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

• 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
• 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

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，并且在成年哺乳动物（包括人类）中通过抗抑郁药治疗（ADT）增加。在重度抑郁症（MDD）中假设神经发生减少。神经发生与新血管生成（血管生成）一起发生，两者都受到啮齿动物营养因子的刺激。血管生成是新神经元分化和存活所必需的，并且脑血容量已被提议作为神经发生的体内测量的替代。营养因子的表达是否与人脑中的神经发生和血管生成相关还没有研究。 研究将分三组进行：1。死亡时正在服用抗抑郁药（MDDT，5例接受选择性5-羟色胺再摄取抑制剂治疗，MDD*SSRI，5例接受三环类抗抑郁药治疗，MDD*TCA）的心境障碍（MDD，n=10）患者; 2. MDD患者（n=10）3个月内未使用抗抑郁药，3.正常、非精神病对照（NC，n=10）。这三个组将在性别、年龄（整个样本在24至62岁之间）、死后间隔（PMI）和种族方面相匹配。所有病例，包括对照组，将根据DSM轴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CD 31（内皮细胞标记物）进行双标记。巢蛋白染色鉴定神经前体细胞，Ki-67染色鉴定分裂细胞，NeuN染色鉴定成熟神经元，神经丝染色鉴定树突。右侧HF的吻尾侧范围将用于研究，并将测定每种抗体的2 mm间隔的一系列切片。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。 我们将检验以下假设：DG中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中表达VEGF、BDNF及其受体的细胞数量大于MDD和NC; HF中神经元数量、大小和树突长度与表达VEGF、BDNF及其受体的细胞数量成正比，MDDT中表达VEGF、BDNF及其受体的细胞数量大于MDD和NC;血管面积和体积与HF中表达VEGF、BDNF及其受体的细胞数量成比例，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）并不是在所有情况下都有效。有证据表明，神经元复制（神经发生）发生在成年哺乳动物（包括人类）中，并且与新血管的生成（血管生成）一起发生。营养因子可能在支持这些现象中发挥关键作用，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患者中神经发生和血管生成的相关性，与正常对照组相比，有和没有ADT。