Effect of Major Depression and antidepressants on human neurogenesis

神经发生发生在成年哺乳动物海马结构（HF）的齿状回（DG）， 在健康（衰老）和疾病（压力，神经损伤）状态下改变。神经发生减少 一个新的模型的病因重性抑郁症（MDD）。抗抑郁治疗（ADT） 增加啮齿动物DG的神经发生。因此，神经发生的恢复可能是一种 抗抑郁治疗作用。然而，这还有待于在人类大脑中进行研究。 研究将分三组进行：1。情绪障碍（MD，n=20）患者， 抗抑郁药（10例接受选择性5-羟色胺再摄取抑制剂（SSRI）治疗，10例接受三环类抗抑郁药治疗） 抗抑郁药，TCA）或锂（n=6）在死亡时; 2. MD患者（n=20）未接受 抗抑郁药治疗3个月和3.正常、非精神病对照组（n=18）。这三个小组将在 性别、年龄（整个样本范围为24至62岁）、死亡时间（PMI）、自杀和 比赛我们还将按比例将MD组与共病诊断相匹配， 患有抑郁症或躁郁症所有病例，包括对照组，都将进行心理尸检， DSM轴I和轴II诊断，以及神经病理学检查和脑毒理学筛查。 Ki 67（一种在有丝分裂期间表达的细胞周期蛋白）的免疫细胞化学将用于鉴定 分裂细胞用抗体双标记多能祖细胞（巢蛋白、Pax 6、GFAP）， 神经元祖细胞和神经母细胞（TUC-4、TUJ-1、PSA-NCAM）或未成熟神经胶质（波形蛋白）将被 用于建立分裂细胞的表型。有和无SSRI的MDD患者的HC， 将测定TCA或锂和对照品。体视学将用于估计细胞中标记的细胞数量。 HF的总指挥分裂细胞（Ki 67-免疫反应[IR]）、多能祖细胞（TUC-4）、 和神经祖细胞/神经母细胞（TUC-4-IR）将沿前-后轴沿着检查。 海马，并在整个生命周期中进行比较，MD和正常对照之间以及MD和正常对照之间。 未接受治疗的患者和接受SSRI、TCA或锂剂治疗的MD受试者。吻尾侧的范围 将使用右侧齿状回进行研究，并对间隔2 mm的一系列切片进行分析， 每个抗体 我们将测试的假设，神经发生：1。在前部比后部更明显 HC; 2.与对照组相比，MD降低，以及3.接受SSRI或TCA的MD患者可能有更多的Ki 67- 与未接受治疗的MDD患者相比，IR和Nestin-IR细胞;另一方面，我们假设 TUC-4-IR细胞在抗抑郁药治疗与未治疗的情况下。在探索性分析中，我们测试了 同样的效果或锂。这些结果对理解脑缺血的病理生理学有重要意义。 抑郁症以及抗抑郁药和锂治疗的作用方式。

Neurogenesis occurs in the dentate gyrus (DG) of the hippocampal formation (HF) of adult mammals and is altered in both health (aging) and disease (stress, neurological damage) states. Decreased neurogenesis is an emerging model for the etiology of major depressive disorder (MDD). Antidepressant treatment (ADT) increases neurogenesis in the DG of rodents. Therefore, restoration of neurogenesis may be an antidepressant therapeutic effect. However, this has yet to be examined in the human brain. Studies will be carried out in three groups: 1. Patients with Mood Disorder (MD, n=20) who were on antidepressants (ten treated with selective serotonin reuptake inhibitors, SSRI, ten treated with tricyclic antidepressants, TCA) or lithium (n=6) at the time of death; 2. MD patients (n=20) who were not on antidepressants for e 3 months and 3. normal, non-psychiatric controls (n=18). The three groups will be matched for sex, age (range 24 to 62 years in the whole sample), postmortem interval (PMI), suicide and race. We will also match the MD groups on proportions with comorbid diagnoses and the percentage that have MDD or bipolar disorder. All cases, including controls, will have psychological autopsies determining DSM Axis I and Axis II diagnosis, as well as neuropathologic examination and brain toxicological screen. Immunocytochemistry for Ki67, a cell cycle protein expressed during mitosis, will be used to identify dividing cells. Double labeling with antibodies for multipotent progenitor cells (Nestin, Pax6, GFAP), neuronal progenitors cells and neuroblasts (TUC-4, TUJ-1, PSA-NCAM), or immature glia (Vimentin) will be used to establish the phenotype of the dividing cells. The HC from MDD patients with and without SSRI, TCA or lithium and controls will be assayed. Stereology will be used to estimate the labeled cell number in the DG of the HF. The number of dividing cells (Ki67-immunoreactive [IR]), multipotent progenitors (TUC-4), and neural progenitor/neuroblasts (TUC-4-IR) will be examined along the antero-posterior axis of the hippocampus, and compared across the lifespan, between MD and normal controls and between MD patients without treatment and MD subjects who were on SSRI, TCA or lithium. The rostrocaudal extent of the right dentate gyrus will be used for the study and series of sections at 2mm intervals will be assayed for each antibody. We will test the hypotheses that neurogenesis: 1. is more pronounced in the anterior versus posterior HC; 2. is decreased in MD versus controls, and 3. MD patients receiving SSRI or TCA may have more Ki67- IR and Nestin-IR cells compared to MDD patients without treatment; on the other way we hypothesize fewer TUC-4-IR cells in antidepressants treated versus untreated cases. In an exploratory analysis we test the same effects for or lithium. These results have implications for understanding the pathophysiology of depression and the mode of action of antidepressants and lithium treatment.