Testosterone action in the sexual differentiation of the mammalian nervous system and behaviour

睾酮在哺乳动物神经系统和行为的性别分化中的作用

• 批准号: RGPIN-2016-06302
• 负责人: Monks, Douglas
• 金额: $ 2.04万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=660082
• 关键词: Testosterone; action; sexual; differentiation; mammalian

Sex is a fundamental feature of biology, and its great importance for virtually all species is reflected by striking anatomical, physiological and behavioural sex differences that have evolved through sexual selection. In our own species, secondary sexual characteristics have enormous influence on our psychology and social identity. Less obvious but equally dramatic sex differences exist in virtually all cells and organ systems. The role of these biological sex differences in shaping gender in humans has been debated extensively, but there is little scientific study of this topic.******Sex differences homologous to those seen in humans exist in laboratory rodents, providing a powerful opportunity to study the mechanisms that govern sexual differentiation of the mammalian brain and behaviour. In mice and rats, sex-typical production of testosterone through the lifespan largely accounts for neuroanatomical and behavioural sexual dimorphisms (i.e. polarized sex differences). This elegant and apparently simple endocrine signal governing sexual differentiation has nonetheless proven to be quite complex mechanistically and we have only a limited understanding of how or even where testosterone acts to produce sexual dimorphisms in the nervous system and behaviour. ***We have been using mice with mutations that allow for selective expression of the gene which codes for receptors for testosterone (androgen receptor or Ar) to gain insight into the site of androgen action in producing sex differences in neuroanatomy and behavior. We have been focusing on relative contributions of neural and non-neural Ar in the sexual differentiation of the hypothalamus and sociosexual behaviour. We find that global but not neural overexpression of masculinizes copulatory behaviour, likely via actions on genitals. Similarly, global but not neural overexpression of Ar interferes with male typical sexual behaviour, likely due to a peripheral deficit in sensation of olfactory sexual cues. Conversely, both neural and global overexpression of Ar interferes with male typical aggressive responses and also masculinizes the structure of the sexually dimorphic nucleus of the preoptic area (SDN-POA) in females.*********We now propose to use these conditional Ar overexpression mice, as well as conditional loss of Ar function mice to further localize testosterone's site of action in sexual differentiation of neuroanatomy and sociosexual behaviour. To do so, we will use tissue-specific genetic drivers as well as a method developed by my lab to activate conditional mutations in a spatially restricted manner. These studies will focus on the roles of the genitals as well as peripheral and central components of the olfactory system in producing sex differences in neural structure and behaviour.**

性别是生物学的一个基本特征，它对几乎所有物种的重要性都体现在通过性别选择进化而来的显著的解剖、生理和行为性别差异上。在我们自己的物种中，第二性特征对我们的心理和社会认同有巨大的影响。在几乎所有的细胞和器官系统中都存在着不那么明显但同样显著的性别差异。这些生物性别差异在塑造人类性别中的作用一直被广泛争论，但关于这个话题的科学研究很少。*实验室啮齿动物中存在着与人类相同的性别差异，这为研究哺乳动物大脑和行为的性别分化机制提供了一个强大的机会。在小鼠和大鼠中，性生活中典型的睾丸素的产生在很大程度上解释了神经解剖学和行为性二型性(即两极分化的性别差异)。尽管如此，这种优雅而看似简单的内分泌信号控制着性别分化，但事实证明，从机制上讲，这是相当复杂的，我们对睾丸激素如何甚至在哪里产生神经系统和行为中的性别二型性只有有限的了解。*我们一直在使用突变小鼠，这种突变允许编码睾酮受体(雄激素受体或AR)的基因的选择性表达，以深入了解雄激素在神经解剖和行为方面产生性别差异的作用部位。我们一直关注神经性和非神经性AR在下丘脑性分化和社会性行为中的相对作用。我们发现，全局的而不是神经性的过度表达使交配行为男性化，可能是通过对生殖器的作用。同样，AR的全局而非神经过度表达会干扰男性典型的性行为，这可能是由于外周对嗅觉性暗示的感觉不足所致。相反，神经和全局AR的过度表达都干扰了男性典型的攻击性反应，并使女性视前区的性二形核(SDN-POA)的结构男性化。我们现在建议使用这些条件性AR过度表达的小鼠，以及条件性AR功能丧失的小鼠来进一步定位睾酮在神经解剖和社会性行为的性别分化中的作用部位。为了做到这一点，我们将使用组织特定的遗传驱动因素以及我的实验室开发的一种方法，以空间受限的方式激活条件突变。这些研究将集中在生殖器以及嗅觉系统的外围和中央组件在神经结构和行为方面产生性别差异方面的作用。