Rapid steroidogenesis in the brain.

描述（由申请人提供）：重要的行为和生理变化发生在几分钟的时间尺度上，然而这些快速变化背后的神经内分泌机制尚未得到很好的理解。类固醇激素代表了一组具有如此快速的神经和行为效应的候选分子。尽管类固醇激素是强大而普遍的神经调节剂，但人们对大脑中的类固醇水平（神经类固醇）是如何在短时间内被调节的知之甚少。缩小对这一整类神经调节剂的理解差距将有助于深入了解神经递质系统和神经类固醇如何在每分钟的基础上相互作用。初步临床研究表明，神经类固醇的病理生理与产后抑郁、妊娠疲劳和癫痫等疾病有关。因此，更深入地了解神经类固醇水平是如何随时间变化的，可能会提高我们对社会行为、心理健康和疾病的理解。在本研究中，描述脑内类固醇生成酶的活性，以及脑内类固醇水平的体内测量，是理解类固醇的神经调节作用和脑内类固醇转化功能的关键和补充方法。该建议旨在阐明脑类固醇水平的快速变化如何促进脑功能和社会行为的变化。在斑胸草雀模型中，拟议的实验将评估歌唱行为与体内脑类固醇水平和类固醇生成酶活性变化的快速变化之间的关系。拟议的实验还将检查急性应激期间脑类固醇水平和类固醇生成酶活性的快速变化。人类和鸣禽都表现出显著的非性腺来源的类固醇生成，包括大脑，因此这些实验提供了一个机会，以提高我们对基本神经类固醇机制的理解。

DESCRIPTION (provided by applicant): Important behavioral and physiological changes occur on a timescale of minutes, yet the neuroendocrine mechanisms that underlie these fast changes are not well understood. Steroid hormones represent one group of candidate molecules for such rapid neural and behavioral effects. Although steroid hormones are powerful and pervasive neuromodulators, little is known about how steroid levels within the brain (neurosteroids) are regulated over rapid time periods. Narrowing the gap in understanding this entire class of neuromodulators will provide insight into how neurotransmitter systems and neurosteroids interact on a minute-by-minute basis. Preliminary clinical investigations have indicated that neurosteroid pathophysiologies are involved in disorders such as postpartum depression, pregnancy fatigue, and epilepsy. Thus, a greater appreciation of how neurosteroid levels change overtime may improve our understanding of social behavior, mental health and disease. In this proposal, characterizing the activity of steroidogenic enzymes in the brain, as well as in vivo measurement of brain steroid levels, are critical and complementary approaches toward understanding the neuromodulatory role of steroids and the function of steroid conversion by the brain. This proposal seeks to clarify how rapid changes in brain steroid levels contribute to changes in brain function and social behavior. In the zebra finch model, the proposed experiments will assess how singing behavior is related to rapid changes in both brain steroid levels in vivo and changes in steroidogenic enzyme activity. The proposed experiments will also examine rapid changes in brain steroid levels and steroidogenic enzyme activity during acute stress. Both humans and songbirds exhibit significant steroidogenesis from non-gonadal origins, including brain, and so these experiments provide an opportunity to improve our understanding of basic neurosteroid mechanisms.