This is an omnibus project that covers a variety of studies on development, validation, refinement, and applications of methods to determine basic biochemical and physiological mechanisms underlying the regulation of cerebral blood flow (CBF) and energy metabolism at rest and in response to functional activation. Findings of the previous year that multiple mechanisms for regulation CBF during functional activation operate at different relay stations along a neural pathway were published this year. Adenosine and adenosine receptors in vascular smooth muscle are involved in increasing CBF in the primary synapses during functional activation while at higher level stations in multisynaptic pathways nitric oxide (NO)produced by neuronal nitric oxide synthase appears to play a role. Neither adenosine nor nitric oxide fully account, however, for the increases in CBF evoked by functional activation, and other factors must be involved. Studies completed and published this year have shown that anesthesia markedly suppresses functional activation of CBF in regions containing higher level synapses of the activated pathway but not in the regions of the primary synapses. Studies in progress but almost completed indicate that there is a symbiotic metabolic relationship between astroglia and neurons and that astroglial metabolism may be intimately involved in the regulation of CBF. Astroglia in culture readily metabolize glucose to lactate but show limited ability to oxidize the lactate to CO2 and water; instead they excrete it. Presumably, in vivo neurons, which can metabolize lactate as well as glucose, take up the lactate and oxidize it to CO2 and water to derive the energy needed to support spike activity in the neurons. Dichloracetate stimulates astroglial oxidation of lactate. When given in vivo dichloracetate enhances the increases in CBF evoked by functional activation suggesting that astroglial oxidative metabolism nay play a role in the regulation of CBF to functional activation. Studies on two types of mutant mice were completed and published or in press this past year. Local CBF and glucose utilization (lCMRglc) wee measured in a mouse model of Fabry’s diseases, in which the alpha-galactosidase A enzyme was knocked out. As in the human disease, this model exhibits deposits of ceramide trihexoside throughout the brain, mainly in vascular smooth muscle and endothelial cells.. These mutants showed widespread reductions in lCMRglc but without the expected corresponding reductions in local CBF. These results suggest that the impairment in cerebral glucose metabolism is not due to inadequate perfusion of the brain but to reduced transport of glucose from blood to brain secondary to the vasculopathy. Studies were also carried out in two strains of mutant mice with either the alpha or the beta thyroid receptor genetically altered so that they could not bind L-triiodothyronine. There was completely normal local cerebral glucose utilization in the mice with the altered beta thyroid hormone receptor, but in the mice with the dysfunctional alpha-receptor, local cerebral glucose utilization was diffusely impaired just as it is in cretinism induced by radiothyrodectomy. These results indicate that the beta thyroid hormone receptor has little if anything to do with normal brain development and that the effects of thyroid hormone on brain development are mediated by the alpha thyroid hormone receptor.
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