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.

项目摘要 人类和其他动物的类固醇激素协调生理和行为过程， 对社会环境的最佳反应。大脑是类固醇激素作用的主要场所;然而，我们的 类固醇激素在调节基因表达和大脑神经可塑性中的作用的知识， 它的婴儿期。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，使得难以描述直接与间接影响。 因此，希望使用大脑激素调节的动物模型的研究人员应该具有 能够分别研究类固醇激素的生理和行为效应。我的研究项目 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 使用的是博氏Astatotilapia burtoni，一种具有复杂社会动态的慈鲷。在野外， 实验室，雄性A. burtoni沿着一个社会等级划分，在这个等级中，占统治地位的雄性拥有鲜艳的色彩， 侵略性地捍卫领土，并与女性交配，而非占主导地位的男性不会。雌性A.布尔托尼杜 不形成社会等级，而是为了交配机会而相互攻击。社会地位 处于支配地位和非支配地位的男性可以根据社会环境改变其地位。这些 复杂的社会交往与一种叫做雄激素的类固醇激素水平密切相关。我 研究计划将利用A. burtoni在实验室中发现的作用 雄激素在控制大脑基因和神经可塑性方面的作用。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边缘技术。为 在这些实验中，我使用了CRISPR/Cas9基因编辑技术， 受体（ARs）。burtoni。这些突变体A. burtoni缺乏ARα、ARβ或两者的功能基因。表现 这些突变体揭示了ARα和ARβ是社会性行为的不同生理和行为方面所必需的。 使其成为拟议项目的理想选择。例如，ARα突变型男性不表现显性， 社会行为，但有大睾丸和明亮的颜色，而ARβ突变的男性进行主导的社会 行为，但拥有小睾丸和单调的颜色。两种受体的雄性突变体都缺乏所有这些特征 并做出女性特有的行为。由于没有其他实验室拥有这些AR 突变体，我的研究计划是高度创新的，并在解决这些问题的独特地位。 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。 激素调节基本的大脑和行为功能。与AR突变体A的基础数据。 burtoni，我们将能够解决有关大脑激素控制的基本问题， 社会行为事实上，这些问题可能会自然地与那些对社会荷尔蒙控制的问题联系起来。 其他物种的行为，如人类，以及社会系统如何在进化过程中出现。