dopamine system both appear to influence symptom expression in TS. On the other hand, particular brain areas have been incriminated in TS. In the proposed experimental animal studies, I continue to explore the relationship among these brain areas, the dopamine-utilizing pathways and a recently discovered neuron system which produces estrogen inside the brain. TS symptoms can wax and wane in severity over the course of hours, days, months or years. It is not difficult to draw a parallel between these cyclic changes and the well-known rhythmicity of various hormonal actions. For example, the severity of symptoms frequently follows elevated estrogen levels during the menstrual cycle. Men are afflicted with TS much more frequently than women. It is thought that before birth, changes in sex hormone levels caused by maternal stress can mediate an increased risk of developing TS. High testosterone levels parallel the increase in TS symptoms seen in early puberty, and mirror the sex differences in TS. TS symptoms of athletes worsen when they abuse high doses of anabolic steroids. Estrogen is produced not only by the ovary and placenta, but also by special neurons inside the brain. These neurons make estrogen with the help of an enzyme called aromatase. What is the role of estrogen in normal and abnormal brain functions? We don’t know. We have recently mapped the aromatase neurons, and their location is similar in the rat and monkey brain. This suggests that these anatomical data can be relevant to the human situation. The aromatase system is the same in both sexes. An intriguing question: Why does the brain (which contains estrogen circulating in blood vessels) need estrogen-producing neurons? A possible answer is that the role of the brain-produced estrogen is different from that of the circulating hormone. Our concept is that the estrogen-producing neurons, when needed, release estrogen from their nerve endings. In this way, estrogen can have powerful effects on target neurons, and can influence disease symptoms. Our data show that estrogen-producing neurons are located exactly in those limbic brain areas which are involved in TS, and that this neuron system forms massive connections within the brain. Our experiments will attempt to clarify these connections, and will determine the neurochemistry of the aromatase system, since, this system seems to have the capacity to influence all brain regions involved in TS. We will endeavor to determine the neurochemical nature of neurons which are controlled by the estrogen-producing neurons. The data obtained may lead to a better understanding of how “neuroactive” steroids of the brain contribute to the onset and exacerbation of TS. Studies on the projection fields and neuron targets of brain aromatase systems can, indirectly, provide neuroanatomical clues for developing new, more target-specific (anti-androgen or anti-aromatase?) medications for TS. Robert L. Jakab, Ph.D. Yale University School of Medicine, New Haven, CT Award $20,000 Tourette Association of America Inc. – Research Grant Award 1994