Neurovascular Coupling and Brain Homeostasis

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

We have made progress in establishing the infrastructure of the Neurovascular Research Unit. We made following progress with the research aims: (1) For structural characterization of the brain vasculature, we are utilizing publicly available large volume electron microscopy databases with mouse and human brains. In our work, we have characterized endothelial and mural cell density and noted cellular and sub-cellular differences across the brain vasculature. We also identified cell polarity by identifying location of the centrioles (in the endothelial cells) and compared it with the direction blood flow in the brain. Our identification and characterization of primary cilia in the endothelial and mural cells showed gradient distribution in the cilia presence across the vasculature. This structural characterization will allow us to compare to functional differences in the NVC mechanisms within the brain vasculature. (2) Our in-vivo characterization of endothelial Ca2+ signals between arteriolar, venule and capillaries using genetic encoded Ca2+ indicator mice showed that arteriolar and venule endothelial Ca2+ activities are different from capillaries. Capillary endothelial cells Ca2+ signals have a wide range of duration (from few seconds to minutes), while arterial and venular endothelial Ca2+ signals are short-periodic events. We are developing analysis approaches to perform a thorough spatiotemporal characterization of the arteriolar and venule Ca2+ signals and to correlate Ca2+ signals with the diameter changes of these vessels. We are also performing experiments to dissect signaling mechanisms contributing to the generation of Ca2+ signals in arteriolar and venous endothelial cells and control of blood flow in the brain. (3) This aim is intertwined with Aim 2. Beyond understanding the role of vascular Ca2+ signals in regulation of the blood flow, we are aiming to identify role of vascular Ca2+ signals in regulation of blood brain barrier permeability and clearance of metabolic by-products. In this work, we are focusing on the venous vasculature that has higher vascular permeability compared to arteriolar and capillary ends. We are performing electrophysiology recordings to identify ion channel distribution in venous vascular cells and also performing isolated vessel experiments to understand the flow & pressure relationship with the vessel permeability changes and affects metabolic clearance. (4) In this aim, our goal is to expand our knowledge about NVC from physiology to pathophysiology of VCID. Currently, we are focusing to evaluate early neurovascular deficits in the mouse model of Alzheimer’s disease (AD). There is a growing recognition about the vascular dysfunction in the pathophysiology of AD. These observations propose structural and functional loss in microvasculature can be involved in initial progression of AD. However, early neurovascular deficits in AD are still lacking a thorough understanding. We are studying early cerebrovascular dysfunction in AD by using 5xFAD mouse model (age: 3-months); a familial model of AD. We are combining in-vivo imaging approaches ranging from arterial spin labelling (ASL) MRI, functional ultrasound (fUS), multi-photon and wide-field microscopy with ion channel recordings and behavioral testing. Our on-going measurements show a deficit in endothelial Ca2+ activity and reduction in functional hyperemia. We also aim to evaluate NVC deficits acute models of Subarachnoid hemorrhage (SAH) and genetic models of small vessel diseases of the brain by using both in-vivo and ex-vivo measurements.