The long term goal of this application is to elucidate the mechanisms regulating the cerebellar microcirculation during neural activity. Although it is well established that synaptic activity is a major determinant of local blood flow in other brain regions, little is known on the neural regulation of 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 two major excitatory inputs to Purkinje cells and interneuron: 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 will be tested that activation, 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. In the third aim, the role of the CF and PF activity in the flow response produced b crus II activation will be defined. IN the fourth aim, transgenic mice with dysfunction (PO3 line) or degeneration of Purkinje cells (P05 line) will be used to define the relative contribution of Purkinje cells and interneuron to 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 fundamental mechanisms linking synaptic activity to blood flow in the brain.