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: 10623346
• 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/10623346
• 关键词: Address; Androgen Receptor; Androgens; Animal Model; Animals; Behavior; Behavior Control; Behavioral; Brain; Brain imaging; CRISPR/Cas technology; Cells; Cichlids; Complex; Data; Evolution; Exhibits; Female; 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。大脑是类固醇动作的主要部位。但是，我们的 了解类固醇训练在调节大脑中基因表达和神经可塑性中的作用 它的婴儿期。解散类固醇激素在脑功能上的作用是一个挑战，因为它们 广泛影响生理和行为，使得很难表征直接和间接影响。 那样，希望使用大脑激素调节动物模型的研究人员应具有 能够分别研究类固醇激素的身体和行为影响。我的研究计划 旨在发现立体激素，大脑中的基因表达与神经可塑性之间的联系 使用Astatotilapia Burtoni，这是一种表现出复杂的社会动态的丽鱼科鱼。像在野外一样 实验室，男性A. Burtoni沿着社会等级制度分层 积极地捍卫一个领土，并与女性交配，而非主导男性则没有。女性A. Burtoni做 不是形成社会等级制度，而是为交配机会而互相积极行事。社会等级 正处于不断变化的情况下，因为主导和非主导男性可以根据社会环境改变自己的地位。这些 复杂的社交互动与称为雄激素的类固醇激素的水平紧密相关。我的 研究计划将利用实验室中的A. Burtoni的社会动态来发现 在控制大脑和神经塑性基因的雄激素中。我们将使用替代解决这些问题 - 边缘技术，例如单细胞基因组学，全脑成像和丰富的社会行为范式。为了 这些实验，我使用CRISPR/CAS9基因编辑技术来遗传删除不同的雄激素 A. Burtoni的受体（ARS）。这些突变的burtoni缺乏ARα，ARβ或两者的功能基因。调查结果 这些突变体揭示了ARα和ARβ是社会的不同生理和行为方面所必需的 地位，使其非常适合拟议的项目。例如，ARα突变雄性不执行主导性 社交行为，但具有较大的测试和明亮的色彩，而ARβ突变男性则表现出色 行为，但具有小的测试和单调的色彩。两种受体的雄性突变体都缺乏所有这些特征 并实际上执行女性典型行为。由于现有的其他实验室都没有这些 突变体，我的研究计划具有很高的创新性，并且是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，从而产生有关类固醇作用的新结果 控制基本大脑和行为功能的骑马。来自Ar突变A的基础数据。 伯顿，我们将能够解决有关大脑荷尔蒙控制和 社会行为。确实，这些问题可能与社会控制的人自然联系 其他物种（例如人类）的行为以及社会系统如何在整个进化中出现。