Trophic factors and regulation of hippocampal neuroplasticity in the human brain

人脑海马神经可塑性的营养因子及其调节

基本信息

批准号：
8277880
负责人：
Maura Boldrini
金额：
$ 23.96万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-08 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8277880
关键词：
Adult Affect Age Animal Model Antibodies Antidepressive Agents Area Atrophic Autopsy Biological Assay Blood Vessels Blood Volume Brain Brain-Derived Neurotrophic Factor Cell Count Cell Death Cell Proliferation Cell Survival Cells Cellular Morphology Cerebrum Cessation of life Data Dendrites Depressed mood Desipramine Diagnosis Diagnostic and Statistical Manual Endothelial Cells Fibroblast Growth Factor 2 Fluoxetine Generations Growth Factor Hippocampal Formation Hippocampus (Brain)Human Image Label Length Major Depressive Disorder Mammals Measures Mental Depression Mitotic Mood Disorders Mus Neuroglia Neuronal Plasticity Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Nuclear Protein PECAM1 gene Patients Play Public Health Race Regulation Reporting Rodent Role Sampling Seizures Selective Serotonin Reuptake Inhibitor Series Source Staining method Stains Stress Suicide Testing Time Tricyclic Antidepressive Agents Triplet Multiple Birth Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vascularization Work adult neurogenesis angiogenesis base density dentate gyrus immunocytochemistry in vivo nerve stem cell nestin protein neuroblast neurofilament neurogenesis neuropeptide Y neurotrophic factor psychologic receptor sex

项目摘要

DESCRIPTION (provided by applicant): Neurogenesis, or the generation of new neurons, occurs in the dentate gyrus (DG) of the hippocampal formation (HF) and it is increased by antidepressant treatment (ADT) in adult mammals including humans. Decreased neurogenesis is hypothesized in major depressive disorder (MDD). Neurogenesis occurs together with the generation of new vasculature (angiogenesis) and both are stimulated by trophic factors in rodents. Angiogenesis is necessary for new neurons to differentiate and survive and cerebral blood volume has been proposed as a surrogate in vivo measure of neurogenesis. It has not been examined if trophic factors expression is correlated with neurogenesis and angiogenesis in the human brain. Studies will be carried out in three groups: 1. Patients with Mood Disorder (MDD, n=10) who were on antidepressants (MDDT, five treated with selective serotonin reuptake inhibitors, MDD*SSRI, five treated with tricyclic antidepressants, MDD*TCA) at the time of death; 2. MDD patients (n=10) who were not on antidepressants for 3 months and 3. normal, non-psychiatric controls (NC, n=10). The three groups will be matched for sex, age (between 24 and 62 in the whole sample), postmortem interval (PMI) and race. All cases, including controls, will have psychological autopsies according to DSM Axis I diagnosis, neuropathologic examination and toxicological screen. Immunocytochemistry for vascular endothelial growth factor (VEGF), its receptor VEGFR-2, brain derived neurotrophic factor (BDNF), its receptor TrkB will be used to identify their expression in HF cells. Vessels will be stained with nestin and double-labeled with CD31 (marker of endothelial cells). Neural progenitor cells (NPCs) will be identified by nestin stain, dividing cells by Ki-67 stain, mature neurons by neuronal-specific nuclear protein (NeuN) and their dendrites labeled by and neurofilament stain. The rostrocaudal extent of the right HF will be used for the study and series of sections at 2mm intervals will be assayed for each antibody. Stereology will be used to estimate the number of labeled cell in the whole HF, vessel area and volume, neuron size and dendrites length. We will test the hypotheses that: the number of NPCs and mitotic cells in the DG is proportional to the number of cells expressing VEGF, BDNF and their receptors in the HF, which will be greater in MDDT compared to MDD and NC; neuron number, size and dendrite length is proportional to the number of cells expressing VEGF, BDNF and their receptors in the HF and that they will be greater in MDDT vs MDD and NC; vessel area and volume are proportional to the number of cells expressing VEGF, BDNF and their receptors in the HF and that they will be greater in MDDT compared to MDD and NC. These results have implications for understanding the possibility to use trophic factors as ADT in MDD.

描述（由申请人提供）：神经发生或新神经元的产生发生在海马形成（HF）的齿状回（DG）中，并且在包括人类在内的成人哺乳动物中通过抗抑郁治疗（ADT）增加了。神经发生降低是在重度抑郁症（MDD）中假设的。神经发生与新的脉管系统的产生（血管生成）一起出现，并且两者都受到啮齿动物的营养因子的刺激。血管生成是新神经元分化和生存所必需的，并且已经提出了作为神经发生体内的替代脑血容量。尚未研究营养因子的表达是否与人脑中神经发生和血管生成相关。研究将分为三组：1。患有抗抑郁药的患者（MDD，n = 10）（MDDT，5例接受了选择性5-羟色胺再摄取抑制剂治疗，MDD*SSRI，MDD*SSRI，五名在死亡时用三环体抗抑郁药治疗，MDD*TCA，MDD*TCA）； 2。MDD患者（n = 10）在3个月内不使用抗抑郁药的患者。这三组将与性别，年龄（在整个样本中24至62之间），验尸间隔（PMI）和种族匹配。所有病例（包括对照）将根据DSM轴I诊断，神经病理检查和毒理学筛查的心理尸检。血管内皮生长因子（VEGF）的免疫细胞化学，其受体VEGFR-2，脑衍生的神经营养因子（BDNF），其受体TRKB将用于鉴定其在HF细胞中的表达。血管将用巢蛋白染色，并用CD31（内皮细胞的标记）双标记。神经祖细胞（NPC）将通过Nestin染色鉴定，除以Ki-67染色，由KI-67染色，成熟的神经元通过神经元特异性核蛋白（NEUN）及其树突和神经丝染色。将使用右HF的右HF的尾mau范围用于研究，每种抗体将以2mm的间隔进行一系列切片。立体病学将用于估计整个HF，血管区域和体积，神经元大小和树突长度的标记细胞数量。我们将测试以下假设：DG中的NPC和有丝分裂细胞的数量与HF中表达VEGF，BDNF及其受体的细胞数量成正比，与MDD和NC相比，MDDT中的NPC和有丝分裂细胞的数量将更大。神经元的数量，大小和树突长度与HF中表达VEGF，BDNF及其受体的细胞数量成正比，并且在MDDT与MDD和NC中它们会更大。血管面积和体积与HF中表达VEGF，BDNF及其受体的细胞数量成正比，与MDD和NC相比，它们在MDDT中的数量将更大。这些结果对理解使用营养因子作为MDD中的ADT的可能性具有影响。