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Synaptic Aromatase: a Novel Form of Estrogen Delivery

突触芳香酶：一种新的雌激素输送形式

基本信息

批准号：
8290068
负责人：
COLIN J SALDANHA
金额：
$ 27.71万
依托单位：
AMERICAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8290068
关键词：
Adolescent Affect Afferent Neurons Aggressive behavior Alzheimer&apos s Disease Animal Model Animals Area Aromatase Behavior Behavioral Behavioral Paradigm Brain Brain Part Chemicals Coupling Disease Electron Microscopy Equilibrium Estrogens Exclusion Female Health Hippocampus (Brain)Hormonal Hormones Human Incidence Interneurons Investigation Learning Measurement Memory Memory Loss Methods Modeling Moods Nervous system structure Neuroendocrinology Neuromodulator Neurons Neurosecretory Systems Neurotransmitters Parkinson Disease Pattern Physiological Physiology Play Prevalence Process Regulation Relative (related person)Rodent Role Signal Transduction Songbirds Source Steroids Stroke Study models Synapses System Techniques Testing Therapeutic Vertebrates Work dimorphism male memory acquisition neuroprotection novel paracrine postsynaptic presynaptic receptor research study sex synthetic enzyme zebra finch

项目摘要

DESCRIPTION (provided by applicant): The estrogen (E) synthetic enzyme aromatase is localized in presynaptic boutons of many vertebrates including humans. In songbirds and rodents, E-receptors at postsynaptic loci support the idea that synaptocrine hormone provision is a bona fide method of steroid delivery. Thus, with prior support we have established the incidence, prevalence, and potential mechanism of action of synaptically produced E. The songbird affords unparalleled advantages towards the further understanding of synaptocrinology. In the zebra finch, synaptic aromatase comprises about half of all aromatase activity in the brain. In contrast to all other species studied, synaptic aromatase is abundant in areas with no somal aromatase. Thus, the specific contribution of synaptic E to local steroid levels in the brain can be easily studied. Presynaptic aromatase is higher in males relative to females, suggesting a sex- associated, behavioral role for synaptic hormone provision. However, we know very little about the how synaptic E contributes to local E levels, how synaptic E may be regulated, and what role synaptic E plays in brain physiology. Using recently developed sensitive measurements of steroid levels, I will specifically test how local brain levels of E are affected by synaptic aromatization. Then, using electron-microscopy, I will test which parts of the brain contribute to local E levels by identifying the projection neurons that contain synaptic aromatase. Lastly, with established behavioral paradigms, I will test the role of synaptic aromatization on the mechanisms of learning and memory. These studies will greatly increase our understanding of how synaptocrine E contributes to the hormonal, electrical, and behavioral functioning of the vertebrate brain. This work, supported by NS 047267, suggests a coupling of chemical and electrical signaling. The abundance and exclusivity of synaptic aromatase in brain areas known to modulate behavior, make the songbird an excellent model to understand this novel mechanism in neuroendocrinology. PUBLIC HEALTH RELEVANCE In humans and other animals, estrogen affects many structural and functional endpoints by its action on the nervous system. These endpoints include aggression, mood, balance, neuroprotection, and learning. How estrogens are provided to discrete brain areas is a field of intense investigation. Estrogen is synthesized in presynaptic boutons of humans, rodents, and songbirds. In previously supported work we have learned that synaptic estrogen synthesis is abundant and localized within brain areas important for learning and plasticity in the songbird brain. The proposed experiments seek to understand the contribution of synaptically produced estrogen to local brain areas, their source, and their physiological function. These studies are critical in order to evaluate the role of synaptic estrogen in learning, memory, and neuroprotection. This will greatly inform therapeutic advances in the treatment of diseases that involve the loss of memory and brain degeneration such as Alzheimer's, Parkinson's, and stroke.

描述(申请人提供)：雌激素(E)合成酶芳香酶定位于包括人类在内的许多脊椎动物的突触前突触周围。在鸣禽和啮齿动物中，突触后部位的E受体支持这样的观点，即提供突触分泌激素是一种真正的类固醇传递方法。因此，在先前的支持下，我们已经建立了突触产生的E的发生率、流行率和潜在的作用机制。鸣禽为进一步了解突触分泌学提供了无与伦比的优势。在斑马雀中，突触芳香酶约占大脑芳香酶活性的一半。与所研究的其他物种不同，突触芳香酶在没有胞体芳香酶的区域丰富。因此，可以很容易地研究突触E对大脑局部类固醇水平的具体贡献。男性的突触前芳香酶高于女性，这表明突触激素的提供是与性别相关的行为作用。然而，我们对突触E如何对局部E水平做出贡献，突触E如何被调节，以及突触E在脑生理中扮演什么角色知之甚少。使用最近开发的类固醇水平的敏感测量，我将专门测试突触芳构化如何影响大脑局部的E水平。然后，使用电子显微镜，我将通过识别含有突触芳香酶的投射神经元来测试大脑的哪些部分对局部E水平有贡献。最后，通过已建立的行为范式，我将测试突触芳构化在学习和记忆机制中的作用。这些研究将大大增加我们对突触素E如何对脊椎动物大脑的荷尔蒙、电和行为功能做出贡献的理解。这项工作得到了NS 047267的支持，提出了化学信号和电信号的耦合。在大脑中已知的调节行为的区域中，突触芳香酶的丰富性和排他性使鸣禽成为了解神经内分泌学中这一新机制的极佳模型。在人类和其他动物中，雌激素通过对神经系统的作用影响许多结构和功能终点。这些终点包括攻击性、情绪、平衡性、神经保护和学习。雌激素是如何被提供给离散的大脑区域的，这是一个深入研究的领域。雌激素是在人类、啮齿动物和鸣禽的突触前突触中合成的。在之前支持的工作中，我们了解到突触雌激素合成丰富，并定位于对鸣禽大脑的学习和可塑性重要的脑区。拟议的实验试图了解突触产生的雌激素对局部脑区的贡献，它们的来源，以及它们的生理功能。这些研究对于评估突触雌激素在学习、记忆和神经保护中的作用至关重要。这将极大地促进治疗阿尔茨海默氏症、帕金森氏症和中风等涉及记忆力丧失和大脑退化的疾病的治疗进展。