PROJECT 3: MOLECULAR & CELLULAR INTEGRITY OF THE SEROTONIN SYSTEM IN DEPRESSION

项目 3：分子

• 批准号: 8167934
• 负责人: MARK C AUSTIN
• 金额: $ 21.7万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167934
• 关键词: Anabolism; Antidepressive Agents; Applications Grants; Autopsy; Autoreceptors; Biochemical; Biological; Brain; Brain imaging; Brain region; Clinical; Clinical Research; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Depressed mood; Depressive disorder; Diagnosis; Enzymes; Estrogens; Female; Functional disorder; Funding; Gender; Gene Expression; Grant; Human; Institution; Lead; Major Depressive Disorder; Measurement; Mental Depression; Midbrain structure; Molecular; Neuromodulator; Neurons; Ovarian hormone; Play; Prefrontal Cortex; Primates; Procedures; Proteins; Research; Research Personnel; Resources; Role; Serotonin; Source; Specimen; System; Testing; Tissues; Tryptophan 5-monooxygenase; United States National Institutes of Health; Woman; depressive symptoms; dorsal raphe nucleus; human male; male; men; neurochemistry; neurotransmission; research study; transcription factor; treatment response; treatment strategy

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A variety of postmortem brain studies and clinical investigations have provided evidence that serotonin neurotransmission is reduced in the brain of subjects diagnosed with major depression. While the clinical and postmortem studies have provided a valuable contribution towards understanding the role of serotonin in the pathophysiology of depression, it remains unclear what specific neurochemical substrate or mechanism is responsible for the deficit in serotonin neurotransmission in major depression. It is also important to note that worldwide women have twice the rate of depression as that of men, and several clinical studies have documented gender-specific differences in treatment responses and in structural and functional brain imaging measurements. Many lines of evidence suggest that ovarian hormones play a role in women's greater vulnerability to depression, and estrogen has been shown to modulate serotonin function. Although progress is being made in understanding the pathophysiology of depression, it remains unknown what the biological mechanisms are that make women vulnerable to developing depressive disorders. This proposal is intended to test the hypothesis that there is a gender-specific alteration in the biosynthesis of one or more key neuronal regulators of serotonin synthesis or neuronal activity which produces a deficit in serotonin neurotransmission in midbrain serotonin neurons of female subjects diagnosed with major depression. The specific aims of this grant proposal are intended to determine the biosynthetic integrity of very specific serotonin-related molecules such as the rate-limiting enzyme for serotonin synthesis, tryptophan hydroxylase, 5-HT1A autoreceptors, serotonin-related transcription factors and important afferent neuromodulators in specific brain regions of subjects diagnosed with major depression. The experiments will be conducted on human postmortem brain specimens of both female and male subjects diagnosed with major depression and matched non-psychiatric control subjects. To determine that the biochemical and cellular changes in depressed subjects are not resulting from the possible confounding influence of antidepressant treatment, the human postmortem biochemical measurements will be compared to identical biochemical measurements conducted in the same brain regions of non-human male and female primates that have been chronically treated with an antidepressant. The studies will utilize several histological, biochemical and molecular biological procedures to quantify protein and gene expression of the various serotonergic molecules in tissue specimens containing the midbrain dorsal raphe nucleus and prefrontal cortex. Understanding the biochemical mechanisms contributing to the alterations in serotonin biosynthesis and neurotransmission in depression, with a special emphasis on gender influences, will provide important information regarding the pathophysiology of the serotonin system in depressive illness that may lead to developing new treatment strategies for depression, particularly in women.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 各种死后大脑研究和临床调查提供的证据表明，被诊断患有重度抑郁症的受试者大脑中的血清素神经传递减少。虽然临床和尸检研究为理解血清素在抑郁症病理生理学中的作用提供了宝贵的贡献，但仍不清楚哪种特定的神经化学底物或机制导致重度抑郁症中血清素神经传递的缺陷。同样重要的是要注意，全世界女性的抑郁症发病率是男性的两倍，并且一些临床研究已经记录了治疗反应以及结构和功能脑成像测量中的性别差异。 许多证据表明，卵巢激素在女性更容易患抑郁症的过程中发挥了作用，而雌激素已被证明可以调节血清素功能。尽管在了解抑郁症的病理生理学方面取得了进展，但导致女性容易患上抑郁症的生物学机制仍然未知。该提案旨在检验以下假设：血清素合成或神经元活动的一种或多种关键神经元调节剂的生物合成存在性别特异性改变，从而导致被诊断为重度抑郁症的女性受试者中脑血清素神经元中血清素神经传递缺陷。 该拨款提案的具体目标是确定非常具体的血清素相关分子的生物合成完整性，例如血清素合成的限速酶、色氨酸羟化酶、5-HT1A自身受体、血清素相关转录因子和重要的传入神经调节剂。被诊断患有重度抑郁症的受试者的特定大脑区域。这些实验将在被诊断患有重度抑郁症的女性和男性受试者以及匹配的非精神病对照受试者的人类死后大脑标本上进行。为了确定抑郁受试者的生化和细胞变化不是由抗抑郁治疗可能的混杂影响引起的，人类死后生化测量结果将与在非人类雄性和雌性灵长类动物的相同大脑区域进行的相同生化测量结果进行比较。长期接受抗抑郁药治疗。这些研究将利用多种组织学、生化和分子生物学程序来量化包含中脑中缝背核和前额皮质的组织样本中各种血清素分子的蛋白质和基因表达。了解导致抑郁症中血清素生物合成和神经传递改变的生化机制，特别强调性别影响，将提供有关抑郁症中血清素系统病理生理学的重要信息，这可能会导致开发新的抑郁症治疗策略，特别是在女性中。