Our aim is to continue the study of the biological role of endogenous cerebral norepinephrine in the control of brain metabolism and its local microvascular perfusion and capillary permeability. The physiological mechanisms underlying this influence of norepinephrine on brain function and their significance in abnormal pathophysiological conditions will be investigated. The results is previously obtained from this laboratory provide ample evidence for such a role, especially when cerebral metabolic requirements are increased, and during pathophysiological conditions such as hypertension, epilepsy, and brain ischemia. One of the paradigms chosen for these studies include the unilateral chemical lesion of the nucleus ceruleus in the rat. The locus ceruleus is the site of origin of most of the noradrenergic innervation of the cerebral cortex and hippocampus. Effects of locus ceruleus lesion will be studied using a combination of physiological, biochemical, pharmacological, and morphological methods in vitro and in vivo. Physiological studies will measure cerebral blood flow and capillary permeability, and will determine whether the noradrenergic innervation of the cerebral circulation plays a role in capillary recruitment and in maintaining the integrity of the blood-brain barrier. Functions of the blood-brain barrier will be assessed by its ability to exclude large molecules such as albumin from entering the brain, and by the active transport of water and electrolytes from blood-to-brain and vice versa. Biochemical and morphological methods will be used to study the response of noradrenergic receptors to the ablation of the putative noradrenergic innervation of cerebral blood vessels, and the mechanisms by which the brain compensates for chronic noradrenergic denervation after locus ceruleus lesion to restitute function. These latter experiments will shed light on the nature of factors that are responsible for the recovery of function, and will provide basic information regarding the phenomena of plasticity, regeneration, and sprouting in the adult mammalian brain.
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