Glial Proliferation and Death in Depression and Alcoholism

抑郁症和酗酒时的胶质细胞增殖和死亡

• 批准号: 7661092
• 负责人: JOSE JAVIER MIGUEL-HIDALGO
• 金额: $ 22.2万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661092
• 关键词: Accounting; Action Potentials; Address; Affect; Alcohol dependence; Alcoholism; Animals; Area; Astrocytes; Autopsy; Brain; Brain region; CSPG4 gene; Cell Death; Cell Proliferation; Cells; Cerebral cortex; Cessation of life; Chronic; Diagnostic; Disease; Equilibrium; Functional disorder; Future; Glial Cell Proliferation; Human; Label; Life; Major Depressive Disorder; Metabolism; Microglia; Mood Disorders; Neocortex; Neuroglia; Neuronal Dysfunction; Neurons; Oligodendroglia; Pathology; Plant Roots; Prefrontal Cortex; Proliferating; Proliferation Marker; Regulation; Testing; Time; Translating; area striata; base; brain metabolism; cell type; density; depression; depressive symptoms; design; gliogenesis; human subject; illness length; internal control; middle age; neurotransmission; non-alcoholic; oligodendrocyte lineage; oligodendrocyte precursor; problem drinker; public health relevance

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.

描述（由申请人提供）：重度抑郁症和酒精中毒的特征是前额叶皮层（PFC）的神经元和神经胶质细胞密度低于正常水平，这是与成瘾和情感障碍密切相关的大脑区域。在建立MDD和酒精中毒的病理生理学时，神经胶质细胞的丧失可能与神经病理学一样相关，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。在我们的死后研究中，我们发现患有抑郁症或酗酒的中青年受试者的神经胶质密度明显较低，并在生命后期增加，这表明神经胶质细胞死亡和增殖平衡的改变可能是PFC神经胶质密度较低的根源，并且这种平衡随着疾病的持续时间而变化。此外，低密度的胶质细胞可能有助于减少酗酒者和抑郁症患者PFC中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的神经胶质细胞减少总体上相似，但这两个诊断组在神经胶质细胞减少的程度和神经胶质与神经元变化的关联方面存在差异。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，是理解这两种疾病的胶质生理病理的异同和设计未来基于胶质细胞的治疗的必要步骤。然而，到目前为止，还没有在人脑中直接研究这两种疾病中胶质细胞增殖/死亡平衡的改变，这两种疾病通常是共病。在胶质细胞中，星形胶质细胞、少突胶质细胞和最近发现的一种与少突胶质细胞谱系相关的亚型（NG2胶质细胞），已知可直接调节神经传递和脑代谢，并可能参与迄今为止在酒精中毒和重度抑郁症中检测到的整体胶质细胞变化。在本项目中，我们建议研究增殖和细胞死亡标志物，并确定慢性酗酒者、抑郁症患者（伴或不伴酒精中毒）和匹配对照中星形胶质细胞、少突胶质细胞、小胶质细胞、NG2胶质细胞和含有增殖/死亡标志物的神经元的密度。与神经元不同，神经胶质细胞能够在正常的新皮层中持续增殖，因此我们假设酗酒者和抑郁症患者死后前额皮质中星形胶质细胞、少突胶质细胞、小胶质细胞和NG2细胞的增殖比例低于对照组，并且这一比例在合并酒精中毒的抑郁症患者中最低。我们还预计，随着酒精依赖或抑郁持续时间的增加，星形胶质细胞增殖的比例也会增加。我们还预计，在任何时候，酗酒者中具有细胞死亡标志的神经胶质细胞的数量都高于抑郁症患者或对照组，并且在合并酒精中毒的抑郁症患者中，这一数字将最高。公共卫生相关性：通过研究神经胶质细胞增殖和死亡的标志物，本项目将提供在抑郁症患者和酗酒者的前额叶大脑皮层中观察到的神经胶质细胞数量较少的直接原因的信息。确定神经胶质细胞增殖和死亡的平衡是很重要的，因为治疗抑郁症和酗酒必须考虑到它们是否会影响这种平衡。相反，能够将神经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酗酒的候选者。