Characterization of Sexual Dimorphism in the Brain

描述(申请人提供)：所有动物都有进化的行为，导致对外部世界的天生反应。这些反应通常可以在没有事先学习或经验的情况下观察到，这表明产生这些反应的神经回路是发育编程的。在小鼠中，性二型行为代表了一组受气味提示和性腺激素等内部调节因素控制的先天行为。性二型性行为是指两性之间在行为上的质或量上的差异，还有很多工作要做，以确定调节这些行为反应的神经回路的特征。两性之间这种与生俱来的行为差异是性别分化神经回路的结果。男性特有的行为需要睾酮及其受体--雄激素受体(AR)。我们和其他人观察到AR在终纹床核内的神经元池中表达的性别二型性。这项研究建议采用遗传学方法来表征这种AR+二态神经元亚群在小鼠性二态行为中的作用。 这个项目将检查AR+BNST神经元在交配和攻击过程中是否被激活，气味线索是否足以激活它们，以及是否利用犁鼻气味检测来传递这些气味线索。利用基因打靶技术，该项目检测了在成年动物体内消融BNST神经元的行为后果。最后，使用遗传策略，该项目将通过删除成年动物中的AR基因来检查AR在二态BNST中的功能。 人类AR功能的遗传性丧失表现为身体和行为的女性化(雄激素不敏感综合征)。在成年人中，抗雄激素治疗或低水平的睾酮可能与性欲和情绪健康的丧失有关。我们对BNST神经元中AR缺失的动物的研究，原则上应该有助于揭示神经元对睾丸激素信号缺失的反应。更广泛地说，我们的研究应该进一步加深我们对大脑离散区域如何将外部感觉线索与内部生理状态相结合以产生有意义的行为的理解。

DESCRIPTION (provided by applicant): All animals have evolved behaviors that result in innate responses to the external world. These responses can often be observed without prior learning or experience, suggesting that the neural circuits that generate them are developmentally programmed. In mice sexually dimorphic behaviors represent a set of innate behaviors that are controlled by odorant cues and by internal regulators such as gonadal hormones. Sexually dimorphic behaviors are qualitative or quantitative differences in behavior between the sexes, and much work remains to be done to characterize the neural circuits that mediates these behavioral responses. Such innate behavioral differences between the sexes result from sexually differentiated neural circuits. Testosterone and its receptor, the androgen receptor (AR), are required for male-specific behaviors. We and others observe sexual dimorphism in AR expression in a pool of neurons within the bed nucleus of the stria terminalis. This research proposal takes a genetic approach to characterize the role of this AR+ dimorphic subpopulation of neurons in sexually dimorphic behaviors in mice. This project will examine whether the AR+ BNST neurons are activated during mating and aggression, whether odorant cues are sufficient to activate them, and whether vomeronasal odorant detection is utilized to relay these odorant cues. Using gene targeting this project examines the behavioral consequences of ablating the dimorphic BNST neurons in the adult animal. Finally, using a genetic strategy this project will examine the function of AR in the dimorphic BNST by deleting the AR gene in the adult animal. An inherited loss of function of AR in humans manifests as physical and behavioral feminization (androgen insensitivity syndrome). In adult humans anti-androgen therapy or low levels of testosterone may be associated with a loss of libido and emotional well-being. Our examination of animals with a deletion of AR in BNST neurons should shed some light, in principle, on how neurons respond to a loss of testosterone signaling. More generally, our studies should further our understanding of how discrete brain regions integrate external sensory cues with internal physiological states to generate meaningful behavior.