Neurons, glia and blood vessels form a highly integrated functional unit collectively termed """"""""the neurovascular unit"""""""" that couples blood flow and metabolism and coordinates cross-talk between cell and tissue elements during health and disease. We provide preliminary evidence for a novel form of neurovascular coupling in which (1) intense neuroglial depolarization is accompanied by abrupt vasoconstriction during focal cerebral ischemia, and (2) by which anoxic depolarization (AD) and peri-infarct spreading depolarizations (PIDs) cause step-wise reductions in blood flow, and by so doing, expand the hypoperfused territory at risk. To obtain preliminary data, we performed two-dimensional cerebral blood flow (CBF), volume and oxygenation mapping with high temporal and spatial resolution (real-time laser speckle flowmetry, simultaneously with multiwavelength reflectance imaging of oxyhemoglobin, deoxyhemoglobin, and total hemoglobin). Here we build on these findings and expand on this novel mechanism to explore the vascular consequences of neuroglial depolarization during ischemia. Our overall hypothesis is that AD and PIDs cause abrupt decreases in cortical perfusion, and by so doing, adversely affect the neurovascular unit within depolarized ischemic tissue, a novel concept of infarct evolution. We postulate that by attenuating AD and PIDs, the occurrence of these punctuated vasoconstrictor events can be inhibited, and the expanding CBF deficit prevented. We propose three specific aims:
Aim 1 will test the novel hypothesis that punctuated depolarizing events early after ischemia (i.e., AD and PIDs) cause acute severe vasoconstriction, and by so doing, further compromise CBF.
Aim 2 will test the hypothesis that treatments known to preserve membrane ionic gradients (e.g., inhibit K+ efflux), such as inhibitors of cortical spreading depression (CSD) (e.g., topiramate, gap junction blockers, sigma-1 agonists), attenuate vasoconstriction, and halt the worsening of CBF during acute stroke as a fundamental mechanism of tissue protection.
Aim 3 will test the hypothesis that impaired vasodilator mechanisms exacerbate the abrupt vasoconstriction during ischemic neuroglial depolarization via molecular changes in vasomotor regulatory proteins such as endothelial nitric oxide synthase. By so doing, we hope to better understand vascular and hemodynamic mechanisms underlying infarct expansion during acute stroke and to develop more rational approaches to protect ischemic tissue.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Kura, Sreekanth; Xie, Hongyu; Fu, Buyin et al. (2018) Intrinsic optical signal imaging of the blood volume changes is sufficient for mapping the resting state functional connectivity in the rodent cortex. J Neural Eng 15:035003
Sadeghian, Homa; Lacoste, Baptiste; Qin, Tao et al. (2018) Spreading depolarizations trigger caveolin-1-dependent endothelial transcytosis. Ann Neurol 84:409-423
Chung, David Y; Sadeghian, Homa; Qin, Tao et al. (2018) Determinants of Optogenetic Cortical Spreading Depolarizations. Cereb Cortex :
Takase, Hajime; Liang, Anna C; Miyamoto, Nobukazu et al. (2018) Protective effects of a radical scavenger edaravone on oligodendrocyte precursor cells against oxidative stress. Neurosci Lett 668:120-125
Maki, Takakuni; Choi, Yoon Kyung; Miyamoto, Nobukazu et al. (2018) A-Kinase Anchor Protein 12 Is Required for Oligodendrocyte Differentiation in Adult White Matter. Stem Cells 36:751-760
Tang, Jianbo; Erdener, Sefik Evren; Li, Baoqiang et al. (2018) Shear-induced diffusion of red blood cells measured with dynamic light scattering-optical coherence tomography. J Biophotonics 11:
Chung, David Y; Sugimoto, Kazutaka; Fischer, Paul et al. (2018) Real-time non-invasive in vivo visible light detection of cortical spreading depolarizations in mice. J Neurosci Methods 309:143-146
Gómez, Carlos A; Sutin, Jason; Wu, Weicheng et al. (2018) Phasor analysis of NADH FLIM identifies pharmacological disruptions to mitochondrial metabolic processes in the rodent cerebral cortex. PLoS One 13:e0194578
Maki, Takakuni; Morancho, Anna; Martinez-San Segundo, Pablo et al. (2018) Endothelial Progenitor Cell Secretome and Oligovascular Repair in a Mouse Model of Prolonged Cerebral Hypoperfusion. Stroke 49:1003-1010
Wang, Hui; Magnain, Caroline; Wang, Ruopeng et al. (2018) as-PSOCT: Volumetric microscopic imaging of human brain architecture and connectivity. Neuroimage 165:56-68

Showing the most recent 10 out of 240 publications