Defense Date


Document Type


Degree Name

Doctor of Philosophy


Anatomy & Neurobiology

First Advisor

John T. Povlishock


The blood-brain barrier (BBB) selectively restricts the blood-to-brain passage of many solutes owing to unique properties of cerebrovascular endothelial cell membranes. This selective blood/brain interface participates in the maintenance of brain homeostasis by controlling nutrient, gas, and fluid exchange necessary for brain function. Normal BBB function can be altered under various pathological and experimental conditions, allowing the transfer into brain parenchyma of blood-borne solutes normally excluded. To date, experimental study of the BBB has been accomplished primarily through the use of two different methodological approaches. Some investigators have focused on the barrier's morphological correlates and its morphopathological alteration under various pathological conditions. Other investigators have attempted to define the physiological transport properties of the BBB.

Morphological studies have employed, for the most part, large molecular weight (MW) tracers to detect morphological alterations underlying increased permeability. Physiological studies, employing smaller, more physiologic tracers have been successful in describing, quantitatively, certain functional aspects of blood-to-brain transfer. The current work attempts to merge these two approaches and to consider barrier function/dysfunction from both a morphological and a functional perspective. Specifically, the study compares in rats, following acute hypertension (a condition well-known to elicit BBB alteration), the cerebrovascular passage of C-alpha-aminois obutyric acid (AIB), a small MW tracer employed in quantitative physiologic barrier studies, and that of horseradish peroxidase (HRP), a large MW protein tracer traditionally employed in morphological barrier studies. The blood-to-brain passage of AIB and HRP were compared, following acute hypertension, with regard to both the topographical distributions of the tracer extravasation patterns and the magnitude of tracer extravasation at two different levels of hypertension. Quantitative measures of cerebrovascular AIB transfer were obtained through macroautoradiography and computerized image analysis. The data, both qualitative and quantitative, revealed dramatic focal permeability increases to AIB in some brain loci which also showed permeability increases to HRP. Such loci included the cerebral cortices and the thalamus. However, many brain regions, such as the caudate-putamen, cerebellum, and brainstem, showed more subtly-elevated AIB passage where no corresponding HRP passage was observed. Linear regression analysis of the physiologic data showed that the rate of cerebrovascular AIB transfer was positively related to the abruptness of the onset of hypertension and not related to other physiologic parameters of the hypertensive insult. The qualitative and quantitative results of this study suggest that traditional morphological barrier studies a lone do not reveal all aspects of altered barrier status and that multiple mechanisms underlying increased BBB permeability may operate simultaneously during BBB dysfunction.


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