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

哺乳动物神经系统的结构和功能存在许多性别差异。实验室啮齿动物的神经系统和行为中也发现了与人类相似的性别差异，这为从实验上研究导致性别差异的过程提供了机会。在啮齿动物神经系统中发现的许多性别差异中，只有一个具有明确的功能，并且已经得到了充分的研究，以至于我们有一个明确的模型来解释它的性别分化。球海绵体脊束核(SNB)是一种调控性反射的神经肌肉系统，在揭示普遍适用于神经系统的性别分化一般原则方面非常成功。 我的实验室一直在积极制造新的突变动物，使我们能够让SNB中的一些细胞(例如神经元或肌肉)制造睾丸激素的功能性受体，而其他细胞则制造非功能性的受体。我们用这些小鼠和大鼠来证明，关于睾丸激素在发育中的SNB作用于哪些细胞的假设是不正确的。我们现在建议确定在发育中的SNB中哪些细胞正常地具有睾酮受体，并对这些受体在SNB的性别分化中的功能进行测试。我们还将使用我的实验室培育的突变小鼠来检查改变成年动物肌肉细胞或神经元制造的AR数量的神经解剖学和行为后果。这些研究将使我们能够评估这些细胞中的成年睾酮受体在确定SNB的结构和功能中的作用。这些研究的结果应该提供一个明确的答案，即睾丸激素在拯救SNB系统和维持其成年功能方面的主要细胞靶点。这反过来将为我们提供一个神经系统结构和功能的性别差异的例子，我们可以从荷尔蒙和细胞水平上解释这一差异。

There are many sex differences in the structure and function of the mammalian nervous system. Sex differences homologous to those in humans are also found in the nervous system and behaviour of laboratory rodents, providing an opportunity to study experimentally the processes that result in sex differences. Of the many sex differences identified in the rodent nervous system, only one has an unambiguous function and has been studied sufficiently that we have a clear model to explain its sexual differentiation. The spinal nucleus of the bulbocavernosus (SNB) is a neuromuscular system mediating sexual reflexes and has been exceptionally successful in uncovering general principles of sexual differentiation that are thought to apply generally to the nervous system. My lab has been active in making new mutant animals that allow us to have some cells in the SNB (e.g. neurons or muscles) make functional receptors for testosterone, and others which make non-functional receptors. We have used these mice and rats to show that the assumptions concerning which cells testosterone acts on in the developing SNB are incorrect. We now propose to determine which cells in the developing SNB normally have receptors for testosterone and to perform tests of the function of these receptors in the sexual differentiation of the SNB. We will also use mutant mice developed in my laboratory to examine the neuroanatomical and behavioral consequences of altering the amount of AR made by muscle cells or neurons in adult animals. These studies will allow us to evaluate the role of adult testosterone receptors in these cells in determining the structure and function of the SNB. The results of these studies should provide a clear answer concerning the primary cellular targets of testosterone in rescuing the SNB system and maintaining its function in adulthood. This in turn will provide us with an example of a sex differences in the structure and function of the nervous system which we can explain at the hormonal and cellular level.