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. ? ? ?
| Rangroo Thrane, Vinita; Thrane, Alexander S; Wang, Fushun et al. (2013) Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering. Nat Med 19:1643-8 |
| Oberheim, Nancy Ann; Goldman, Steven A; Nedergaard, Maiken (2012) Heterogeneity of astrocytic form and function. Methods Mol Biol 814:23-45 |
| Rangroo Thrane, V; Thrane, A S; Chang, J et al. (2012) Real-time analysis of microglial activation and motility in hepatic and hyperammonemic encephalopathy. Neuroscience 220:247-55 |
| Nedergaard, Maiken; Verkhratsky, Alexei (2012) Artifact versus reality--how astrocytes contribute to synaptic events. Glia 60:1013-23 |
| Thrane, Alexander S; Rappold, Phillip M; Fujita, Takumi et al. (2011) Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema. Proc Natl Acad Sci U S A 108:846-51 |
| Hertz, Leif; Lovatt, Ditte; Goldman, Steven A et al. (2010) Adrenoceptors in brain: cellular gene expression and effects on astrocytic metabolism and [Ca(2+)]i. Neurochem Int 57:411-20 |
| Nedergaard, Maiken; Verkhratsky, Alexei (2010) Calcium dyshomeostasis and pathological calcium signalling in neurological diseases. Cell Calcium 47:101-2 |
| Iadecola, Costantino; Nedergaard, Maiken (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369-76 |
