Glial Proliferation and Death in Depression and Alcoholism

描述(申请人提供)：重度抑郁症和酒精中毒的特征是前额叶皮质(PFC)中神经元和神经胶质细胞的密度低于正常水平，这是一个与成瘾和情感障碍密切相关的脑区。在建立MDD和酒精中毒的病理生理学过程中，胶质细胞的丢失可能与神经元病理学一样相关，因为神经胶质细胞在神经传递、动作电位传导和神经元代谢的调节中是必不可少的。在我们的尸检研究中，我们发现患有抑郁症或酒精中毒的年轻人和中年人的胶质细胞密度显著降低，并在晚年有所增加，这表明胶质细胞死亡和增殖的平衡改变可能是PFC神经胶质密度降低的根源，而且这种平衡随着疾病持续时间的不同而不同。此外，低密度的神经胶质细胞可能有助于减少酗酒者和抑郁症患者前额叶皮质持续的神经元功能障碍。同样重要的是，尽管酗酒者和抑郁症患者在胶质细胞减少方面总体上相似，但这两个诊断组在神经胶质细胞减少的程度和胶质细胞与神经元变化的联系方面存在差异。因此，确定胶质细胞增殖和死亡平衡的改变是否(以及在多大程度上)解释了胶质细胞缺陷，是了解这两种疾病的神经胶质生理病理的异同并设计未来基于胶质细胞的治疗方法的必要步骤。然而，到目前为止，还没有在人脑中直接解决这两种疾病中神经胶质细胞增殖/死亡平衡改变的研究，这两种疾病往往是并存的。在胶质细胞中，星形胶质细胞、少突胶质细胞和最近发现的与少突胶质细胞谱系有关的一个亚型(NG2胶质细胞)被认为直接调节神经传递和脑代谢，并可能参与迄今在酒精中毒和MDD中检测到的整体神经胶质细胞的变化。在本项目中，我们建议研究增殖和细胞死亡的标记物，并测定星形胶质细胞、少突胶质细胞、小胶质细胞、NG2胶质细胞和含有增殖/死亡标记物的神经元在慢性酒精中毒、抑郁症(合并和不合并酒精中毒)和匹配对照组中的密度。由于与神经元不同，神经胶质细胞能够在正常的新皮质中持续增殖，我们推测酗酒和抑郁症患者死前额叶皮质中增殖的星形胶质细胞、少突胶质细胞、小胶质细胞和NG2细胞的比例将低于对照组，并且这一比例在合并酒精中毒的抑郁症患者中将是最低的。我们还预计，随着酒精依赖或抑郁持续时间的延长，增殖的星形胶质细胞的比例将会增加。我们还预计，在任何时候，酗酒者中带有细胞死亡标志的胶质细胞的数量都会高于抑郁者或对照组，并且在伴有酒精中毒的抑郁者中，这个数字将是最高的。公共卫生相关性：通过研究胶质细胞增殖和死亡的标记物，本项目将提供抑郁症和酗酒者大脑前额叶皮质中观察到的胶质细胞数量减少的直接原因的信息。确定胶质细胞增殖和死亡的平衡很重要，因为抑郁症和酒精中毒的治疗必须考虑到它们是否影响了这种平衡。相反，能够将胶质细胞增殖和死亡的平衡恢复到正常水平的化合物可能是未来治疗抑郁症和酒精中毒的候选药物。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.