Hormones and Brain Protection

描述（由申请人提供）：鸟鸣控制相关脑区的季节性消退为研究调节神经元变性和与类固醇激素自然发生变化相关的保护机制以及学习感觉运动行为的神经保护功能后果提供了一个引人注目的独特机会。这项提案的目的是解决激素作为成人大脑神经保护剂的基本问题。这些包括间接基因组信号通路在激素神经保护中的作用（目标1-4），激酶级联在介导激素跨突触神经保护作用中的作用（目标3），以及类固醇是否可以以不依赖于激素受体的方式具有神经保护作用（目标2）。鸟鸣系统是研究神经保护激素机制的一个很好的模型。这是一个定义明确且易于处理的神经回路，显示出极端的季节性模式，由神经元调节的神经元回归和保护。这些神经变性和保护的过程与繁殖相关的激素周期一起发生，因此可以在体内进行研究，而无需侵入性操作。这项研究将通过以下方式推进这一领域：1）提供歌曲系统中的第一个证据， 激酶级联是激素神经保护的“间接”基因组贡献者（目的1-4）; 2）研究激素通过跨突触作用具有神经保护作用的机制，以及激酶级联是否介导这种作用（目的3）;和3）确定激酶级联对类固醇的神经保护作用的贡献是否需要激素受体活化（Aim 2），一个持续不确定性的问题。

DESCRIPTION (provided by applicant): Seasonal regression of brain regions involved in the control of birdsong provides a striking and unique opportunity to investigate the mechanisms regulating neuronal degeneration and protection associated with naturally occurring variation in steroid hormones, and the functional consequences of neuroprotection for a learned sensorimotor behavior. The aims in this proposal address fundamental issues of hormones as neuroprotective agents in adult brains. These include the role of indirect genomic signaling pathways in hormonal neuroprotection (Aims 1-4), the role of kinase cascades in mediating transynaptic neuroprotective effects of hormones (Aim 3), and whether steroids can have neuroprotective effects in a manner independent of hormone receptors (Aim 2). The birdsong system excels as a model for studies of hormonal mechanisms of neuroprotection. It is a well-defined and tractable neural circuit that shows extreme seasonal patterns of hormone-regulated neuronal regression and protection. These processes of neural degeneration and protection occur with breeding-related hormonal cycles and thus can be studied in vivo without invasive manipulations. This research will advance the field by 1) providing the first evidence in the song system that kinase cascades are "indirect" genomic contributors to hormonal neuroprotection (Aims 1-4); 2) investigating the mechanisms by which hormones act transynaptically to have neuroprotective effects, and whether kinase cascades mediate this effect (Aim 3); and 3) determining whether the contribution of kinase cascades to the neuroprotective effect of steroids requires hormone receptor activation (Aim 2), an issue of continuing uncertainty.