Synaptic Aromatase: a Novel Form of Estrogen Delivery

描述（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终扣中。在鸣禽和啮齿类动物中，突触后位点的E受体支持突触分泌激素供应是类固醇递送的真正方法的想法。因此，在先前的支持下，我们已经建立了突触产生的E。鸣禽为进一步了解突触分泌学提供了无可比拟的优势。在斑胸草雀中，突触芳香酶占大脑中所有芳香酶活性的一半左右。与所有其他物种的研究，突触芳香化酶是丰富的地区没有体芳香化酶。因此，可以很容易地研究突触E对大脑中局部类固醇水平的具体贡献。突触前芳香化酶在男性中相对于女性更高，提示突触激素提供的性相关行为作用。然而，我们对突触E如何影响局部E水平，突触E如何被调节，以及突触E在脑生理学中起什么作用知之甚少。使用最近开发的类固醇水平的敏感测量，我将专门测试如何局部大脑水平的E受到突触芳构化。然后，利用电子显微镜，我将通过识别含有突触芳香化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，在已建立的行为范例中，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分泌E如何促进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，表明化学信号和电信号的耦合。在已知调节行为的大脑区域中，突触芳香化酶的丰富性和排他性使得鸣禽成为理解神经内分泌学中这种新机制的极好模型。 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。雌激素是如何被提供给离散的大脑区域是一个深入研究的领域。雌激素在人类、啮齿动物和鸣禽的突触前终扣中合成。在以前的研究中，我们已经了解到，突触雌激素合成是丰富的，并定位在大脑区域内的学习和可塑性在鸣禽大脑的重要。拟议的实验旨在了解突触产生的雌激素对局部脑区的贡献，它们的来源及其生理功能。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。这将极大地为治疗涉及记忆丧失和脑退化的疾病（如阿尔茨海默氏症、帕金森氏症和中风）的治疗进展提供信息。

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.