Regulation of CBF by the Rostral Ventrolateral Medulla

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DESCRIPTION (provided by the applicant): The long-term objective of this study is to identify the neuronal pathways, and the cellular elements and functions, by which the brain regulates its own blood flow. It posits the existence of a dedicated cerebro-vasodilator network, which can elevate regional cerebral blood flow (rCBF) globally without parallel changes in local metabolism (regional cerebral glucose utilization, rCGU) as a primary vasodilation. This pathway (a) is closely linked to brainstem centers in the rostral ventrolateral medulla (RVLM) that sense and initiate elevations of rCBF in response to hypoxia; (b) is relayed through an adjacent area of the medulla, the medullary cerebro-vascular vasodilator area (MCVA), to a novel subthalamic area, the subthalamic vasodilator area (SVA). The vasodilator pathway (RVLM-MCVA-SVA) and its elements may also participate in initiating elevations of cortical rCBF that are coupled to rCGU; i.e., we propose that cortical vasodilation may be mediated by a population of cortical vasodilator neurons also excited by brainstem pathways. Two studies are proposed. Study 1, using autoradiographic measurement of rCBF and rCGU, electrical or chemical stimulation or blockade, and extracellular recording combined with juxtacellular staining, tests the hypothesis that SVA is a major relay of vasodilator signals to cortical vasodilator neurons by demonstrating that (a) SVA neurons are excited by MCVA stimulation, hypoxic excitation of RVLM, hypoxia, and vibrissa stimulation; (b) electrical stimulation of SVA globally increases rCBF independent of rCGU; and (c) lesions of SVA neurons interrupt the vasodilation elicited from vibrissa stimulation, while preserving metabolic changes in the somatosensory cortex. Study2 uses extra- and intracellular electrophysiological recording, and staining techniques to test the hypotheses that a specific subpopulation of cortical neurons excited through the cortical afferent projection mediates the vasodilation elicited by RVLM-MCVA-SVA excitation or somatosensory stimulation. This will be accomplished by (a) demonstrating that the increase in rCBF evoked by excitation of MCVA is dependent upon the integrity of local cortical neurons; (b) showing that cortical vasodilation evoked by stimulation of MCVA or SVA and hypoxia is neurogenic rather than vasogenic in nature (c) characterizing the morphological and physiological properties of purported cortical vasodilator neurons; and (d) examining whether cortical vasodilator neurons themselves are oxygen sensitive.