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

剖析荷尔蒙

• 批准号: 8616086
• 负责人: Scott Alan Juntti
• 金额: $ 5.51万
• 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/8616086
• 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.

在整个动物群落中，领地和生殖行为通常是与生俱来的，这表明它们潜在的神经基础是遗传上的硬连接。在脊椎动物中，这些行为中的许多都是由类固醇激素睾酮及其代谢产物控制的。将发育中的和成年的大脑暴露在睾丸素下会导致行为的男性化，在大多数物种的雄性中，睾酮(或代谢物)是成年后引发交配和攻击行为所必需的。性腺类固醇的产生，如睾酮，由表达神经肽促性腺激素释放激素(GnRH1)的下丘脑神经元控制。其中一些神经元投射到脑下垂体，在那里它们控制促性腺激素、黄体生成素和卵泡刺激素释放到血液中。这些激素与睾丸中的受体结合，刺激睾丸素的产生。GnRH1神经元的另一个子集投射到大脑的其他地方，但这些神经元的功能相关性尚未得到测试。GnRH1神经元表现出动态的细胞、电生理和基因转录与生殖和区域行为的相关性，使它们成为调节行为输出的候选神经元。为了操纵GnRH1神经元，我将转基因修改一种叫Astatotilapia burtoni的慈鱼，使其在这些细胞中特异性地表达硝酸还原酶，从而能够以一种时间可控的方式消融它们。在这项提议中利用这些FISH的实验将直接测试GnRH1神经元在转基因成年伯顿艾美耳球虫中的行为功能。此外，比较激素操作和GnRH1神经元消融对行为的影响，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，而不是直接连接到产生这些行为的神经回路。在这种转基因动物模型中，GnRH1神经元可以在成年鱼中有条件地消融，这将提供一个系统来了解这些神经元如何对行为做出贡献，并可能为它们对生育、青春期和更年期的调节提供洞察力。