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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS012311-10
Application #
3394777
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1978-07-01
Project End
1986-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
10
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Oakman, S A; Faris, P L; Cozzari, C et al. (1999) Characterization of the extent of pontomesencephalic cholinergic neurons' projections to the thalamus: comparison with projections to midbrain dopaminergic groups. Neuroscience 94:529-47
Oakman, S A; Faris, P L; Kerr, P E et al. (1995) Distribution of pontomesencephalic cholinergic neurons projecting to substantia nigra differs significantly from those projecting to ventral tegmental area. J Neurosci 15:5859-69
Chedotal, A; Umbriaco, D; Descarries, L et al. (1994) Light and electron microscopic immunocytochemical analysis of the neurovascular relationships of choline acetyltransferase and vasoactive intestinal polypeptide nerve terminals in the rat cerebral cortex. J Comp Neurol 343:57-71
Chedotal, A; Cozzari, C; Faure, M P et al. (1994) Distinct choline acetyltransferase (ChAT) and vasoactive intestinal polypeptide (VIP) bipolar neurons project to local blood vessels in the rat cerebral cortex. Brain Res 646:181-93
Iadecola, C; Faris, P L; Hartman, B K et al. (1993) Localization of NADPH diaphorase in neurons of the rostral ventral medulla: possible role of nitric oxide in central autonomic regulation and oxygen chemoreception. Brain Res 603:173-9
Wozniak, D F; Stewart, G R; Finger, S et al. (1989) Comparison of behavioral effects of nucleus basalis magnocellularis lesions and somatosensory cortex ablation in the rat. Neuroscience 32:685-700
Wozniak, D F; Stewart, G R; Finger, S et al. (1989) Basal forebrain lesions impair tactile discrimination and working memory. Neurobiol Aging 10:173-9
Wong, Y H; Kalmbach, S J; Hartman, B K et al. (1987) Immunohistochemical staining and enzyme activity measurements show myo-inositol-1-phosphate synthase to be localized in the vasculature of brain. J Neurochem 48:1434-42
Rubin, E H; Preskorn, S H; Hartman, B K (1986) The role of the central adrenergic system in the regulation of the cerebromicrocirculation. Basic and clinical implications. Ann N Y Acad Sci 462:224-31
Stewart, G R; Price, M; Olney, J W et al. (1986) N-methylaspartate: an effective tool for lesioning basal forebrain cholinergic neurons of the rat. Brain Res 369:377-82