A fundamental goal in neurobiology is understanding the relationship between structure and function. The use of immunohistochemical techniques has added a biochemical dimension to this equation. This proposal consists of two projects: (a) defining the anatomical organization of the central adrenergic systems, and (b) investigating a now well-defined function of this system--the regulation of cerebral vascular permeability and flow. This function was originally hypothesized on the basis of our previous anatomical studies. The efferent connections of the central adrenergic system are now established. In this grant period our emphasis will be shifted to defining important afferent connections to this system. To this end we have prepared a specific antiserum to choline acetyltransferase and developed the technology for localizing the cholinergic system using immunohistochemistry. The entire central cholinergic system will, therefore, be mapped and at the same time the cholinergic afferents to the central catecholamine neuron systems will be defined. Previous anatomical work has defined possible neuronal circuits which may mediate physiologically induced changes in vascular permeability. These circuits will be tested using a combination of physiological and pharmacological techniques, first a rat and finally a monkey. The structure and function of the central catecholamine system has many clinical implications. Most centrally acting drugs effect this system either directly or indirectly. A clear understanding of the action of these drugs has been hampered by the lack of a well-defined and measurable function to study. Our discovery that this system regulates capillary permeability to water has provided such a function. In addition, this funding has broadened the concept of the blood-brain barrier, and given insight into possible mechanisms of cerebral edema.
The aims of the present proposal to define the anatomical circuits utilized in permeability regulation and determine the pharmacological means of manipulating this function may not only leaf to a better understanding of the central catecholamine system in general, but also may lead to the development of drug treatments for cerebral fluid imbalance.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology B Subcommittee 1 (NEUB)
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Washington University
Schools of Medicine
Saint Louis
United States
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