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：
8176838
负责人：
Maura Boldrini
金额：
$ 21.46万
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 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8176838
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. PUBLIC HEALTH RELEVANCE: Major Depression (MDD) is a serious public health problem and antidepressant treatment (ADT) is not effective in all cases. There is evidence that neuronal replication (neurogenesis) occurs in adult mammals including humans and it occurs together with the generation of new vasculature (angiogenesis). Trophic factors might play a crucial role in support of these phenomena and angiogenesis appears necessary for ADT to work in rodents and therefore, we propose to examine the expression of trophic factors and its correlation with neurogenesis and angiogenesis in MDD patients, with and without ADT, compared to normal controls.

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结构（HF）的齿状回（DG）中，并且在包括人类在内的成年哺乳动物中，通过抗抑郁治疗（ADT）可以增加神经发生。据推测，重度抑郁症 (MDD) 的神经发生减少。神经发生与新脉管系统（血管生成）的产生同时发生，并且两者都受到啮齿动物的营养因子的刺激。血管生成对于新神经元的分化和存活是必要的，并且脑血容量已被提议作为神经发生的体内替代指标。尚未检查营养因子表达是否与人脑中的神经发生和血管发生相关。研究将分三组进行： 1. 正在服用抗抑郁药的情绪障碍患者（MDD，n=10）（MDDT，5 名患者接受选择性血清素再摄取抑制剂治疗，MDD*SSRI，5 名患者接受三环类抗抑郁药治疗，MDD*TCA ) 死亡时； 2. 3 个月未服用抗抑郁药物的 MDD 患者 (n=10) 和 3. 正常、非精神病对照 (NC, n=10)。这三组将在性别、年龄（整个样本中的年龄在 24 岁到 62 岁之间）、死后间隔 (PMI) 和种族方面进行匹配。所有病例，包括对照组，都将根据 DSM Axis I 诊断、神经病理学检查和毒理学筛查进行心理尸检。血管内皮生长因子（VEGF）及其受体VEGFR-2、脑源性神经营养因子（BDNF）及其受体TrkB的免疫细胞化学将用于鉴定它们在HF细胞中的表达。血管将用巢蛋白染色并用 CD31（内皮细胞标记）进行双标记。神经祖细胞 (NPC) 将通过巢蛋白染色进行鉴定，分裂细胞通过 Ki-67 染色进行鉴定，成熟神经元通过神经元特异性核蛋白 (NeuN) 进行鉴定，其树突通过神经丝染色进行标记。右侧 HF 的轴尾范围将用于研究，并且将对每种抗体以 2mm 间隔进行一系列切片进行分析。体视学将用于估计整个 HF 中标记细胞的数量、血管面积和体积、神经元大小和树突长度。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，MDDT 中的细胞数量比 MDD 和 NC 中的细胞数量要多；神经元数量、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 MDDT 中的神经元数量、大小和树突长度比 MDD 和 NC 中的细胞数量更大；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，并且与 MDD 和 NC 相比，MDDT 中的血管面积和体积更大。这些结果对于理解在 MDD 中使用营养因子作为 ADT 的可能性具有重要意义。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。有证据表明，神经元复制（神经发生）发生在包括人类在内的成年哺乳动物中，并且与新脉管系统的生成（血管发生）一起发生。营养因子可能在支持这些现象中发挥关键作用，并且血管生成似乎是 ADT 在啮齿动物中发挥作用所必需的，因此，我们建议检查营养因子的表达及其与 MDD 患者神经发生和血管生成的相关性，无论是否接受 ADT，与正常对照相比。