Development of the basal telencephalic limbic system

描述(申请人提供)：哺乳动物的基础端脑边缘系统由许多结构组成，这些结构参与调节复杂的情绪和动机行为。其中最突出的两个是伏隔核和杏仁核，前者负责调节积极的奖赏刺激，后者负责调节情绪记忆的特定方面和对厌恶刺激的条件性反应。这里提出的工作旨在理解这些结构中神经细胞多样性的胚胎空间和时间起源(特定目标1和2)，以及这些细胞的一个独特子集迁移到其最终目的地的机制(特定目标3)。考虑到杏仁核-伏隔核通路是药物滥用的主要目标，了解这些结构正常发展的机制可能有助于深入了解这些区域受到影响的此类疾病的病因。考虑到物质成瘾的经济和社会代价，确定调控这些关键大脑区域发育的生物程序是一个关键的、基本上没有得到满足的挑战。此外，这些拟议的研究将为随后的工作提供一个框架，旨在了解滥用药物如何影响伏隔核和杏仁核的正常发育，并对指导合理地产生成瘾行为的遗传小鼠模型具有宝贵的价值。这项建议的具体目标是：具体目标1：使用超声引导的宫内移植定位来自四个不同的胚胎端脑前体区域(内侧、外侧、尾侧神经节隆起和皮质-纹状体边缘)的祖细胞，我们将检验这一假设，即这些区域中的每个区域在发育过程中的不同时间为成熟的伏隔核和杏仁核贡献了独特的神经元亚型队列。具体目标2：使用分子命运图谱技术，我们将检验这一假设，即皮质-纹状体边界是两个独立的祖细胞群体的来源，这两个群体将在成熟的伏隔核和杏仁核产生不同的抑制性神经元和兴奋性神经元亚群。具体目标3：采用体外和体内相结合的方法，我们将检验这一假设，即来自皮质-纹状体边界的两个不同的祖细胞群体通过差别链和放射状迁移模式迁移到发育中的伏隔核和杏仁核。

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.