Sexual Differentiation of the Brain and Behaviour: Central and Peripheral Targets of Androgens

我的研究项目的首要重点是确定神经发育和行为中个体差异的潜在机制。为了做到这一点，我的研究项目集中在哺乳动物中最保守的个体差异——性别差异。拟议中的研究将评估激素在哪里起作用，以及在确定的作用部位内激素的作用如何影响大脑中“社会-性”回路的发育。这项工作源于这样一种假设，即社会性行为是由多种神经和非神经组织中的激素作用介导的，每一种组织在形成构成性别典型行为基础的神经回路中都有不同的作用。我的实验室的短期目标是确定大脑和身体中哪些地方的激素会影响性别典型行为，并研究大脑中已建立的回路中区域之间的相互作用（例如，评估一个大脑区域的性别分化如何影响同一回路中其他区域的发育）。为了做到这一点，我们将从一个小鼠模型开始，由于雄激素受体（AR）的突变，整个大脑和身体对雄激素（如睾酮）不敏感——睾丸雌性化突变（Tfm）小鼠。这些携带XY染色体的男性在身体、大脑和行为上表现为典型的女性。然后，我们将使用Cre-loxP转基因系统，在Tfm小鼠的“社会-性”神经通路中，在选择的结构中恢复功能性AR。具体来说，我们将Tfm小鼠与具有被Cre激活的AR转基因的小鼠杂交；不同的小鼠Cre系将只在大脑的目标区域以及与社会性行为相关的候选外周目标（例如犁鼻器官和生殖器）驱动AR表达。我们创建的小鼠模型将在目标区域（即，雄性典型）相对于动物的所有其他方面（即，其他身体和神经区域将保持雌性典型）的性别反转。目的1将通过在完全没有AR的小鼠模型（即Tfm小鼠）中单独或整体恢复功能AR到神经组织中，来描述AR在神经组织与非神经组织中对社会性行为的充分性。目标2将确定选定的神经区域中的雄激素作用如何影响目标区域本身的发育，以及整个“社会-性”神经回路和行为。目标3将评估AR在大脑周围的选定组织（即生殖器和VNO）中的作用，以促进“社会-性”神经回路和行为的发展。总之，拟议的研究将表明激素在哪里以及如何调节大脑和行为的性别分化。虽然拟议的研究将集中在一个给定的神经回路上，但它可以作为一个很好的原型，促进我们对大脑和行为个体差异出现的机制的理解。

The overarching focus of my research program is identifying the mechanisms underlying individual differences in neural development and behaviour. To do this, my research program focuses on the most well-conserved individual differences among mammals - sex differences. The proposed research will evaluate where hormones are acting and how hormone action within identified sites of action influence the development of the `socio-sexual' circuit in the brain. This work stems from the hypothesis that socio-sexual behaviours are mediated by hormone action in multiple neural and non-neural tissues, each having a distinct role in shaping the neural circuitry that underlies sex-typical behaviours.  The short-term goals of my lab are to identify where in the brain and body hormones act to affect sex-typical behaviours, and investigate the interaction between regions within an established circuit in the brain (e.g., evaluate how the sexual differentiation of one brain region affects the development of other regions within the same circuit). To do so, we will begin with a mouse model that is insensitive to androgens, like testosterone, throughout the brain and body due to a mutation in the androgen receptor (AR) - the testicular feminization mutation (Tfm) mouse. These XY chromosomal males present as female-typical in their body, brain and behaviour. We will then restore functional AR in select structures along the "socio-sexual" neural pathway in Tfm mice using the Cre-loxP transgenic system. Specifically, we will cross Tfm mice with mice that have an AR transgene activated by Cre; distinct mouse Cre lines will drive AR expression exclusively in target regions in the brain as well as candidate peripheral targets associated with socio-sexual behaviours (e.g., vomeronasal organ and genitalia). The mouse models we create will be sex-reversed in the targeted region (i.e., male-typical) relative to all other aspects of the animal (i.e., other body and neural regions will remain female-typical). Aim 1 will delineate the sufficiency of AR in neural vs non-neural tissue for socio-sexual behaviour by restoring functional AR to either neural tissue alone or globally in a mouse model completely null for AR (i.e., Tfm mice). Aim 2 will identify how androgen action in selected neural regions affect the development of the target region itself, as well as the entirety of the `socio-sexual' neural circuitry and behaviour. Aim 3 will assess the role of AR in selected tissues peripheral to the brain (i.e., genitalia and VNO) for the development of the `socio-sexual' neural circuitry and behaviours. Together, the proposed research will indicate where and how hormones act to mediate the sexual differentiation of brain and behaviour. While the proposed research will focus on a given neural circuit, it serves as an excellent prototype for advancing our understanding of the mechanisms involved in the emergence of individual differences in brain and behaviour.