UNIVERISTY OF MISSISSIPPI MEDICAL CENTER
Grant: $222,000 - National Institutes of Health - Apr. 28, 2009
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Award Description: Major depression and alcoholism feature lower-than-normal densities of neurons and glial cells in the prefrontal cortex (PFC) brain region heavily involved in addictive and affective disorders. In establishing the pathophysilology of MDD and alcoholism, loss of glial cells might be as relevant as neuronal pathology, because glial cells are essential in the regulation of neurotransmission, conduction of action potentials, and neuronal metabolism. In our postmortem studies we have found that glial density is significantly low in young and middle-aged subjects with depression or alcoholism and increases later in life, suggesting that an altered balance of glial cell death and proliferation may be at the root of lower glial densities in the PFC, and that this balance differs along the duration of the disorders. Furthermore, low density of glial cells may contribute to reduce ongoing neuronal dysfunction in the PFC of alcoholics and depressives. It is also important that, despite an overall similarity in the reduction of glial cells between alcoholics and depressives, there are differences between these two diagnostic groups in the extent of glial reductions and the association of glial to neuronal changes. Thus, determining whether (and to what extent) an altered balance of glial proliferation and death explains glial deficits is a necessary step to understand similarities and differences in the glial physiopathology of these two disorders and to design future glia-based therapies. However, so far there are no available studies in the human brain directly addressing an altered proliferation/death balance for glia in the two disorders, which are often comorbid. Among glial cells, astrocytes, oligodendrocytes, and a more recently discovered subtype related to the oligodendrocyte lineage (NG2 glia), are known to directly regulate neurotransmission and brain metabolism and might be involved in the overall glial changes detected so far in alcoholism and MDD. In the present project, we propose to investigate markers of proliferation and cell death, and determine the density of astrocytes, oligodendrocytes, microglia, NG2 glial cells and neurons containing proliferation/death markers in chronic alcoholics, depressives (with and without comorbid alcoholism) and matched controls. Since, unlike neurons, glial cells are continuously capable of proliferating astrocytes, oligodendrocytes, microglia and NG2 cells in the postmortem prefrontal cortex from alcoholics and depressives than in controls, and that this proportion will be the lowest in depressives with comorbid alcoholism. We will also expect that with increased duration of alcohol dependence or depression there will be an increase in the proportion of proliferating astrocytes. We also expect that at all times there will be a higher number of glial cells with markers of cell death in alcoholics than in depressives or controls, and that the numbers will be highest in depressives with comorbid alcoholism. By studying markers of glial cell proliferation and death, the present project will provide information on immediate causes for lower numbers of glial cells observed in the prefrontal cerebral cortex of depressives and alcoholics. Determining the balance of glial cell proliferation and death is important because therapies for depression and alcoholism must take into account if they affect that balance. Conversely, compounds that can restore the balance of glial cell proliferation and death to normal levels may be candidates for future treatments for depression and alcoholism.
Project Description: During the first three months of the present project the PI searched and hired first a research technician at the end of May 2009. This technician first set to collect histological sections from the postmortem brain of at least ten subjects per group (4 groups included in the present project). At the moment of this report the technician has already collected sections from at least a total of forty subjects (at least 70 sections per subject). Collection of sections has also involved documenting with digital photographs each of the brain tissue blocks processed. From the same blocks we have also collected tissue punches to be processed for quantification of the levels of specific proteins. More recently after a more time-demanding search, the PI has hired a postdoctoral fellow who will be in charge of studies of protein levels, the prefrontal cortex, and other molecular determinations. The postdoc has already started to prepare the tissue punches for determination of total protein levels and for the future running of Western blots in which to determine the levels of proteins. The postdoc has also performed preliminary experiments to detect caspase 3 and phosphorylated and ki-67 in sections of the brains recently cut by the research technician. Some of the preliminary experiments have already provided partial data markers of cell death in specific cell types and now the technician is starting systematic immunohistochemistry of histological sections to determine the first data of proliferation and cell death markers in oligodendrocytes. Other activities that have involved the PI have been preliminary results of cell counting in serveral subjects per group of caspase 3 immunoreactive cells in the orbitofrontal cortex and separately for oligodendrocytes in adjacent sections.
Jobs Summary: Two positions created: A Research Technician (Researcher II) was hired May 2009 and a Postdoctoral Fellow (Postdoctoral Researcher I) will be hired with the funds provided by this grant. (Total jobs reported: 1)
Project Status: Less Than 50% Completed
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