Neurovascular Coupling in the Retina: Modulation by Diabetic Retinopathy and Oxygen
Assistant Professor, Department of Medicine, Oregon Health Sciences University.
Post-doctoral Researcher, University College, London
Undergraduate Institution and Major/Degree:
Minnesota State University, Moorhead, BA, Biology and Chemistry, 2004
One of the fundamental aspects of healthy brain function is the spatial and temporal control of blood flow to meet increased energy demands in regions of neuronal activity. The fundamental cellular mechanisms underlying this response, termed functional hyperemia, are not well understood. Recent evidence suggests that glial cells are the primary mediators of neurovascular coupling in the brain. A previous student in Dr. Newman's lab, Monica Metea, demonstrated in the rat retina that light and glial stimulation evoke both vasodilations and vasoconstrictions. The generation of bi-directional vasomotor activity raises the question of how such responses are controlled. Monica demonstrated that nitric oxide is an important modulator of this response. Low levels of nitric oxide in the retina result in a primarily vasodilatory response while high levels result in increased vasoconstriction. I am now investigating whether oxygen, another important small molecule with an important function in many biochemical pathways, can also modulate neurovascular coupling. In whole mount retinas exposed to 20% oxygen, light stimulation results in vasodilation mediated by the combined action of EETs and prostaglandins. Retinas exposed to 100% oxygen, in contrast, show both light-evoked vasodilation and vasoconstriction. In high oxygen, vasodilations are mediated entirely by EETs, while vasoconstrictions are mediated by 20-HETE. The increase in 20-HETE synthesis and absence of prostaglandin-mediated vasodilation in oxygen appear to be responsible for the differences in light-evoked vasomotor responses in the two different concentrations of oxygen.
Another project that I am working on is related to the disruption of functional hyperemia in diabetic retinopathy. It has been shown that light stimulated vascular responses are diminished in diabetic patients. I have found the same to be true in a Streptozotocin model of diabetes in rats. Based on preliminary experiments, it appears that inhibiting production of NO by the inducible form of nitric oxide synthase (iNOS) may be enough to restore normal neurovascular responses to diabetic retinas.
- Eric A. Newman
- Paulo Kofuji (chair)
- Esam E. El-Fakahany
- Cheryl Olman
- Paul Mermelstein
- Karen Ashe
- Eric Newman
- Karen Mesce
Courses Taken Beyond the Core Courses:
- PUBH 6450 Biostatistics I
- PUBH 6451 - Biostatistics II
- PHYS 5201 Computational Neuroscience I
- CMB 8361 Neuro-Immune Interactions
Graduate Level Minor:
- Statistical and Computational Analysis
Conferences Attended and Presentations:
- Society for Neuroscience - November, 2010
- FENS forum of European Neuroscience - July, 2010
- European Glial Meeting on Glial Cells in Health and Diseases - September, 2009
- International Symposium on Cerebral Blood Flow, Metabolism and Function - July, 2009
- Gordon Research Conference: Glial Biology - March, 2009
- Glia in Health and Disease - July, 2008
- Cerebral Blood flow and Metabolism - April, 2008
- US Japan Meeting for Glial Research - March, 2008
- Society for Neuroscience - Fall 2005, 2006, 2007
- Americal Society for Biochemistry and Molecular Biology - June, 2004
- Minnesota Academy of Sciences - 2003, 2004
- Midwest Regional Developmental Biology Meeting and Singer Symposium - 2004
- Mishra A, Newman EA. Aminoguanidine reverses the loss of flicker-induced vasodilation in a rat model of diabetic retinopathy. Front Neuroenergetics. 2012 Jan 10;3:10.
- Srienc AI, Kornfield TE, Mishra A, Burian MA, Newman EA. Assessment of glial function in the in vivo retina. Methods Mol. Biol. 2012;814:499-514.
- Mishra A, Hamid A, Newman EA. Oxygen modulation of neurovascular coupling in the rat retina. Proc Natl Acad Sci USA 2011;108:17827-17831.
- Mishra A, Newman EA. Inhibition of inducible nitric oxide synthase reverses the loss of functional hyperemia in diabetic retinopathy. Glia. 2010;58:1996-2004.
- Kurth-Nelson ZL, Mishra A, Newman EA. Spontaneous glial calcium waves in the retina develop over early adulthood. J Neurosci. 2009;29:11339-46.
- Mishra A, Newman EA. Nitric Oxide and Oxygen Modulate Glial-Mediated Neurovascular Coupling. Gordon Research Conference: Glial Biology: 2009, Ventura, CA
- Mishra A, Hu M, Newman, EA. Nitric Oxide and Oxygen Modulate Glial-Mediated Neurovascular Coupling. Glia in Health and Disease: 2008, Cold Spring Harbor, NY
- Mishra A, Hu M, Newman, EA. Nitric Oxide and Oxygen Modulate Neurovascular Coupling. US-Japan Joint Meeting for Glial Research: 2008, Philadelphia, PA
- Mishra A, Hamann B, Brisch E, Wisenden BD. Development and behavioral ontogeny of antipredator behavior in cichlid larvae. Northern Plains Biological Symposium: 2003, Fargo, ND
- Mishra A, Hamann B, Brisch E, Wisenden BD. Development and behavioral ontogeny of antipredator behavior in cichlid larvae. Minnesota Academy of Sciences: 2003, Saint Paul, MN
- Mishra A, Hu M, Newman EA. Oxygen and Nitric Oxide Modulate Glial-Mediated Neurovascular Coupling. Gordon Resaerch Conference on Glial Biology: Functional Interactions Among Glia & Neurons, 2009.
- Mishra A, Hu M, Newman EA. Oxygen modulates neurovascular coupling in the rat retina. Society for Neuroscience Annual Meeting, 2007.
- Mishra A, Sorra KE, Kirov SA, Harris, KM. Dense core vesicles as a substrate for synaptogenesis in the hippocampus. Society for Neuroscience Annual Meeting, 2005.
- Teaching Assistant, Introduction to Neuroscience II: Biological Basis of Behavior, University of Minnesota , MN - Spring, 2007 & 2010
Awards and Honors:
- MinnCResT Fellowship (2009-2010)
- 3M fellowship (2005-2009)
- Stark Award (2008)
- Society for Neuroscience Chapter Travel Award (2010)
- Society for Neuroscience
- Kathmandu, Nepal