Effect of Major Depression and antidepressants on human neurogenesis

重度抑郁症和抗抑郁药对人类神经发生的影响

• 批准号: 7591378
• 负责人: Maura Boldrini
• 金额: $ 40.02万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-09 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591378
• 关键词: 2' -Deoxythymidine; Adrenal Gland Hyperfunction; Adult; Age; Aging; Animal Model; Animals; Anterior; Antibodies; Antidepressive Agents; Atrophic; Autopsy; Behavioral; Biological Assay; Bipolar Disorder; Brain; Bromodeoxyuridine; Cell Count; Cell Cycle; Cell Cycle Proteins; Cell Death; Cell Proliferation; Cells; Cessation of life; Chronic; Control Groups; Corticosterone; DNA biosynthesis; Dendrites; Diagnosis; Diagnostic and Statistical Manual; Disease; Emotional; Etiology; Fluoxetine; Functional disorder; Glial Fibrillary Acidic Protein; Health; Hippocampal Formation; Hippocampus (Brain); Human; Human Volunteers; Imipramine; Incubated; Injection of therapeutic agent; Label; Lead; Lithium; Longevity; Magnetic Resonance; Major Depressive Disorder; Malignant neoplasm of larynx; Mammals; Memory; Mental disorders; Methods; Mitosis; Mitotic; Modeling; Mood Disorders; Mood stabilizers; Multipotent Stem Cells; Nervous System Trauma; Neuroglia; Neurons; Patients; Pharmaceutical Preparations; Phenotype; Prefrontal Cortex; Primates; Proliferating; Proteins; Psychiatric Diagnosis; Public Health; Race; Reporting; Rodent; Sampling; Schizoaffective Disorders; Selective Serotonin Reuptake Inhibitor; Series; Staging; Stem cells; Stress; Structure of molecular layer of cerebellar cortex; Suicide; Testing; Therapeutic; Therapeutic Effect; Thymidine; Time; Tricyclic Antidepressive Agents; Triplet Multiple Birth; Undifferentiated; Vimentin; adult neurogenesis; analog; density; dentate gyrus; depressed; depression; disorder control; frontal lobe; granule cell; immunocytochemistry; improved; indexing; interest; irradiation; nerve stem cell; nervous system disorder; nestin protein; neuroblast; neurogenesis; neurotrophic factor; newborn neuron; nonhuman primate; polysialyl neural cell adhesion molecule; prevent; progenitor; psychologic; public health relevance; research study; response; restoration; sex; stressor; treatment effect

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.

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，并且在健康（衰老）和疾病（压力、神经损伤）状态下都会发生改变。神经发生减少是重度抑郁症（MDD）病因学的一个新兴模型。抗抑郁治疗 (ADT) 会增加啮齿类动物 DG 的神经发生。因此，恢复神经发生可能是一种抗抑郁治疗作用。然而，这还有待在人脑中进行检查。研究将分三组进行： 1. 服用抗抑郁药的情绪障碍患者（MD，n=20）（其中 10 名患者接受选择性血清素再摄取抑制剂 SSRI 治疗，10 名患者接受三环类抗抑郁药 TCA 治疗）或锂剂（n= 6) 死亡时； 2. 3 个月内未服用抗抑郁药物的 MD 患者 (n=20) 和 3. 正常、非精神病对照 (n=18)。这三组将在性别、年龄（整个样本范围为 24 至 62 岁）、死后间隔 (PMI)、自杀和种族方面进行匹配。我们还将根据合并症诊断的比例以及患有 MDD 或双相情感障碍的百分比来匹配 MD 组。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，以及神经病理学检查和脑毒理学筛查。 Ki67（一种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识别分裂细胞。使用多能祖细胞（Nestin、Pax6、GFAP）、神经元祖细胞和神经母细胞（TUC-4、TUJ-1、PSA-NCAM）或未成熟神经胶质细胞（Vimentin）的抗体双标记来建立表型正在分裂的细胞。将测定使用或不使用 SSRI、TCA 或锂的 MDD 患者和对照的 HC。体视学将用于估计 HF DG 中标记的细胞数量。将沿着海马的前后轴检查分裂细胞（Ki67-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，并进行比较MD 与正常对照之间以及未经治疗的 MD 患者与服用 SSRI、TCA 或锂剂的 MD 受试者之间的寿命。右侧齿状回的轴尾范围将用于研究，并且将以 2mm 间隔进行的一系列切片将针对每种抗体进行分析。我们将检验神经发生的假设： 1. 前侧 HC 与后侧 HC 相比更明显； 2. 与对照组相比，MD 中的细胞减少，并且 3. 与未经治疗的 MDD 患者相比，接受 SSRI 或 TCA 的 MD 患者可能具有更多的 Ki67-IR 和 Nestin-IR 细胞；另一方面，我们假设与未治疗的病例相比，接受抗抑郁药治疗的病例中 TUC-4-IR 细胞较少。在探索性分析中，我们测试了锂的相同效果。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，抗抑郁治疗 (ADT) 并非对所有病例都有效。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，但它可以因压力而减少，并通过ADT而改善，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，无论是否接受 ADT，与正常健康对照相比，评估 MDD 中的神经发生是否减少并通过 ADT 恢复。