Blood flow regulation – food for thoughts may be regulated by very delicate mechanisms

Changes in brain activity are accompanied by changes in brain metabolism and perfusion. This relationship is the basis of functional neuroimaging techniques where deviations in cerebral blood flow (CBF) or the blood oxygenation level-dependent (BOLD) signals are used to track brain activity.

Blood vessels filled with red fluorescent marker (TRITC-dextran) and green calcium indicator in smooth muscle cells.

Astrocytic end-feet are in close contact with blood vessels and may regulate stimulation-induced increases in cerebral blood flow, but this is a matter of debate. The main point of controversy is the timing and the size of the Ca2+ changes in astrocytic end-feet. In our previous work, we used organic dyes to demonstrate fast Ca2+ increases in astrocytic end-feet that were strongly correlated to the stimulation-induced rise in cerebral blood flow.  In our current project we develop a new method for unbiased detection of rises of localized calcium activity with high specificity for astrocytes using organic fluorophores or astrocyte-specific, genetically encoded Ca2+ indicators

Another controversy is whether the major point of cerebrovascular resistance resides in arterioles or capillaries and what role pericytes play in local vascular control. Do pericytes the sense local metabolic needs?

In the past, it has been difficult to reliably identify capillary pericytes in living tissue.  This problem has now been solved by the development of transgenic mice with fluorescent markers in pericytes. We use mice with pericytes expressing the fluorescent protein dsRed under control of the NG2 promoter allowing us to readily identify pericytes by two-photon microscopy in vivo. Experimental evidence supports a variety of functions for brain pericytes including formation, maintenance and regulation of the cerebral capillaries and control of the properties of the blood brain barrier (BBB). Recently, the lab has disclosed a new role for pericytes in living animals by demonstrating active regulation of blood flow in the capillaries. This was based on segmental alterations in capillary diameter in response to neural activity that concurred with the localization of pericyte cell bodies. These findings suggest that blood flow regulation not only takes place in arterioles (as previously believed) but that capillaries may constitute a major player. In ischemia, abnormal release of constricting molecules or defective release of dilators leads to pericytes constricting capillaries. This will lead to an augmented neuronal damage and is expected to produce dysfunction of the BBB. Similar pericyte malfunction may contribute to brain frailty in ageing due to loss of capillary blood flow control, but the mechanisms are incompletely understood.

Our current project develops experimental and analytical tools to study pericyte signaling in vivo. These tools are then used to study signaling within and between pericytes and the cells in the neurovascular unit. We use two-photon microscopy combined with electrophysiology, laser speckle and optogenetics. The number of pericytes decreases with age paralleling an increase in BBB permeability, and in disease states such as cerebral ischemia. Hence we study the blood flow regulation in both young healthy adults and in disease models and aging.