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）：重度抑郁症和酒精中毒具有前额叶皮层（PFC）中神经元和神经胶质细胞的低正常密度，大脑区域很大程度上涉及上瘾和情感障碍。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元病理一样重要，因为神经胶质细胞在调节神经传递，传导作用电位和神经元代谢中至关重要。在我们的验尸研究中，我们发现，患有抑郁症或酒精中毒的年轻和中年受试者的神经胶质密度显着低，并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PFC中降低神经胶质密度的根源，并且这种平衡沿各自的持续时间差异。此外，低密度的神经胶质细胞可能有助于减少酗酒和抑郁症的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之间的神经胶质细胞的总体相似性，但这两个诊断组在胶质降低的程度以及神经胶质变化与神经元变化的关联方面存在差异。因此，确定神经胶质增殖和死亡的平衡是否（以及在何种程度上）解释了神经胶质缺陷是了解这两种疾病的神经胶质生理病理学的相似性和差异的必要步骤，并设计了未来的基于神经胶质的疗法。但是，到目前为止，人脑中还没有可用的研究直接解决两种疾病中神经胶质的增殖/死亡平衡的改变，这通常是合并症。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与少突胶质细胞谱系（NG2 GliA）相关的亚型，已知可以直接调节神经传递和脑代谢，并可能与迄今为止在酒精中毒和MDD中发现的整体胶质变化有关。在本项目中，我们建议研究增殖和细胞死亡的标志物，并确定星形胶质细胞，少突胶质细胞，小胶质细胞，NG2神经胶质细胞和神经元的密度，这些神经元和神经元含有慢性酒精中毒，抑郁症，抑郁症（具有和无稳态酒精中毒）和匹配的对照组中的增殖/死亡标记。由于与神经元不同，因此神经胶质细胞在正常的新皮层中不断增殖，因此我们假设在酗酒和抑郁症中，与对照组相比，在酗酒和抑郁症中，少突胶质细胞，小胶质细胞，小胶质细胞和NG2细胞的增殖将较低。酗酒。我们还可以预期，随着酒精依赖或抑郁症的持续时间，增殖的星形胶质细胞比例会增加。我们还期望在任何时候，与抑郁症或对照组相比，在酗酒者或对照组中，具有细胞死亡标记的神经胶质细胞会更高，并且与合并症酒精中毒的抑郁症中的数量最高。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，本项目将提供有关抑郁症和酗酒者前额叶大脑皮层中观察到的胶质细胞数量较低的直接原因的信息。确定神经胶质细胞增殖和死亡的平衡很重要，因为抑郁症和酒精中毒的疗法必须考虑到这种平衡。相反，可以恢复神经胶质细胞增殖和死亡到正常水平平衡的化合物可能是抑郁症和酒精中毒的未来治疗方法。

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