Imaging the effects of microvascular network morphology on neurovascular coupling

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The hundred billion neurons that make up the brain are organized in a highly complex and interconnected network. As brain has very limited capacity for energy storage, the high energetic need of these neurons is supported by an intricate, hierarchical network of brain vessels that carry a very high resting blood flow. Notwithstanding, upon an increase in local neuronal activity, the blood flow of the surrounding vessels invariably rises above the resting levels: this coordination is achieved through a great diversity of electrochemical interactions between neuronal and vascular networks. Although central to healthy brain functioning, this phenomenon - termed neurovascular coupling - is still incompletely understood. Hitherto investigations of neurovascular coupling have been impeded by the methodological difficulty of stimulating specific neurons and recording their activity levels and the ensuing effects on neighboring vessels. Recent methodological developments, however, have greatly improved optical means of stimulating individual neurons, recording their activity and measuring the blood flow changes in individual brain vessels. The goal of this proposal is to combine these state-of-the-art optical methods with electrophysiological techniques so as to examine how the heterogeneity in the resting blood flow levels across brain vessels in the network affects the neurovascular coupling. Using our established imaging and computational analysis techniques, we will concomitantly capture, in mathematical terms, the architecture of local neuronal and vascular networks. We will employ two photon fluorescence microscopy, which affords cellular scale resolution, in live, anesthetized mice prepared with cranial windows to permit high resolution imaging of the underlying brain tisuse. To allow non-invasive stimulation of individual neurons, we will make use of transgenic mice whose neurons express light activatable ion channels in their membranes. Linear array electrodes will be employed to record local neuronal activity. The distribution of resting flow across the microvascular network will be modulated experimentally so as to either irreversibly or reversibly change the variability of resting blood flow across cortical vessels. In each instance, we will examine the effect of the modulation on the neurovascular coupling. We will thus identify the optimal resting state dispersion in the vascular flow rates with respect to ensuring effective vascular support of the neurons. Combined, these studies will give us a mechanistic understanding of the link between neurons and brain microvessels, thus providing the foundation for processes that underlie "brain plasticity" and that are often progressively compromised in aging. The insight on resting vascular state dependence of neurovascular coupling obtained in these studies will also enable quantitative interpretation of functional MRI, the most widely used neuroimaging method for studying human brain function.