Regulation of Cerebral Blood Flow in Health and in Disease

Background:

The brain requires a continuous supply of blood, bringing in oxygen and glucose, in order to meet the demands of its energy needs. Even a brief interruption in blood flow may cause irreversible damage. Activation of neurons in the brain leads to fast and precise increases in cerebral blood flow (CBF) in the region of activity.

The problem is that the mechanisms coupling neuronal activity to CBF changes are not well understood. Moreover, there is a lack of precise knowledge regarding the relationship between blood flow and neuronal activity.

Ischemic stroke, which occurs when a blood vessel is blocked, is a major cause of morbidity and mortality. In addition to causing damage to neurons and glia, cerebral ischemia may impair vascular function in the brain. In particular, ischemia may adversely impact the mechanisms that couple cerebral blood flow responses to functional activity in the brain. My research focuses on the mechanisms that regulate blood flow during neuronal activity in the cerebral cortex, and how ischemia may affect these mechanisms.

Research Question:

To study the mechanisms that link vascular responses to neuronal activity in the brain, we use a model that involves the stimulation of a somatosensory pathway. The following diagram illustrates the ‘neurovascular’ events that may take place during activation of the cerebral cortex. Briefly, activation of a somatosensory pathway results in (a) the release of neurotransmitters at thalamocortical synapses, (b) synaptic activity and subsequent release of vasodilator molecules (adenosine, H, K+, and nitric oxide), that dilate parenchymal microvessels in the vicinity of the active region, and (c) the spreading of the dilator signal to surface (pial ) vessels, resulting in a coordinated vasomotor response that optimizes tissue perfusion.

The specific details of this general scheme remain poorly understood. We ask the following questions:

1. How does glutamate lead to the release of vasoactive molecules that dilate cerebral blood vessels?
   
2. How does vasomotor responses initiated in microvessels inside the cortex spread upstream to their feeding vessels, such as surface (pial) arteries? What is the role of gap junctions in this ‘conducted’ vascular response?
   
3. How does focal ischemia and reperfusion affect cerebral circulatory responses? How does ischemia and other pathological conditions affect vascular communication and gap junction expression? What may contribute to the recovery of brain perfusion after ischemia?
   

Research Highlights:

I. During somatosensory stimulation, cerebral blood flow is coupled to integrated neuronal activity but not to averaged evoked potentials.

II. The dilation response of brain surface arterioles during somatosensory activity most likely involves the intercellular conduction of membrane currents along intracerebral blood vessels. We have produced evidence against the involvement of a) a flow-mediated dilation mechanism, related to increases in blood shear rate, and b) the brain-to-CSF diffusion of vasoactive metabolites.

III. Conducted dilation correlates with membrane potential changes in isolated cerebral arterioles. This is an ongoing study.

Research Methods:

We use a multidisciplinary approach involving whole animal and isolated vascular preparations, tissue culture, and electrophysiological methods.
Animals: rats
Techniques: animal surgery including anesthesia and implant of cranial windows, laser-Doppler flowmetry, videometry, optical imaging, evoked potential measurements, other electrophysiological techniques including sharp electrode recordings and cell labeling, an in vitro preparation of cannulated and perfused arterioles, tissue culture methods, and HPLC.
Ischemia model: Middle Cerebral Artery Occlusion (intraluminal filament method)

Schematic Diagram of Cranial Window

Collaborators:

Gavin Britz, M.D.
Christine Gleason, M.D. (Neonatology)
Paul Lampe, Ph.D. (Fred Hutch Cancer Research Center)
Raimondo D’Ambrosio, Ph.D.
Kyra Becker, M.D. (Neurology)
Joe Meno
Son Nguyen

Bibliography:

SELECTED PUBLISHED AND ACCEPTED ARTICLES IN REFEREED JOURNALS:

1. Ngai, A.C., J.R. Meno, and H.R. Winn. Simultaneous measurements of pial arteriolar diameter and laser-Doppler flow during somatosensory stimulation. J Cereb. Blood Flow Metab. 15: 124-127, 1995.

2. Ngai, A.C., and H.R. Winn. Modulation of cerebral arteriolar diameter by intraluminal flow and pressure. Circ. Res. 77: 832-840, 1995.

3. Ngai, A.C., J.R. Meno, and H.R. Winn. L-NNA suppresses cerebrovascular response and evoked potentials during somatosensory stimulation in rats. Am. J. Physiol. 269 (Heart Circ. Physiol. 38): H1803-H1810, 1995.

4. Ngai, A.C., and H.R. Winn. Estimation of shear and flow rates in pial arterioles during somatosensory stimulation. Am. J. Physiol. 270 (Heart Circ. Physiol. 39): H1712-H1717, 1996.

5. Ngai, A.C., J.R. Meno, M. A. Jolley, and H.R. Winn. Suppression of somatosensory evoked potentials by nitric oxide synthase inhibition in rats: methodological differences. Neuroscience Letters 245: 171-174, 1998.

6. Ngai, A.C., J.R. Meno, K.R. Ko, and H.R. Winn. Role of adenosine in cerebral vasodilator responses to sciatic nerve stimulation. J. Cereb. Blood Flow Metab. 18: 580-581, 1998.

7. Ngai, A.C., M.A. Jolley, R. D’Ambrosio, J.R. Meno, and H.R. Winn. Frequency-dependent changes in cerebral blood flow and evoked potentials during somatosensory stimulation in the rat. Brain Research 837: 221-228, 1999.

8. Ngai, A.C., E.F. Coyne, and H.R. Winn. Receptor subtypes mediating adenosine-induced dilation of cerebral arterioles. Am. J. Physiol. Heart Circ. Physiol., Am J Physiol Heart Circ Physiol 280: H2329-H2335, 2001.

9 . Ngai, A.C., and H.R. Winn. Pial arteriole dilation during somatosensory stimulation is not mediated by an increase in CSF metabolites. Am. J. Physiol. Heart Circ. Physiol. 282: H902-H907, 2002.

10 . Iliff, J.J., R.D’Ambrosio, A.C. Ngai, and H.R. Winn. Adenosine receptors mediate glutamate-evoked arteriolar dilation in the rat cerebral cortex. Am. J. Physiol. Heart Circ. Physiol. 284: H1631-H1637, 2003.

11 . Meno, J.R., T.K. Nguyen, E.M. Jensen, G.A. West, L. Goysman, D.K. Kung, A.C. Ngai, G.W. Britz, and H.R. Winn. Effect of caffeine on cerebral blood flow response to somatosensory stimulation. J. Cereb. Blood Flow Metabol. 25: 775-784, 2005.

12. Ngai, A.C., T.-S. Nguyen, J.R. Meno, and G.W. Britz. Postischemic augmentation of conducted dilation in cerebral arterioles. Stroke, in press, 2006.