36 research outputs found
Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain
Pericytes are perivascular mural cells of brain capillaries. They are positioned centrally in the neurovascular unit between endothelial cells, astrocytes and neurons. This position allows them to regulate key neurovascular functions of the brain. The role of pericytes in the regulation of cerebral blood flow (CBF) and neurovascular coupling remains, however, under debate. Using loss-of-function pericyte-deficient mice, here we show that pericyte degeneration diminishes global and individual capillary CBF responses to neuronal stimuli, resulting in neurovascular uncoupling, reduced oxygen supply to the brain and metabolic stress. Neurovascular deficits lead over time to impaired neuronal excitability and neurodegenerative changes. Thus, pericyte degeneration as seen in neurological disorders such as Alzheimer's disease may contribute to neurovascular dysfunction and neurodegeneration associated with human disease.R01 AG023084 - NIA NIH HHS; P50 AG005142 - NIA NIH HHS; R01 AG039452 - NIA NIH HHS; R24 NS092986 - NINDS NIH HHS; R01 EB000790 - NIBIB NIH HHS; R01 NS034467 - NINDS NIH HHS; R01 NS091230 - NINDS NIH HHS; R01 NS100459 - NINDS NIH HHS; P01 NS055104 - NINDS NIH HHS; P01 AG052350 - NIA NIH HHS; R01 MH111359 - NIMH NIH HHSAccepted manuscrip
Stochastic explanation of speckle contrast detection in ultrasound-modulated optical tomography
Modulation of multiply scattered coherent light by ultrasonic pulses: An analytical model
Direct measurement of local oxygen concentration in the bone marrow of live animals
Characterizing how the microenvironment, or niche, regulates stem cell activity is central to understanding stem cell biology and to developing strategies for therapeutic manipulation of stem cells1. Low oxygen tension (hypoxia) is commonly thought to be a shared niche characteristic in maintaining quiescence in multiple stem cell types2–4. However, support for the existence of a hypoxic niche has largely come from indirect evidence such as proteomic analysis5, expression of HIF-1 and related genes6, and staining with surrogate hypoxic markers (e.g. pimonidazole)6–8. Here we perform direct in vivo measurements of local oxygen tension (pO2) in the bone marrow (BM) of live mice. Using two-photon phosphorescence lifetime microscopy (2PLM), we determined the absolute pO2 of the BM to be quite low (<32 mmHg) despite very high vascular density. We further uncovered heterogeneities in local pO2, with the lowest pO2 (~9.9 mmHg, or 1.3%) found in deeper peri-sinusoidal regions. The endosteal region, by contrast, is less hypoxic as it is perfused with small arteries that are often positive for the marker nestin. These pO2 values change dramatically after radiation and chemotherapy, pointing to the role of stress in altering the stem cell metabolic microenvironment
A mathematical model of the metabolic and perfusion effects on cortical spreading depression
Cortical spreading depression (CSD) is a slow-moving ionic and metabolic
disturbance that propagates in cortical brain tissue. In addition to massive
cellular depolarization, CSD also involves significant changes in perfusion and
metabolism -- aspects of CSD that had not been modeled and are important to
traumatic brain injury, subarachnoid hemorrhage, stroke, and migraine.
In this study, we develop a mathematical model for CSD where we focus on
modeling the features essential to understanding the implications of
neurovascular coupling during CSD. In our model, the sodium-potassium--ATPase,
mainly responsible for ionic homeostasis and active during CSD, operates at a
rate that is dependent on the supply of oxygen. The supply of oxygen is
determined by modeling blood flow through a lumped vascular tree with an
effective local vessel radius that is controlled by the extracellular potassium
concentration. We show that during CSD, the metabolic demands of the cortex
exceed the physiological limits placed on oxygen delivery, regardless of
vascular constriction or dilation. However, vasoconstriction and vasodilation
play important roles in the propagation of CSD and its recovery. Our model
replicates the qualitative and quantitative behavior of CSD --
vasoconstriction, oxygen depletion, extracellular potassium elevation,
prolonged depolarization -- found in experimental studies.
We predict faster, longer duration CSD in vivo than in vitro due to the
contribution of the vasculature. Our results also help explain some of the
variability of CSD between species and even within the same animal. These
results have clinical and translational implications, as they allow for more
precise in vitro, in vivo, and in silico exploration of a phenomenon broadly
relevant to neurological disease.Comment: 17 pages including 9 figures, accepted by PLoS On