Muscarinic regulation of plasticity in the brain

描述（由申请人提供）：本项目旨在阐明将经验转化为大脑结构变化的机制，从而使成年动物提高其行为表现。我们的模型系统是蜜蜂体内蘑菇体（昆虫学习和记忆的大脑中心）的觅食诱导生长，允许在行为、细胞和分子水平上进行研究。我们的建议是基于一个令人惊讶但有力的证明，即用一种毒蕈碱激动剂——匹罗卡品治疗关在笼子里的蜜蜂，其大脑可塑性与一周的真实觅食经历所产生的大脑可塑性相同。我们将：1；利用一种新的经验替代技术，确定通过胆碱能途径的信号如何与觅食诱导的蘑菇体神经细胞体积增加有关；2. 利用高尔基技术测定匹罗卡品诱导的蘑菇体神经元（Kenyon细胞）变化的细胞表型；和3。利用全蜜蜂基因组微阵列鉴定蘑菇体中对毒蕈碱信号通路响应的基因表达，然后用定量RT-PCR和原位杂交证实和扩展这些结果。蜜蜂为这些研究提供了一个极好的模型系统，因为合适的工具，如基因组测序，现在是可用的，因为有可能在自然条件下严格地操纵蜜蜂的经验，并在神经解剖学和分子水平上研究影响。这项研究的主要意义在于它揭示了经验是如何与大脑的可塑性相关联的。在动物王国中，神经系统功能在分子水平上的广泛保护使得我们对一种昆虫的研究结果在行为发育领域广泛适用。这项研究与公共卫生有关，因为可以利用更简单的昆虫神经系统进行有效的实验，可能会揭示学习如何改变包括人类在内的所有动物的大脑。这样的理解是开发治疗方法以提高脑损伤后人类学习能力的第一步。我们的研究结果也将为治疗伴随人类衰老的心理功能衰退提供方向。

DESCRIPTION (provided by applicant): This project is designed to elucidate mechanisms that translate experience into changes in brain structure that allow adult animals to enhance their behavioral performance. Our model system, foraging-induced growth of the mushoom bodies (insect brain center for learning and memory) in the honey bee, permits investigations at the behavioral, cellular, and molecular levels. Our proposal is based on the surprising, but robust, demonstration that treatment of caged bees with a muscarinic agonist, pilocarpine, results in brain plasticity identical to that produced by a week of real foraging experience. We will: 1. determine how signaling via cholinergic pathways is related to foraging-induced increases in the volume of mushroom body neuropil using a novel experience-replacement technique; 2. determine the cellular phenotype of pilocarpine-induced changes in mushroom body neurons (Kenyon cells) using the Golgi technique; and 3. identify genes expressed in the mushroom bodies responsive to signaling via muscarinic pathways using whole bee genome microarrays, and then confirm and extend these results with quantitative RT-PCR and in situ hybridization. The bee provides a superb model system for these studies because appropriate tools, such as a sequenced genome, are now available, and because it is possible to rigorously manipulate the experience of the bee under naturalistic conditions and study effects at the neuroanatomical and molecular levels. The principal significance of this research is that it will reveal how experience is coupled to brain plasticity. Extensive conservation of nervous system function at the molecular level across the animal kingdom makes the results of our investigations on an insect broadly applicable within the field of behavioral development. This research is relevant to public health because experiments that can be efficiently performed using the simpler insect nervous system are likely to reveal how learning changes the brain in all animals, including humans. Such understanding is the first step in the development of therapies to improve human learning after brain damage. Our results will also suggest directions for the development of treatments for the decline in mental function that accompanies human aging.