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 pathophysiology 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 in the normal neocortex, we hypothesize that there will be a lower proportion 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.
|Miguel-Hidalgo, José Javier; Hall, Katherine O; Bonner, Hannah et al. (2017) MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism. Prog Neuropsychopharmacol Biol Psychiatry 79:503-514|
|Miguel-Hidalgo, Jose J; Whittom, Angela; Villarreal, Ashley et al. (2014) Apoptosis-related proteins and proliferation markers in the orbitofrontal cortex in major depressive disorder. J Affect Disord 158:62-70|
|Miguel-Hidalgo, José Javier; Wilson, Barbara A; Hussain, Syed et al. (2014) Reduced connexin 43 immunolabeling in the orbitofrontal cortex in alcohol dependence and depression. J Psychiatr Res 55:101-9|
|Whittom, Angela; Villarreal, Ashley; Soni, Madhav et al. (2014) Markers of apoptosis induction and proliferation in the orbitofrontal cortex in alcohol dependence. Alcohol Clin Exp Res 38:2790-9|
|Miguel-Hidalgo, José Javier; Waltzer, Robert; Whittom, Angela A et al. (2010) Glial and glutamatergic markers in depression, alcoholism, and their comorbidity. J Affect Disord 127:230-40|