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

大脑和行为的性别分化：雄激素的中枢和外周目标

• 批准号: RGPIN-2019-04999
• 负责人: SwiftGallant, Ashlyn
• 金额: $ 2.4万
• 依托单位: Memorial University of Newfoundland
• 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=715315
• 关键词: Sexual; Differentiation; Brain; Behaviour; Central

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.

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。这项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。