Local increases in blood flow during neural activity form the basis for functional brain imaging, yet the mechanisms of such activity-dependent hyperemia remain poorly defined. Astrocytes, with their extensive fiber arbors, provide an anatomical link between synapses and the microvasculature, and several recent studies have implicated them in the regulation of vasomotor tone. Using 2-photon imaging of anesthetized adult mice, we have found that astrocytic Ca2+ signaling in cortex potently triggers local vasodilatation. Cytosolic Ca2+ was selectively elevated by photolysis of caged Ca2+ in astrocytes, and invariably associated with vasodilation. In this set of studies, we intent to evaluate the relative contribution of astrocytes to functional hyperemia within the parietal sensory cortex, as evoked by whisker stimulation. Several vasoactive compounds, including COX-1 and -2 products, adenosine, NO, and cytochrome P450 vasoactive compounds have previously been implicated in such functional hyperemia. These compounds may affect vascular tone directly by acting on smooth muscle cells, or indirectly through astrocytic intermediaries. By concomitant imaging of Ca2+ and local perfusion, we will first assess the effects of these vasoactive agents upon the astrocytes and vascular tone in vivo, with an emphasis on discriminating which agents operate on astrocytes, which on vasculature downstream of astrocytic stimulation, and which at both loci. We will then use pharmacological approaches to block or enhance Ca2+ signaling in combination with whisker stimulation, so as to establish the relative contribution of astrocytic calcium signaling to functional hyperemia. Next, we will analyze the role of astrocytes in vascular dysregulation following brain injury. Both arterial vasospasm and microvascular vasoconstriction with secondary ischemia are common late complications of brain injury, and their genesis coincides with the appearance of reactive astrocytosis. In addition, we have already noted that following experimental intracerebral hemorrhage, reactive astrocytes display sustained increases in resting Ca2+ and fail to trigger vasodilation. On the basis of these observations, we will assess whether the role of injury-elicited astrocytosis contributes to delayed hypoperfusion following brain injury. This set of studies comprises a concerted effort to define the relationship of glial signaling to vascular tone, in both normal physiology and disease. These experiments promise to yield much information of real clinical utility;the pharmacological modification of vasomotor tone and blood flow may be of critical importance to the treatment of disorders as diverse as acute stroke microvascular angiopathies, trauma, and both subarachnoid and intracerebral hemorrhage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056188-05
Application #
7845564
Study Section
Special Emphasis Panel (ZRG1-BINP-L (01))
Program Officer
Hicks, Ramona R
Project Start
2006-09-10
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$333,087
Indirect Cost
Name
University of Rochester
Department
Neurosurgery
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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