UNDERGRADUATE SUMMER RESEARCH PROGRAM
2010 NSSP Information
Grazyna Rajkowska, Ph.D.
 |
CPN Project Principal Investigator Director, Imaging Core Basic Science Mentor to Beata Karolewicz, Ph.D. Professor of Psychiatry and Human Behavior University of Mississippi Medical Center Jackson, Mississippi 39216 Contact Dr. Rajkowska Publications Key Research Personnel: Javier Miguel-Hidalgo, Ph.D., Co-Investigator Samuel Newton Sathyanesan, Ph.D., Co-Investigator John E. Hall, Ph.D., Clinical Consultant David C. Steffens, M.D., M.H.S., Clinical Consultant Laboratory Personnel: Dorota Maciag, Ph.D., Instructor Yilianys Rodriguez, Researcher III Joan Dickerson, Researcher II |
PROJECT 1
VASCULAR AND CELLULAR PATHOLOGY
IN DEPRESSION
Growing evidence indicates a bi-directional link between major depressive disorder and cardiovascular disease. Depression might precipitate a malfunction of the cardiovascular system, and cardiovascular disorders may precede depressive episodes. Clinical studies report impairment of endothelial functions and increased inflammatory markers (risk factor for cardiovascular disease) in depressed patients. In vivo neuroimaging studies demonstrate gross morphological pathology of blood vessels in the prefrontal cortex (PFC) in depression. However, no studies of vascular morphology and related growth factors at the microscopic and molecular level have been conducted in depression to date.
Our preliminary data on microscopic analysis of vessel number and morphology in postmortem brain tissue reveal significant increases in the density of abnormal vessels in the prefrontal cortex (PFC) in depression. These vascular changes were observed in the same subjects that were used in our previous cell counting studies on reductions in the density of neurons and glial cells. Moreover, our recent gene expression studies in these depressed subjects reveal downregulation of genes for fibroblast growth factor (FGF) and brain-derived neurotrophic factor (BDNF), and rodent studies indicate that these factors are reduced in stressed animals and elevated after treatment with electroconvulsive shock or antidepressants.
Thus, we hypothesize that in depression there are alterations in vascular morphology that are associated with deficits in angiogenic and neurotrophic factors as well as pathology of neurons and glial cells in the PFC. We further hypothesize that these changes are due to the depressive disorder itself and not due to treatment with antidepressant medication, therefore they will not be observed in the PFC of monkeys treated with antidepressants. The above hypothesis will be tested on sections from human postmortem PFC by: Aim 1: quantification of the density and size of cortical vessels and endothelial cells using immunohistochemistry and 3-D cell counting; Aim 2: analysis of the distribution and intensity of staining of angiogenic and neurotrophic factors and studies of the co-localization of these factors with vessels and astrocytes by using double immunohistochemistry and 3-D counting; Aim 3: studies of the expression of genes and proteins for angiogenic and neurotrophic factors using DNA microarrays, PCR, in situ hybridization and Western blotting; and Aim 4: conducting similar morphometric analyses in the PFC tissue from monkeys chronically treated with fluoxetine vs. vehicle . This proposal will be the first quantitative microscopic study of cortical vasculature in major depression. It will likely reveal a link between dysfunctional genes and the expression of angiogenic and neurotrophic factors and the pathology of blood vessels, neurons and glial cells in the prefrontal cortex of depressed individuals. This may reveal novel cellular and molecular targets of antidepressant action and possibly lead to the design of more effective medications for depressed patients with vascular disease.