Exploratory Studies of Androgen Receptors in Axons

描述(申请人提供)：雄激素对中枢和外周神经系统的功能产生强大的影响，改变许多区域神经元的形态、功能、存活和恢复。雄激素被认为只通过雄激素受体发挥作用，而雄激素受体传统上被认为是一种配体依赖的核转录因子。然而，自70年代末S以来，已有相当多的证据表明性腺类固醇激素的非转录作用，并在最近几年呈指数级积累，但受体或替代机制仍很大程度上仍不清楚。该实验室最近发现，雄激素受体不仅存在于神经元核中，而且存在于哺乳动物大脑皮层的轴突和树突中。这一发现指出了一种耐人寻味的可能性，即雄激素受体在哺乳动物皮质中具有一种新颖的核外作用模式。本申请中描述的探索性研究将提供必要的信息，以产生关于这一潜在的雄激素作用核外途径的假说。一组简单的实验将使用组织化学方法以及光学显微镜、电子显微镜和共聚焦显微镜分析相结合的方法：1)确定雄激素受体免疫反应在轴突和终末的亚细胞分布；2)确定大脑皮层雄激素受体免疫反应阳性轴突的来源；3)确定雄激素受体在轴突中的表达是否有性分化和激素调节。在广泛的精神和神经障碍中的性别差异表明，雄激素在某些情况下是保护性的，在其他情况下是有害的。因此，了解雄激素的作用机制可能为理解和利用内源性和外源性雄激素配体对男性和女性健康和患病神经系统的细胞和全球影响提供必要的关键。

DESCRIPTION (provided by applicant): Androgens exert powerful effects on the function of the central and peripheral nervous system, modifying the morphology, function, survival and recovery of neurons in many regions. Androgens have been thought to exert their effects exclusively through the androgen receptor, traditionally considered to be a ligand dependent nuclear transcription factor. However, considerable evidence for non-transcriptional effects of gonadal steroid hormones has been in the literature since the late 70's and has accumulated exponentially in recent years, yet the receptors or alternative mechanisms remain largely unknown. This laboratory recently discovered that androgen receptors are present not only in neuronal nuclei, but in axons and dendrites in the mammalian cerebral cortex. This discovery points to the intriguing possibility that androgen receptors have a novel, extranuclear mode of action in the mammalian cortex. The exploratory studies described in this application will provide information essential to generating hypotheses about this potential extranuclear route of androgen action. A straightforward set of experiments will use combinations of histochemical methods along with light microscopic, electron microscopic and confocal microscopic analysis to: 1) Identify the subcellular distribution of androgen receptor immunoreactivity in axons and terminals; 2) Identify the source of androgen receptor immunoreactive axons in the cerebral cortex; and 3) Determine whether the expression of androgen receptors in axons is sexually differentiated and hormonally regulated. Sex differences in a broad range of mental and neurological disorders suggest that androgens are in some cases protective and in others deleterious. Thus, understanding the mechanisms of action of androgens may provide an essential key to understanding and exploiting the cellular and global impact of endogenous and exogenous androgenic ligands on the healthy and diseased nervous system in both men and women.