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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038252-02
Application #
6126397
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Jacobs, Tom P
Project Start
1998-12-15
Project End
2003-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
2
Fiscal Year
2000
Total Cost
$195,390
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Neurology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Iadecola, Costantino; Park, Laibaik; Capone, Carmen (2009) Threats to the mind: aging, amyloid, and hypertension. Stroke 40:S40-4
Park, Laibaik; Anrather, Josef; Girouard, Helene et al. (2007) Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. J Cereb Blood Flow Metab 27:1908-18
Park, Laibaik; Anrather, Josef; Zhou, Ping et al. (2005) NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. J Neurosci 25:1769-77
Iadecola, Costantino; Gorelick, Philip B (2005) The Janus face of cyclooxygenase-2 in ischemic stroke: shifting toward downstream targets. Stroke 36:182-5
Iadecola, Costantino; Gorelick, Philip B (2004) Hypertension, angiotensin, and stroke: beyond blood pressure. Stroke 35:348-50
Wang, Gang; Anrather, Josef; Huang, Jie et al. (2004) NADPH oxidase contributes to angiotensin II signaling in the nucleus tractus solitarius. J Neurosci 24:5516-24
Kazama, Ken; Anrather, Josef; Zhou, Ping et al. (2004) Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ Res 95:1019-26
Park, Laibaik; Anrather, Josef; Zhou, Ping et al. (2004) Exogenous NADPH increases cerebral blood flow through NADPH oxidase-dependent and -independent mechanisms. Arterioscler Thromb Vasc Biol 24:1860-5
Park, Laibaik; Anrather, Josef; Forster, Colleen et al. (2004) Abeta-induced vascular oxidative stress and attenuation of functional hyperemia in mouse somatosensory cortex. J Cereb Blood Flow Metab 24:334-42
Zhang, Yi; Forster, Colleen; Milner, Teresa A et al. (2003) Attenuation of activity-induced increases in cerebellar blood flow by lesion of the inferior olive. Am J Physiol Heart Circ Physiol 285:H1177-82

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