Development of Molecular Mechanisms Underlying Neuron-astrocyte Control of Cerebral Blood Flow
Principal Investigators: KAI KAILA1, BRIAN MACVICAR2, CLAUDIO RIVERA1,3, JUHA VOIPIO1
1University of Helsinki, Dept. Biological and Environmental Sciences, Finland, 2University of British Columbia, Brain Research Centre, Vancouver, Canada, 3University of Helsinki, Institute of Biotechnology, Finland
One of the major evolutionary constraints that have shaped the evolution of the mammalian brain is the optimization of energy metabolism. Brain development is associated with dramatic, qualitative and quantitative, changes in various aspects of energy metabolism. The adult human brain accounts for about 2-3% of the body weight, but it is responsible for 20% of the total energy consumption at rest, and in infants, this figure can be as high as 60%. Increased cerebral blood flow (CBF) as well as changes in O2 binding to hemoglobin underlie functional MRI (BOLD) and intrinsic optical signals which are widely used to monitor brain activity. In spite of the long history of research in this area and the utility of measuring CBF, the precise mechanisms by which local blood flow increases with neuronal activation are still unclear. Strikingly, next to nothing is known about the developmental profiles of the mechanisms involved in activity-dependent control of CBF in the immature nervous system.
We will test the novel hypotheses that (i) CO2 is an unrecognized signal for rapid vasodilation of arterioles during neuronal activity; and that (ii) astrocytes produce vasodilation by fast generation of CO2 through the action of carbonic anhydrase (CA). We will also (iii) examine the actions of calcium transients induced by two photon uncaging of calcium in astrocytes at different developmental ages postnatally (from a few days to a few weeks) on inducing arteriole vasoconstrictions. Here, we propose that the calcium induced vasoconstriction will only appear 1 week after birth with the establishment of significant calcium waves in astrocytes.
The experiments will be carried out on rodent acute hippocampal slices in conjunction with two-photon laser scanning microscopy, two photon photolysis of caged calcium and glutamate, and a wide range of electrophysiological techniques including real-time CO2 measurements by a liquid-membrane microelectrode developed for this purpose. Parallel studies will be conducted on key molecules with developmental expression patterns critical for the main aims of this work. These include the CA isoform CAVII and the K-Cl cotransporter KCC2 expressed in neurons; the Na-HCO3 cotransporter NBC1, CAII and AQP4 expressed in glia; as well as the interstitial CA which we have identified (unpublished) as isoform CAXIV in the hippocampus.
This work will provide novel insights into fundamental mechanisms related to the cross-talk among neuronal activity, CBF and other factors that control activity-dependent brain energy consumption and resource allocation. This is an area, which is practically unexplored, despite its obvious, high impact for both basic and applied neuroscience. In addition, the results will have direct clinical implications for neonatology, where brain hypoxia as well as hyper- and hypocapnia are problems of central importance.
Contact: kai.kaila(at)helsinki.fi, tel. +358 9 1915 9860