One of the major findings in neuroscience in the past decade is that adult mammalian brain is plastic, especially after brain injury. In the so-called Neurovascular Niche in gray matter, cell-cell signaling between cerebral endothelium and neuronal precursor cells sustains pockets of ongoing neurogenesis and angiogenesis that may contribute to brain remodeling/repair. However, mechanisms for white matter plasticity are still mostly unknown. Here we hypothesize that a corresponding """"""""Oligovascular Niche"""""""" in white matter is essential for oligodendrocyte-endothelial trophic coupling, which mediates oligodendrogenesis and angiogenesis for white matter remodeling/repair.
In Aim 1, we propose to use cell cultures to show that the trophic coupling between oligodendrocytes and cerebral endothelium is altered after brain injury. We will also test the hypothesis that conditioned media from oligodendrocytes change the microglial phenotype after white matter injury (in collaboration with Project 1).
In Aim 2, we will use cell and brain slice cultures to demonstrate that VEGF and MMP-9 are key mediators for the oligodendrocyte-endothelium interaction to promote angiogenesis and oligodendrogenesis after white matter injury. We will also test the hypothesis that Rho-kinase pathway can be a promissing target for promoting white matter remodeling (in collaboration with Project 3).
In Aim 3, we will use mouse models of white matter injury (chronic cerebral hypoperfusion, focal demyelination, and focal stroke) to confirm that the trophic coupling between oligodendrocytes and endothelium contributes to white matter plasticity after injury. Imaging experiments and behavioral assessments will be supported by Core A and Core B, respectively. White matter damage is a clinically important aspect of several CNS diseases including stroke and vascular dementia. However, compared to mechanisms in gray matter, white matter pathophysiology remains relatively understudied and poorly understood. The experiments we propose should help define a novel mechanism by which oligodendrocytes and cerebral endothelial cells regulate white matter remodeling after injury. Dissecting these cell-cell pathways may lead to new therapeutic approaches for patients with disorders affecting white matter.

Public Health Relevance

; Oligodendrocytes and cerebral endothelial cells work together to maintain white matter homeostasis. Elucidating the mechanisms by which oligodendrocyte-endothelial trophic coupling mediate white matter remodeling after injury will help find novel approaches to boost endogneous brain repair signaling for CNS disease patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
2P01NS055104-06A1
Application #
8663353
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
$307,140
Indirect Cost
$128,698
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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

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