The ultimate goal of this proposal is to elucidate the mechanisms regulating the increases in cerebral blood flow (CBF) elicited by neural activity. While it is well established that one of the major factors regulating CBF is the activity of local neurons, the neural events leading to the increases in CBF remain poorly understood. One major problem has been the lack of a relatively """"""""simple"""""""" model system on which these mechanisms could be studied. The parallel fiber system of the cerebellar cortex is an ideal substrate for studying the interaction between neurons and local vessels since its circuitry and the neural events occurring during its activation have been well characterized. Furthermore, these neural events can be selectively inhibited using pharmacological agents. The goal of this proposal is therefore to use the parallel fiber system as a model for studying the mechanisms mediating the increases in CBF elicited by neural activation. The major aims of this proposal are the following: First, the changes in CBF elicited by stimulation of the parallel fibers will be characterized with respect to magnitude, relationship to stimulation parameters, spatial distribution, and relationship to local glucose utilization. These experiments will establish the basic characteristics of the flow response and will provide the foundation for the studies described in the other aims. Second, it will determine whether the increases in CBF result from: (a) presynaptic release of neurotransmitters or (b) neural events linked to post-synaptic effects of neurotransmitters. Our hypothesis is that the increases in CBF are initiated by post-synaptic effects of excitatory aminoacids, probably glutamate, released from parallel fibers. Third, it will be established whether the activity of inhibitory interneurons in the molecular layer contributes to the flow increases elicited by stimulation of the parallel fibers. Fourth, we will test the hypothesis that glutamate, released from the parallel fibers, increases CBF by stimulating the production of the powerful cerebrovasodilator nitric oxide (NO) in cerebellar cortical neurons. NO is an important molecular messenger in cerebellum and its production in cerebellar cortex is activated by excitatory aminoacids such as glutamate. These studies will provide new information that will help further our understanding of the specific neural events that initiate the increases in CBF elicited by neural activity and the mediators responsible for the vasodilation.
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