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形成（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。神经发生减少是重度抑郁症（MDD）病因学的一个新兴模型。抗抑郁药治疗（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的治疗效果。然而，这还有待于在人脑中进行检验。研究将分为三组进行：1。心境障碍患者（MD, n=20）在死亡时正在服用抗抑郁药（10例使用选择性血清素再摄取抑制剂，SSRI治疗，10例使用三环抗抑郁药，TCA治疗）或锂（n=6）；2. 未服用抗抑郁药3个月和3个月的MD患者（n=20）。正常，非精神病对照（n=18）。这三组将在性别，年龄（整个样本的范围为24至62岁），死后间隔（PMI），自杀和种族方面进行匹配。我们还将根据共病诊断的比例和重度抑郁症或双相情感障碍的比例对MD组进行匹配。所有病例，包括对照组，将进行心理尸检，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。免疫细胞化学的Ki67，在有丝分裂期间表达的细胞周期蛋白，将用于鉴定分裂细胞。多能祖细胞（Nestin, Pax6， GFAP），神经祖细胞和神经母细胞（TUC-4, TUJ-1, PSA-NCAM）或未成熟胶质细胞（Vimentin）抗体的双重标记将用于建立分裂细胞的表型。MDD患者的HC将被检测，这些患者有或没有SSRI、TCA或锂和对照。体视学将用于估计HF的DG中的标记细胞数。将沿海马前后轴检测分裂细胞（ki67 -免疫反应性[IR]）、多能祖细胞（tuc4）和神经祖细胞/神经母细胞（tuc4 -IR）的数量，并在整个生命周期内比较MD和正常对照以及未治疗的MD患者和服用SSRI、TCA或锂的MD受试者。研究将使用右侧齿状回的背侧部，每隔2mm进行一系列切片，检测每种抗体。我们将测试神经发生的假设：1。在HC的前部和后部更为明显；2. 与对照组相比，MD降低；与未接受治疗的重度抑郁症患者相比，接受SSRI或TCA治疗的MD患者可能有更多的Ki67- IR和巢蛋白-IR细胞；另一方面，我们假设服用抗抑郁药物的患者与未服用抗抑郁药物的患者相比，TUC-4-IR细胞较少。在一项探索性分析中，我们测试了锂的同样效果。这些结果对理解抑郁症的病理生理以及抗抑郁药和锂治疗的作用模式具有重要意义。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，抗抑郁药物治疗（ADT）并非对所有病例都有效。研究表明，成年啮齿动物的神经发生对于记忆和情绪反应是必要的，但它可以因压力而减少，并在ADT中得到改善，因此神经发生受损可能导致重度抑郁症。我们建议检测与正常健康对照相比，有或没有ADT的MDD患者的神经发生，评估MDD患者的神经发生是否减少并通过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.