Synaptic Aromatase: a Novel Form of Estrogen Delivery

突触芳香酶：一种新的雌激素输送形式

• 批准号: 7864076
• 负责人: COLIN J SALDANHA
• 金额: $ 39.45万
• 依托单位: LEHIGH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7864076
• 关键词: Adolescent; Affect; Afferent Neurons; Aggressive behavior; Alzheimer' s Disease; Animal Model; Animals; Area; Aromatase; Behavior; Behavioral; Behavioral Paradigm; Brain; Brain Part; Chemicals; Coupling; Disease; Electron Microscopy; Equilibrium; Estrogens; Exclusion; Female; 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; public health relevance; receptor; research study; sex; synthetic enzyme; zebra finch

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（由申请人提供）：雌激素（E）合成酶芳香酶位于包括人类在内的许多脊椎动物的突触前神经节中。在鸣禽和啮齿类动物中，突触后位点的 E 受体支持这样的观点：突触分泌激素的提供是一种真正的类固醇递送方法。因此，在事先的支持下，我们已经确定了突触产生的大肠杆菌的发生率、流行率和潜在作用机制。鸣禽为进一步了解突触分泌学提供了无与伦比的优势。在斑胸草雀中，突触芳香酶约占大脑中所有芳香酶活性的一半。与所研究的所有其他物种相比，突触芳香酶在没有体细胞芳香酶的区域丰富。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。相对于女性，男性的突触前芳香酶较高，这表明突触激素供应具有与性别相关的行为作用。然而，我们对突触 E 如何影响局部 E 水平、突触 E 如何调节以及突触 E 在大脑生理学中发挥的作用知之甚少。使用最近开发的类固醇水平敏感测量方法，我将专门测试突触芳香化对大脑局部 E 水平的影响。然后，我将使用电子显微镜，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，我将测试突触芳香化对学习和记忆机制的作用。这些研究将极大地增进我们对突触分泌 E 如何影响脊椎动物大脑的激素、电和行为功能的理解。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。已知调节行为的大脑区域中突触芳香酶的丰富性和排他性，使鸣禽成为理解神经内分泌学中这种新机制的绝佳模型。 公共卫生相关性 在人类和其他动物中，雌激素通过其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、神经保护和学习。如何向不同的大脑区域提供雌激素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神经节中合成的。在之前支持的工作中，我们了解到突触雌激素合成丰富且位于对鸣禽大脑的学习和可塑性很重要的大脑区域内。拟议的实验旨在了解突触产生的雌激素对局部大脑区域的贡献、其来源及其生理功能。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。这将为治疗涉及记忆丧失和大脑退化的疾病（如阿尔茨海默病、帕金森病和中风）的治疗进展提供极大的信息。