Our goal is to explore neural connections which mediate the symptoms of Tourette’s Syndrome (TS). Clinical and experimental data show that sex steroids influence symptom expression in TS. On the other hand, particular brain areas have been incriminated in TS. In the proposed studies, we attempt to “link” these theories, by exploring the relationship between these brain areas 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. The thoughts and behaviors of many TS patients, regardless of their sex, sometimes have sexual or aggressive content. 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. Moreover, TS symptoms of athletes seem to worsen when they abuse high doses of anabolic steroids. Estrogen is produced not only by the ovary and the 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 anatomical data gathered in the rat 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 aromatase neurons are able to store the produced estrogen and, when needed, release it 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 our preliminary data suggest that this neuron system forms massive connections within the brain. Our experiments will attempt to both clarify these connections, and determine the neurochemistry, and inhibitory or stimulatory nature of the aromatase system, since this system seems to have the capacity to influence all brain regions involved in TS. We will also try to determine the neurochemical nature of neurons which are under direct control of 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 symptoms. Studies on the projection fields and neuron targets of brain aromatase systems also have clinical importance. Such studies can provide neuroanatomical clues for therapeutical strategies and for developing new, more target-specific anti-androgen and anti-aromatase drugs for TS. Therapies using anti-androgens or aromatase inhibitors against TS are in a very preliminary phase, but some promising results have been reported. Robert L. Jakab, Ph.D. Yale University School of Medicine New Haven, CT Award $25,000 Tourette Association of America Inc. – Research Grant Award 1992