Steroid hormone dependent gene expression and neuroplasticity in the brain

类固醇激素依赖性基因表达和大脑中的神经可塑性

• 批准号: 10455610
• 负责人: Beau Alward
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10455610
• 关键词: Address; Androgen Receptor; Androgens; Animal Model; Animals; Behavior; Behavior Control; Behavioral; Behavioral Mechanisms; Brain; Brain imaging; CRISPR/Cas technology; Cells; Cichlids; Color; Complex; Data; Evolution; Exhibits; Female; Foundations; Gene Expression; Genes; Genetic; Genomics; Hormonal; Human; Knowledge; Laboratories; Link; Neuronal Plasticity; Neurons; Organism; Partner in relationship; Physiological; Physiology; Positioning Attribute; Process; Research; Research Personnel; Role; Site; Social Behavior; Social Controls; Social Environment; Social Hierarchy; Social Interaction; Social status; System; Techniques; Technology; Testis; Testosterone; Vertebrates; Work; experimental study; infancy; innovation; male; mind control; mutant; neurobiological mechanism; novel; programs; receptor; response; social; steroid hormone; trait

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.

项目概要 人类和其他动物的类固醇激素协调生理和行为过程 然而，大脑是类固醇激素作用的主要部位； 关于类固醇激素在调节大脑基因表达和神经可塑性中的作用的知识是 解开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，因此很难描述直接影响和间接影响。 因此，希望使用大脑激素调节动物模型的研究人员应该具备以下能力： 能够分别研究类固醇激素的生理和行为影响。 旨在揭示类固醇激素、大脑基因表达和神经可塑性之间的联系 使用Astatotilapia burtoni，一种慈鲷鱼，在野外和在野外都表现出复杂的社会动态。 实验室中，雄性A. burtoni沿着社会等级分层，其中占主导地位的雄性拥有明亮的颜色， 积极地保卫领地，并与雌性交配，而非优势雄性则不会这样做。 不形成社会等级，但为了交配机会而相互攻击。 处于不断变化的状态，因为占主导地位的男性和非占主导地位的男性可以根据社会环境改变自己的地位。 复杂的社交互动与一类称为雄激素的类固醇激素的水平密切相关。 研究计划将利用实验室中 A. burtoni 的社会动态来发现 雄激素控制大脑基因和神经可塑性我们将通过切割来解决这些问题。 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。 在这些实验中，我使用了 CRISPR/Cas9 基因编辑技术从基因上删除了不同的雄激素 A. burtoni 中的受体 (AR)。这些突变体 A. burtoni 缺乏 ARα、ARβ 或两者的功能基因。 这些突变体揭示了 ARα 和 ARβ 是社交的不同生理和行为方面所必需的 地位，使它们成为拟议项目的理想选择，例如，ARα突变雄性不表现出优势。 社会行为，但有大量的测试和明亮的颜色，而 ARβ 突变雄性表现出主导的社会行为 两种受体的雄性突变体都缺乏所有这些特征。 并且实际上表现出女性典型的行为，因为没有其他实验室拥有这些 AR。 突变体，我的研究项目具有高度创新性，并且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中进行，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激素利用来自 AR 突变体 A 的基础数据。 伯托尼，我们将能够解决有关大脑荷尔蒙控制的基本问题 事实上，这些问题可能与社会荷尔蒙控制问题自然相关。 其他物种（例如人类）的行为以及社会系统在进化过程中如何出现。