The mammalian brain depends upon glucose as its main source of energy, and tight regulation of glucose metabolism is critical for brain physiology. Consistent with its critical role for physiological brain function, disruption of normal glucose metabolism as well as its interdependence with cell death pathways forms the pathophysiological basis for many brain disorders. Here, we review recent advances in understanding how glucose metabolism sustains basic brain physiology. We aim at synthesizing these findings to form a comprehensive picture of the cooperation required between different systems and cell types, and the specific breakdowns in this cooperation which lead to disease.

Summary:We investigated the combined effect of increased brain topical K+ concentration and reduction of the nitric oxide (NO') level caused by nitric oxide scavenging or nitric oxide synthase (NOS) inhibition on regional cerebral blood flow and subarachnoid direct current (DC) potential. Using thiopental anesthetized male Wistar rats with a closed cranial window preparation, brain topical superfusion of a combination of the NO' scavenger hemoglobin (Hb; 2 mmollL) and increased K+ concentration in the artificial cerebrospinal fluid ([K+1A csF) at 35 mmollL led to sudden spontaneous transient ischemic events with a decrease of CBF to 14 ± 7% (n = 4) compared with the baseline (100%). The ischemic events lasted for 53 ± 17 min utes and were associated with a negative subarachnoid DC shift of -7.3 ± 0.6 mV of 49 ± 12 minutes' duration. The combina tion of the NOS inhibitor N-nitro-L-arginine (L-NA, I mmollL) with [K+1A csF at 35 mmollL caused similar spontaneous tran sient ischemic events in 13 rats. When cortical spreading de pression was induced by KCI at a 5-mm distance, a typical cortical spreading hyperemia (CSH) and negative DC shift were measured at the closed cranial window during brain topi cal superfusion with either physiologic artificial CSF (n = 5), 20 mmollL propagated at a speed of 3. 4 ± 0.6 mmlmin, indi cating cortical spreading ischemia (CSI). Although CSH did not change oxygen free radical production, as measured on-line by in vivo lucigenin-enhanced chemiluminescence, CSI re sulted in the typical radical production pattern of ischemia and reperfusion suggestive of brain damage (n = 4). Nimodipine (2 j-Lg/kg body weight/min intravenously) transformed CSI back to CSH (n = 4). Vehicle had no effect on CSI (n = 4). Our data suggest that the combination of decreased NO' levels and increased subarachnoid K+ levels induces spreading depression with acute ischemic CBF response. Thus, a disturbed coupling of metabolism and CBF can cause ischemia. We speculate that CSI may be related to delayed ischemic deficits after subarach noid hemorrhage, a clinical condition in which the release of Hb and K+ from erythrocytes creates a microenvironment simi lar to the one investigated here. Key Words: Cerebral blood flow-Nitric oxide-Potassium-Spreading depression Vasospasm-Migraine-Migrainous stroke-Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like epi sodes (MELAS)-Ischemia-Delayed ischemic deficits Subarachnoid hemorrhage.

Modern functional imaging techniques of the brain measure local hemodynamic responses evoked by neuronal activity. Capillary pericytes recently were suggested to mediate neurovascular coupling in brain slices, but their role in vivo remains unexplored. We used two-photon microscopy to study in real time pericytes and the dynamic changes of capillary diameter and blood flow in the cortex of anesthetized mice, as well as in brain slices. The thromboxane A 2 analog, 9,11-dideoxy-9α,11α-methanoepoxy Prostaglandin F2α (U46619), induced constrictions in the vicinity of pericytes in a fraction of capillaries, whereas others dilated. The changes in vessel diameter resulted in changes in capillary red blood cell (RBC) flow. In contrast, during brief epochs of seizure activity elicited by local administration of the GABA A receptor antagonist, bicuculline, capillary RBC flow increased without pericyte-induced capillary diameter changes. Precapillary arterioles were the smallest vessels to dilate, together with penetrating and pial arterioles. Our results provide in vivo evidence that pericytes can modulate capillary blood flow in the brain, which may be important under pathological conditions. However, our data suggest that precapillary and penetrating arterioles, rather than pericytes in capillaries, are responsible for the blood flow increase induced by neural activity.cerebral blood flow | neurovascular coupling | cortical spreading depolarization | electrophysiology

Modern functional neuroimaging methods, such as positron-emission tomography (PET), optical imaging of intrinsic signals, and functional MRI (fMRI) utilize activity-dependent hemodynamic changes to obtain indirect maps of the evoked electrical activity in the brain. Whereas PET and f low-sensitive MRI map cerebral blood f low (CBF) changes, optical imaging and blood oxygenation level-dependent MRI map areas with changes in the concentration of deoxygenated hemoglobin (HbR). However, the relationship between CBF and HbR during functional activation has never been tested experimentally. Therefore, we investigated this relationship by using imaging spectroscopy and laser-Doppler f lowmetry techniques, simultaneously, in the visual cortex of anesthetized cats during sensory stimulation. We found that the earliest microcirculatory change was indeed an increase in HbR, whereas the CBF increase lagged by more than a second after the increase in HbR. The increased HbR was accompanied by a simultaneous increase in total hemoglobin concentration (Hbt), presumably ref lecting an early blood volume increase. We found that the CBF changes lagged after Hbt changes by 1 to 2 sec throughout the response. These results support the notion of active neurovascular regulation of blood volume in the capillary bed and the existence of a delayed, passive process of capillary filling.