Effect of Major Depression and antidepressants on human neurogenesis

神经发生发生在成年哺乳动物的海马结构的齿状回(DG)。 在健康(衰老)和疾病(压力、神经损伤)状态下都会发生变化。神经发生减少是 一种新兴的抑郁症(MDD)病因学模型。抗抑郁治疗(ADT) 增加啮齿类动物DG的神经发生。因此，神经再生的恢复可能是一种 抗抑郁治疗效果。然而，这还有待于在人脑中进行检验。 研究将分三组进行：1.情绪障碍患者(MD，n=20) 抗抑郁药(10例用选择性5-羟色胺再摄取抑制剂SSRI治疗，10例用三环类药物治疗 死亡时服用抗抑郁药(TCA)或锂盐(n=6)；2.未服用的MD患者(n=20) 服用3个月的抗抑郁药和3.正常的非精神病对照组(n=18)。这三个小组将是 匹配的性别、年龄(整个样本范围为24至62岁)、死亡间隔(PMI)、自杀和 种族。我们还将匹配MD组与共病诊断的比例和 患有MDD或双相情感障碍。所有病例，包括对照组，都将进行心理尸检，以确定 DSM Axis I和Axis II诊断，以及神经病理检查和脑毒物筛查。 Ki67是一种在有丝分裂过程中表达的细胞周期蛋白，将用于鉴定 分割细胞。多能祖细胞(Nestin、Pax6、GFAP)抗体的双重标记 神经前体细胞和神经母细胞(TUC-4、TUJ-1、PSA-NCAM)或未成熟胶质细胞(Vimentin)将 用于确定分裂细胞的表型。有无SSRI的MDD患者的HC， 将对三氯乙烷或锂和对照进行检测。将使用体视学来估计标记细胞的数量 高频的DG。分裂细胞(Ki67免疫反应阳性细胞[IR])、多能祖细胞(TUC-4)、 和神经前体细胞/神经母细胞(TUC-4-IR)将沿着前后轴进行检测 海马体，并比较了MD和正常对照组之间以及MD之间的寿命 未接受治疗的患者和服用SSRI、TCA或锂盐的MD患者。肩尾部范围 右侧齿状回将用于研究，每隔2 mm进行一系列切片检查 每一种抗体。 我们将测试以下假设：1.神经发生在大脑的前部比后部更明显 2.MD组与对照组相比，Hc；IS降低；3.接受SSRI或TCA治疗的MD患者的Ki67- 与未经治疗的MDD患者相比，IR和Nestin-IR细胞；另一方面，我们假设更少 抗抑郁药物治疗与未治疗病例中的TUC-4-IR细胞。在探索性分析中，我们测试 对锂也有同样的影响。这些结果对理解糖尿病的病理生理学有一定的意义。 抑郁症与抗抑郁剂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.