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

在整个动物王国中，领土行为和繁殖行为通常是天生的，这表明它们潜在的神经基质是遗传的。在脊椎动物中，许多这些行为是由类固醇激素睾丸激素及其代谢物控制的。发育中的和成年的大脑暴露于睾丸激素会导致行为的男性化，在大多数物种的雄性中，睾丸激素（或一种代谢物）对于成年后的交配和攻击行为的激发是必要的。性腺类固醇如睾酮的产生受下丘脑神经元表达神经肽促性腺激素释放激素（GnRH1）的控制。其中一些神经元投射到脑垂体，在那里它们控制促性腺激素、促黄体生成素和促卵泡激素释放到血液中。这些激素与睾丸中的受体结合，刺激睾丸激素的产生。GnRH1神经元的另一个子集分布在大脑的其他地方，但这些神经元的功能相关性尚未得到测试。GnRH1神经元表现出与生殖和领土行为相关的动态细胞、电生理和基因转录，使其成为调节行为输出的候选神经元。为了操纵GnRH1神经元，我将对一种鱼进行转基因修饰，使其在这些细胞中特异性表达硝基还原酶，使其以一种暂时可控的方式消融。本研究利用这些鱼进行的实验将直接测试GnRH1神经元对转基因成年白腹棘虫行为的影响。此外，比较激素操纵与GnRH1神经元消融的行为影响将揭示GnRH1神经元通过激素合成与直接连接产生这些行为的神经回路对生殖和领土行为的相对贡献。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切除，这将为了解这些神经元如何影响行为提供一个系统，并可能为它们对生育、青春期和更年期的调节提供见解。

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.