Steroid hormone dependent gene expression and neuroplasticity in the brain

项目总结 人类和其他动物中的类固醇激素协调潜在的生理和行为过程 对社会环境的最佳反应。大脑是类固醇激素作用的主要部位；然而，我们的 关于类固醇激素在大脑中调节基因表达和神经可塑性的作用的知识在 它还处于初级阶段。要弄清类固醇激素对大脑功能的作用一直是一个挑战，因为它们 广泛影响生理和行为，因此很难区分直接影响和间接影响。 因此，希望使用荷尔蒙调节大脑的动物模型的研究人员应该拥有 能够分别研究类固醇激素的生理和行为影响。我的研究计划 旨在揭示类固醇激素、大脑中的基因表达和神经可塑性之间的联系 以伯顿拟罗非鱼为例，这是一种显示出复杂的社会动态的慈鱼科鱼类。在野外，就像在 实验室里，雄性伯顿亚种沿着社会等级分层，其中占主导地位的雄性具有鲜艳的色彩， 进攻性地保卫领地，并与雌性交配，而非优势雄性则不这样做。雌性白纹伊蚊 不是形成一个社会等级，而是为了交配机会而对彼此表现得咄咄逼人。社会等级 处于变化中，因为主导和非主导的男性可以根据社会环境改变他们的地位。这些 复杂的社会互动与一种名为雄激素的类固醇激素水平密切相关。我的 研究计划将利用A.burtoni在实验室的社会动态来发现 雄激素在控制大脑基因和神经可塑性中的作用。我们将通过削减来解决这些问题- 单细胞基因组学、全脑成像和丰富的社会行为范式等前沿技术。为 在这些实验中，我使用了CRISPR/Cas9基因编辑技术来从基因上删除不同的雄激素 伯顿沙门氏菌中的受体(AR)。这些突变体缺乏ARα和/或ARβ的功能基因。中的发现 这些突变体揭示了ARα和ARβ是社会生活中不同的生理和行为方面所必需的 状态，使其成为拟议项目的理想之选。例如，ARα突变的雄性不表现为显性 社会行为，但有较大的睾丸和鲜艳的颜色，而ARβ突变的雄性表现出主导的社会行为 行为但睾丸较小，颜色单调。这两种受体突变的雄性缺乏所有这些特征 并实际执行女性典型的行为。因为现有的任何实验室都没有这些AR 突变者，我的研究项目具有很高的创新性，在解决这些问题方面处于独特的地位。 这些实验将在男性和女性身上进行，产生关于类固醇作用的新结果 调节基本大脑和行为功能的荷尔蒙。用AR突变体A. Burtoni，我们将能够解决有关大脑荷尔蒙控制和 社交行为。事实上，这些问题可能会自然而然地与那些关于社会中荷尔蒙控制的问题联系在一起。 人类等其他物种的行为以及社会制度在整个进化过程中是如何出现的。

PROJECT SUMMARY Steroid hormones in humans and other animals coordinate physiological and behavioral processes underlying optimal responses to the social environment. The brain is a major site of steroid hormone action; however, our knowledge of the role of steroid hormones in regulating gene expression and neuroplasticity in the brain is in its infancy. It has been a challenge to disentangle the role of steroid hormones on brain function because they broadly influence physiology and behavior, making it difficult to characterize direct versus indirect effects. Thus, researchers wishing to use animal models of the hormonal modulation of the brain should have the ability to study separately the physiological and behavioral effects of steroid hormones. My research program aims to uncover the connections between steroid hormones, gene expression in the brain, and neuroplasticity using Astatotilapia burtoni, a cichlid fish that exhibits sophisticated social dynamics. In the wild as in the laboratory, male A. burtoni stratify along a social hierarchy where dominant males possess bright coloration, aggressively defend a territory, and mate with females, while non-dominant males do not. Female A. burtoni do not form a social hierarchy but behave aggressively towards one another for mating opportunities. Social rank is in flux, as dominant and non-dominant males can change their status depending on the social milieu. These complex social interactions are tightly linked to levels of a class of steroid hormones called androgens. My research program will leverage the social dynamics of A. burtoni in the laboratory to discover the role of androgens in controlling genes in the brain and neuroplasticity. We will tackle these questions using cutting- edge techniques such as single-cell genomics, whole-brain imaging, and rich social behavior paradigms. For these experiments, I have used CRISPR/Cas9 gene editing technology to genetically delete distinct androgen receptors (ARs) in A. burtoni. These mutant A. burtoni lack functional genes for ARα, ARβ, or both. Findings in these mutants reveal ARα and ARβ are required for distinct physiological and behavioral aspects of social status, making them ideal for the proposed projects. For example, ARα mutant males do not perform dominant social behaviors but have large testes and bright coloration, while ARβ mutant males perform dominant social behaviors but possess small testes and drab coloration. Males mutant for both receptors lack all of these traits and actually perform female-typical behaviors. As no other laboratory in existence possesses these AR mutants, my research program is highly innovative and in a unique position for addressing these questions. These experiments will be performed in both males and females, yielding novel results about the role of steroid hormones in regulating fundamental brain and behavioral functions. With foundational data from AR mutant A. burtoni, we will be able to address fundamental questions regarding the hormonal control of the brain and social behavior. Indeed, these questions may connect naturally to those on the hormonal control of social behavior in other species such as humans and how social systems emerge throughout evolution.