Effect of Major Depression and antidepressants on human neurogenesis

描述（由申请人提供）：神经发生发生在成年哺乳动物海马结构（HF）的齿状回（DG）中，并在健康（衰老）和疾病（应激、神经损伤）状态下发生改变。神经发生减少是重性抑郁症（MDD）病因学的一个新模型。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抗抑郁药的治疗作用。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。在死亡时正在服用抗抑郁药（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（TCA）治疗）或锂（n=6）的情绪障碍（MD，n=20）患者; 2. MD患者（n=20）未服用抗抑郁药3个月和3个月。正常、非精神病对照组（n=18）。这三个组将在性别、年龄（整个样本范围为24至62岁）、死后间隔（PMI）、自杀和种族方面相匹配。我们还将匹配MD组与共病诊断的比例和MDD或双相情感障碍的百分比。所有病例，包括对照组，将进行心理尸检，以确定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。将使用多能祖细胞（巢蛋白、Pax 6、GFAP）、神经元祖细胞和成神经细胞（TUC-4、TUJ-1、PSA-NCAM）或未成熟神经胶质（波形蛋白）的抗体进行双标记，以建立分裂细胞的表型。将对使用和不使用SSRI、TCA或锂的MDD患者和对照的HC进行分析。体视学将用于估计HF DG中的标记细胞数量。将沿着海马体的前后轴检查分裂细胞（Ki 67-免疫反应性[IR]）、多能祖细胞（TUC-4）和神经祖细胞/神经母细胞（TUC-4-IR）的数量，并在整个寿命期间比较MD和正常对照之间以及未接受治疗的MD患者和接受SSRI、TCA或锂的MD受试者之间的数量。右侧齿状回的吻尾侧范围将用于研究，并将测定每种抗体的2 mm间隔的一系列切片。我们将测试的假设，神经发生：1。在前HC中比后HC更明显; 2.与对照组相比，MD降低，以及3.接受SSRI或TCA的MD患者与未接受治疗的MDD患者相比可能具有更多的Ki 67- IR和Nestin-IR细胞;另一方面，我们假设抗抑郁药治疗的TUC-4-IR细胞少于未治疗的病例。在探索性分析中，我们测试了或锂的相同效果。这些结果对于理解抑郁症的病理生理学以及抗抑郁药和锂治疗的作用方式具有意义。公共卫生相关性：重度抑郁症（MDD）是一个严重的公共卫生问题，抗抑郁治疗（ADT）并不是在所有情况下都有效。研究表明，成年啮齿类动物的神经发生对于记忆和情绪反应是必要的，但它可以通过压力减少，并通过ADT改善，因此受损的神经发生可能导致MDD。我们建议检查MDD患者的神经发生，有和没有ADT，与正常健康对照组相比，评估神经发生是否减少MDD和ADT恢复。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Major Depression (MDD) is a serious public health problem and antidepressant treatment (ADT) is not effective in all cases. It has been shown that neurogenesis in adult rodents is necessary for memory and emotional responses, but it can be reduced by stress and improves with ADT, so that impaired neurogenesis may lead to MDD. We propose to examine neurogenesis in MDD patients, with and without ADT, compared to normal healthy controls, evaluating whether neurogenesis is reduced in MDD and restored by ADT.