Hormones and Brain Protection

描述(申请人提供)：参与鸟鸣控制的大脑区域的季节性回归提供了一个惊人而独特的机会来研究与类固醇激素自然发生变化相关的神经元退化和保护的调节机制，以及神经保护对习得的感觉运动行为的功能后果。这项提案的目的是解决荷尔蒙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荷尔蒙神经保护中的作用(AIMS 1-4)，激酶级联在调节激素跨突触神经保护效应中的作用(AIM 3)，以及类固醇是否具有独立于激素受体的神经保护作用(AIM 2)。BirdSong系统是研究神经保护的荷尔蒙机制的典范。这是一个定义明确且易于处理的神经回路，显示了激素调节的神经元回归和保护的极端季节性模式。这些神经退化和保护的过程发生在与繁殖相关的激素周期，因此可以在没有侵入性操作的情况下在体内进行研究。这项研究将通过1)提供歌曲系统中的第一个证据来推动这一领域的发展 激动级联是激素神经保护的“间接”基因组贡献者(目标1-4)；2)研究激素跨突触作用产生神经保护作用的机制，以及是否激动级联调节这一效应(目标3)；以及3)确定激动级联对类固醇神经保护作用的贡献是否需要激素受体激活(目标2)，这是一个仍然不确定的问题。

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.