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的海马形成（HF）的齿状回（DG）中，并且在健康（衰老）和疾病（压力，神经系统损害）状态下都改变了。降低神经发生是主要抑郁症（MDD）病因的新兴模型。抗抑郁药治疗（ADT）增加了啮齿动物DG的神经发生。因此，恢复神经发生可能是抗抑郁药的治疗作用。但是，这尚未在人脑中进行检查。研究将分为三组：1。具有抗抑郁药的情绪障碍（MD，n = 20）的患者（十种用选择性的5-羟色胺再摄取抑制剂治疗，SSRI，十个在死亡时用三环抗抑郁药，TCA）或锂（n = 6）治疗； 2。MD患者（n = 20）E 3个月不服用抗抑郁药。这三组将与性别，年龄（在整个样本中范围24至62岁），验尸间隔（PMI），自杀和种族匹配。我们还将在合并症诊断和患有MDD或双相情感障碍的百分比上与MD组相匹配。所有病例（包括对照）将具有确定DSM轴I和Axis II诊断的心理尸检，以及神经病理学检查和脑毒理学筛查。 Ki67的免疫细胞化学是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。使用用于多能祖细胞（Nestin，Pax6，GFAP），神经元祖细胞和神经细胞（TUC-4，TUJ-1，PSA-NCAM）或未成熟神经胶质（VEMENTIN）的抗体双重标记。将分析有或没有SSRI，TCA或锂的MDD患者的HC以及对照组。立体病学将用于估计HF DG中标记的细胞数。分裂细胞（KI67-免疫反应[IR]），多元祖细胞（TUC-4）和神经祖/祖细胞/神经细胞（TUC-4-ir）的数量将沿着河马的前后轴进行检查，并在MD和MD之间进行比较，并在MD和正常人之间进行比较。或锂。右齿状回的尾象范围将用于研究，每种抗体将以2mm的间隔进行一系列切片。我们将测试神经发生的假设：1。在前HC和后HC中更为明显。与未经治疗的MDD患者相比，MD与对照组的MD与对照相比，MD与对照组的降低可能更高。另一方面，我们假设在治疗的抗抑郁药与未处理病例的抗抑郁药中，TUC-4-IR细胞更少。在探索性分析中，我们测试了对或锂的相同效果。这些结果对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影响。公共卫生相关性：严重抑郁症（MDD）是一个严重的公共卫生问题，在所有情况下，抗抑郁药治疗（ADT）均不有效。已经表明，成年啮齿动物的神经发生对于记忆和情绪反应是必要的，但是可以通过ADT来减少压力并改善它，因此神经发生受损可能导致MDD。我们建议与正常的健康对照组相比，检查有或没有ADT的MDD患者的神经发生，以评估MDD中的神经发生是否降低并由ADT恢复。