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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709904
• 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.

性是生物学的一个基本特征，它对几乎所有物种的重要性都反映在通过性选择进化而来的惊人的解剖学、生理学和行为学性别差异上。在我们自己的物种中，第二性征对我们的心理和社会认同有着巨大的影响。几乎所有的细胞和器官系统都存在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已经被广泛讨论，但很少有科学研究这个话题。 在实验室啮齿动物中存在与人类相似的性别差异，这为研究哺乳动物大脑和行为的性别分化机制提供了有力的机会。在小鼠和大鼠中，在整个生命周期中睾丸激素的性别典型产生在很大程度上解释了神经解剖学和行为的性二态性（即极化的性别差异）。然而，这种优雅而看似简单的内分泌信号控制着性分化，但事实证明，它在机制上是相当复杂的，我们对睾丸激素如何甚至在哪里在神经系统和行为中产生性二型性的理解也很有限。 我们一直在使用突变的小鼠，允许选择性表达编码睾酮受体（雄激素受体或Ar）的基因，以深入了解雄激素在神经解剖学和行为中产生性别差异的作用部位。我们一直专注于神经和非神经Ar的下丘脑和社会性行为的性分化的相对贡献。我们发现，全球而不是神经过度表达的男性化交配行为，可能通过对生殖器的行动。同样，全球性的，但不是神经过度的Ar干扰男性典型的性行为，可能是由于外周赤字的嗅觉性线索的感觉。相反，无论是神经和全球过度表达的Ar干扰男性典型的侵略性反应，也masculinizes的结构的性二形核的视前区（SDN-POA）的女性。 我们现在建议使用这些条件性Ar过表达小鼠，以及条件性Ar功能丧失小鼠，以进一步定位睾酮在神经解剖学和社会性行为的性分化中的作用位点。为此，我们将使用组织特异性遗传驱动因素以及我的实验室开发的方法，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成部分在神经结构和行为方面产生性别差异的作用。