Modern functional neuroimaging methods, such as Positron Emission Tomography (PET), and functional Magnetic Resonance Imaging (fMRI), rely on the coupling of neuronal electrical activity to changes in local metabolic demands--called """"""""cerebrometabolic coupling""""""""--and to the hemodynamic regulation of energy supply and waste removal--called """"""""cerebrovascular coupling""""""""--to measure brain activity through indirect surrogate markers of such activity. Understanding the relationship between local brain activity and the major physiological markers that are measured is of paramount importance for the correct interpretation and quantification of functional neuroimaging data. My main research interests are to understand and elucidate the mechanisms of regulation of cerebral blood flow during normal and stimulation induced brain activity. Amongst the several key aspects of this magnificently broad task, I have directed research efforts in the first year on investigating two major signaling pathways - the nitric oxide (NO)pathway, and the prostaglandin (PGE2) pathway, known to be involved in translating a change in brain activity into a vascular response. The first experiments have focused on the use of rats and mice and functional MRI, combined with simultaneous electrophysiological recordings, to measure the hemodynamic response and the increased electrical activity to stimulation of the somatosensory cortex, before and after the use of potent and specific inhibitors of nitric oxide synthase (NOS) and of cyclooxygenase-2 (COX-2). Preliminary results show a significant decrease (50-90%) of the hemodynamic response to somatosensory stimulation after inhibition of either COX-2 or NOS, respectively, with minimal decrease of electrical activity. Such results confirm the hypothesis that NO and PGE2 are important mediators of the cerebrovascular coupling. These results have been submitted for publication. A few collaborators have been of essential help in this project. Prof. Mathias Hoehn, of the Max-Planck Institute for Neurological Research, Cologne, Germany, has helped develop the protocol for somatosensory stimulation of the rat and for recording of SEPs in the magnet. In NINDS, Dr. Leonardo Belluscio in NINDS has been collaborating in developing 2-photon confocal techniques to directly visualize the cortical microvasculature. And Dr. Francesca Bosetti, NIA, has helped with assays to measure COX-2 activity. For example, in the lab of Dr. Francesca Bosetti, basal activity of COX-2 was measured in control and experimental rats showing at least 64% inhibition of COX-2 by meloxicam.
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