Development of the basal telencephalic limbic system

描述（由申请人提供）：哺乳动物基底端脑边缘系统由参与复杂情绪和动机行为调节的许多结构组成。其中两个最突出的是丘脑核，它的功能是调节积极的奖励刺激，以及杏仁核，它调节情绪记忆的特定方面和对厌恶刺激的条件反应。本文提出的工作旨在了解这些结构中神经元细胞多样性的胚胎空间和时间起源（具体目标1和2）以及这些细胞的独特子集迁移到其最终目的地的机制（具体目标3）。考虑到杏仁核-杏仁核通路是药物滥用的主要靶点，了解这些结构正常发育的机制可能会深入了解这些区域受影响的疾病的病因。考虑到物质成瘾的经济和社会成本，确定调节这些关键大脑区域发育的生物程序是一个至关重要且在很大程度上尚未解决的挑战。此外，这些拟议中的研究将为随后的工作提供一个框架，旨在了解药物滥用如何影响杏仁核和杏仁核的正常发育，以及指导成瘾行为遗传小鼠模型的合理生成。具体目标1：超声引导子宫内移植对胚胎端脑四个不同祖细胞区系的命运定位（内侧、外侧、尾侧神经节隆起和皮质-纹状体边界），我们将检验这样一个假设，即这些区域中的每一个都在不同的时间为成熟的丘脑核和杏仁核贡献了一组独特的神经元亚型。在发展过程中。具体目标二：使用分子命运映射技术，我们将测试的假设，皮质纹状体边界是两个独立的祖细胞，将引起不同的抑制性神经元的子集，兴奋性神经元，在成熟的杏仁核和杏仁核的来源。具体目标3：使用体外和体内方法的组合，我们将测试的假设，即来自皮质-纹状体边界的祖细胞的两个不同的人口迁移到发展中的核丘脑和杏仁核通过差分链和径向迁移模式。

DESCRIPTION (provided by applicant): The mammalian basal telencephalic limbic system is comprised of a number of structures that are involved in the regulation of complex emotional and motivational behaviors. The two most prominent of these are the nucleus accumbens, which functions in the regulation of positive reward stimuli, and the amygdala, which regulates specific aspects of emotional memory and conditioned responses to aversive stimuli. The work proposed here is designed toward understanding the embryonic spatial and temporal origin of neuronal cell diversity in these structures (Specific Aims 1 & 2) and the mechanisms by which a unique subset of these cells migrate to their final destinations (Specific Aim 3). Considering that the amygdala-nucleus accumbens pathway is a major target of drugs of abuse, understanding the mechanisms that govern normal development of these structures may provide insight into the etiology of such disorders in which these regions are affected. Given the economic and societal cost of substance addiction, determination of the biological programs that regulate development of these key brain regions is a crucial and largely unmet challenge. Furthermore, these proposed studies will provide a framework for ensuing work aimed at understanding how drugs of abuse may affect normal development of the nucleus accumbens and the amygdala, as well as be invaluable in guiding the rational generation of genetic mouse models of addictive behavior. The specific aims of this proposal are: Specific Aim 1: Using ultrasound guided in utero transplantation to fate map progenitor cells from four distinct embryonic telencephalic progenitor zones (the medial, lateral, caudal ganglionic eminences and the cortico- striatal border), we will test the hypothesis that each of these regions contributes a unique cohort of neuronal subtypes to the mature nucleus accumbens and amygdala and at different times during development. Specific Aim 2: Using molecular fate mapping techniques, we will test the hypothesis that the cortico-striatal border is a source of two separate populations of progenitor cells that will give rise to distinct subsets of inhibitory neurons, and excitatory neurons, in the mature nucleus accumbens and amygdala. Specific Aim 3: Using a combination of in vitro and in vivo approaches, we will test the hypothesis that the two distinct populations of progenitor cells derived from the cortico-striatal border migrate to the developing nucleus accumbens and amygdala via differential chain and radial modes of migration.