Dissecting hormonal & neural control of social behavior in a transgenic cichlid

剖析荷尔蒙

• 批准号: 8471549
• 负责人: Scott Alan Juntti
• 金额: $ 5.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-07 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471549
• 关键词: Ablation; Address; Adult; African; Aggressive behavior; Androgens; Animal Model; Animals; Behavior; Behavior Control; Behavioral; Biological Models; Blood Circulation; Brain; Cell Culture Techniques; Cells; Cichlids; Complex; Controlled Study; Data; Delayed Puberty; Development; Disease; Dissection; Endocrine; Environment; Estrogens; Exhibits; Fertility; Fishes; Follicle Stimulating Hormone; Gene Transfer Techniques; Genetic; Genetic Transcription; Genome; Gonadal Hormones; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropin-Releasing Hormone Receptor; Gonadotropins; Hormonal; Hormones; Human; Hypothalamic structure; Immediate-Early Genes; Individual; Infertility; Luteinizing Hormone; Menopause; Molecular Genetics; Nervous system structure; Neurons; Neuropeptides; Nitroreductases; Output; Partner in relationship; Patients; Perception; Phenotype; Pituitary Gland; Play; Premature Menopause; Process; Production; Puberty; Regulation; Regulatory Element; Relative (related person); Reproductive Behavior; Role; Signal Transduction; Site; Social Behavior; Source; System; Testing; Testis; Testosterone; Transgenes; Transgenic Animals; Transgenic Organisms; Vertebrates; basal forebrain; base; controlled release; exhibitions; feeding; hypothalamic pituitary gonadal axis; insight; male; mature animal; neural circuit; neuromechanism; neuronal cell body; neuroregulation; promoter; receptor binding; relating to nervous system; reproductive; research study; response; sensory integration; steroid hormone; tool; transgene expression

Throughout the animal kindgdom, territorial and reproductive behaviors are often innate, indicating that their underlying neural substrates are genetically hardwired. Among vertebrates, many of these behaviors are controlled by the steroid hormone testosterone and its metabolites. Exposure of developing and adult brains to testosterone results in the masculinization of behavior, and in males of most species testosterone (or a metabolite) is necessary for the elicitation of mating and aggressive behavior as adults. The production of gonadal steroids such as testosterone is controlled by neurons of the hypothalamus expressing the neuropeptide gonadotropin releasing hormone (GnRH1). Some of these neurons project to the pituitary, where they control the release of the gonadotropins luteinizing hormone and follicle stimulating hormone into the bloodstream. These hormones bind receptors in the testes, stimulating the production of testosterone. Another subset of GnRH1 neurons project elsewhere in the brain, but the functional relevance of these neurons has not been tested. GnRH1 neurons exhibit dynamic cellular, electrophysiological, and gene transcription correlates of reproductive and territorial behaviors, making them candidate neurons to regulate behavioral outputs. To manipulate GnRH1 neurons, I will transgenically modify a cichlid fish, Astatotilapia burtoni, to express nitroreductase specifically in these cells, enabling their ablation in a temporally controlled manner. Experiments utilizing these fish in this proposal will directly test the function of GnRH1 neurons for behavior in transgenic adult A. burtoni. Further, comparison of the behavioral effects of hormone manipulation to GnRH1 neuron ablation will reveal the relative contributions of GnRH1 neurons to reproductive and territorial behavior via hormone synthesis versus direct connections to the neural circuits that generate these behaviors. This transgenic animal model in which GnRH1 neurons can be conditionally ablated in adult fish will provide a system to understand how these neurons contribute to behavior, and may provide insight into their regulation of fertility, puberty, and menopause.

在整个动物阶层中，领土和生殖行为通常是先天的，表明其潜在的神经底物是遗传上的。在脊椎动物中，其中许多行为都由类固醇激素睾丸激素及其代谢产物控制。发育和成年大脑暴露于睾丸激素中会导致行为的男性化，而在大多数物种的男性中，睾丸激素（或代谢产物）对于成年人的交配和侵略性行为是必要的。性腺类固醇（如睾丸激素）的产生由表达神经肽促性腺激素释放激素的下丘脑神经元控制。这些神经元中的一些向垂体投射，在那里他们控制了促性腺激素的释放，使激素和卵泡刺激激素刺激到血液中。这些激素在睾丸中结合受体，刺激睾丸激素的产生。 GNRH1神经元在大脑中其他地方项目的另一个子集，但是这些神经元的功能相关性尚未进行测试。 GNRH1神经元表现出动态细胞，电生理和基因转录相关性的生殖和领土行为，使其成为候选神经元以调节行为输出。为了操纵GNRH1神经元，我将跨基因修饰酸毛虫的鱼类，astatotilapia burtoni，以特别表达这些细胞中的硝化化酶，以时间控制的方式使其消融。在该提案中利用这些鱼类的实验将直接测试GNRH1神经元的功能，以在转基因成人burtoni中进行行为。此外，比较激素操纵与GNRH1神经元消融的行为效应将揭示GNRH1神经元通过激素合成对生殖和领土行为的相对贡献，以及与产生这些行为的神经回路的直接连接。这种转基因动物模型可以在成年鱼类中有条件地融入GNRH1神经元，将提供一个系统，以了解这些神经元如何促进行为，并可以洞悉其对生育能力，青春期和更年期的调节。