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

我的研究计划的首要重点是确定神经发育和行为的个体差异的机制。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。这项拟议中的研究将评估激素在哪里起作用，以及在已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展。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，每种组织在形成性典型行为的神经回路方面都有不同的作用。 我的实验室的短期目标是确定大脑和身体中激素作用于影响性典型行为的位置，并研究大脑中既定回路内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）。为此，我们将开始一个小鼠模型，这是不敏感的雄激素，如睾酮，整个大脑和身体，由于突变的雄激素受体（AR）-睾丸雌性化突变（Tfm）小鼠。这些XY染色体男性在身体、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小鼠中沿着沿着“社会性”神经通路的选择结构中恢复功能性AR。具体而言，我们将Tfm小鼠与具有由Cre激活的AR转基因的小鼠杂交;不同的小鼠Cre系将仅在大脑中的靶区域以及与社会性行为相关的候选外周靶点（例如，犁鼻器和生殖器）。我们创建的小鼠模型将在目标区域进行性别逆转（即，雄性典型的）相对于动物的所有其它方面（即，其他身体和神经区域将保持女性典型）。目的1将通过在小鼠模型中将功能性AR恢复到单独的神经组织或整体上对AR完全无效（即，Tfm小鼠）。目标2将确定雄激素在选定的神经区域的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。目的3将评估AR在脑外周的选定组织中的作用（即，生殖器和VNO）用于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.