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: 7816834
• 负责人: JOSE JAVIER MIGUEL-HIDALGO
• 金额: $ 18.5万
• 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 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7816834
• 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; Mental Depression; 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; 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）：重度抑郁症和酗酒的特点是前额皮质（PFC）中神经元和神经胶质细胞的密度低于正常水平，该大脑区域与成瘾和情感障碍密切相关。在建立 MDD 和酗酒的病理生理学过程中，神经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至关重要。在我们的尸检研究中，我们发现患有抑郁症或酗酒的年轻和中年受试者的神经胶质密度明显较低，并且在以后的生活中增加，这表明神经胶质细胞死亡和增殖的平衡改变可能是神经胶质密度较低的根源在 PFC 中，这种平衡随着疾病的持续时间而变化。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皮质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相似，但这两个诊断组之间在神经胶质细胞减少的程度以及神经胶质细胞与神经元变化的关联方面存在差异。因此，确定神经胶质细胞增殖和死亡的平衡改变是否（以及在何种程度上）解释了神经胶质细胞缺陷，是了解这两种疾病的神经胶质细胞病理生理学相似性和差异以及设计未来基于神经胶质细胞的疗法的必要步骤。然而，到目前为止，还没有针对人脑的研究直接解决这两种疾病中神经胶质细胞增殖/死亡平衡的改变，这两种疾病通常是共存的。在神经胶质细胞中，星形胶质细胞、少突胶质细胞以及最近发现的一种与少突胶质细胞谱系相关的亚型（NG2 神经胶质细胞）已知可直接调节神经传递和脑代谢，并且可能参与迄今为止在酗酒和抑郁症中检测到的总体神经胶质细胞变化。在本项目中，我们建议研究增殖和细胞死亡标记物，并确定慢性酗酒者、抑郁症患者（伴或不伴酒精中毒）和匹配的控件。由于与神经元不同，神经胶质细胞能够在正常新皮质中持续增殖，因此我们假设酗酒者和抑郁症患者死后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 细胞的比例低于对照组，并且在患有共病酗酒的抑郁症患者中，这一比例最低。我们还预计，随着酒精依赖或抑郁持续时间的增加，增殖的星形胶质细胞的比例也会增加。我们还预计，在任何时候，酗酒者中带有细胞死亡标记的神经胶质细胞的数量都会比抑郁症患者或对照组更高，而且在患有共病酗酒的抑郁症患者中，该数量最高。公共健康相关性：通过研究神经胶质细胞增殖和死亡的标志物，本项目将提供有关在抑郁症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减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很重要，因为抑郁症和酗酒的治疗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药物。

项目成果

MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism.

MicroRNA-21：少突胶质细胞中的表达及其与抑郁症和酗酒中低髓磷脂 mRNA 的相关性。

• DOI: 10.1016/j.pnpbp.2017.08.009
• 发表时间: 2017-10-03
• 期刊: Progress in neuro-psychopharmacology & biological psychiatry
• 影响因子: 5.6
• 作者: Miguel-Hidalgo JJ;Hall KO;Bonner H;Roller AM;Syed M;Park CJ;Ball JP;Rothenberg ME;Stockmeier CA;Romero DG
• 通讯作者: Romero DG

Reduced connexin 43 immunolabeling in the orbitofrontal cortex in alcohol dependence and depression.

• DOI: 10.1016/j.jpsychires.2014.04.007
• 发表时间: 2014-08
• 期刊: JOURNAL OF PSYCHIATRIC RESEARCH
• 影响因子: 4.8
• 作者: Miguel-Hidalgo, Jose Javier;Wilson, Barbara A.;Hussain, Syed;Meshram, Ashish;Rajkowska, Grazyna;Stockmeier, Craig A.
• 通讯作者: Stockmeier, Craig A.

Apoptosis-related proteins and proliferation markers in the orbitofrontal cortex in major depressive disorder.

• DOI: 10.1016/j.jad.2014.02.010
• 发表时间: 2014-04
• 期刊: JOURNAL OF AFFECTIVE DISORDERS
• 影响因子: 6.6
• 作者: Miguel-Hidalgo, Jose J.;Whittom, Angela;Villarreal, Ashley;Soni, Madhav;Meshram, Ashish;Pickett, Jason C.;Rajkowska, Grazyna;Stockmeier, Craig A.
• 通讯作者: Stockmeier, Craig A.

Markers of apoptosis induction and proliferation in the orbitofrontal cortex in alcohol dependence.

酒精依赖中眶额皮质细胞凋亡诱导和增殖的标志物。

• DOI: 10.1111/acer.12559
• 发表时间: 2014
• 期刊: Alcoholism, clinical and experimental research
• 作者: Whittom,Angela;Villarreal,Ashley;Soni,Madhav;Owusu-Duku,Beverly;Meshram,Ashish;Rajkowska,Grazyna;Stockmeier,CraigA;Miguel-Hidalgo,JoseJ
• 通讯作者: Miguel-Hidalgo,JoseJ