The long-term goal of this project is to elucidate the mechanisms regulating the cerebellar microcirculation during neural activity. Although it is well established that neural activity is a major determinant of local blood flow in cerebellum. The cerebellar cortex possesses a unique and relatively well-characterized structure and functional organization that lends itself well to investigations of the relationship between neural activity and blood flow. The proposed studies will test the hypothesis that, during normal cerebellar function, blood flow is regulated by the interaction between the major excitatory inputs to Purkinje cells and interneurons: the parallel fibers (PF) and the climbing fibers (CF). As a model of cerebellar activation, crus II, a region of the cerebellar cortex which receives a well-defined somatosensory input from the face, will be activated by cutaneous stimulation. In the first aim, the hypothesis that will be tested that activation of crus II increases local blood flow and that the response is linked to local synaptic activity. In the second aim, we will begin to define the transmitters and mediators responsible for the flow increase. In particular, pharmacological inhibitors and neuronal nitric oxide synthase null mice will be used to test the hypothesis that the response is mediated by activation of glutamate receptors, in part, via nitric oxide and cGMP. Preliminary results suggest that nitric oxide plays a prominent role in the vasodilation evoked by crus II activation. In the third aim, the role of the CF and PF activity in the flow response produced by crus II activation will be defined. In the fourth aim, transgenic mice with dysfunction (P03 line) or degeneration of Purkinje cells (P05) will be used to define the relative contribution of Purkinje cells and interneurons to the flow response. While these experiments will address an important aspect of cerebellar function on which very little is known, they will also expand our understanding of the cellular mechanisms linking synaptic activity to blood flow in brain.
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