Development of the basal telencephalic limbic system

描述（申请人提供）：哺乳动物的基底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调节积极奖励刺激的伏隔核和调节情绪记忆的特定方面以及对厌恶刺激的条件反应的杏仁核。这里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（特定目标1和2）以及这些细胞的独特子集迁移到最终目的地的机制（特定目标3）。考虑到杏仁核-伏隔核通路是药物滥用的主要靶点，了解控制这些结构正常发育的机制可能有助于深入了解这些区域受到影响的疾病的病因学。鉴于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学程序是一个至关重要的、很大程度上尚未实现的挑战。此外，这些拟议的研究将为后续工作提供一个框架，旨在了解药物滥用如何影响伏隔核和杏仁核的正常发育，以及在指导合理产生成瘾行为的遗传小鼠模型方面具有宝贵的价值。具体目的1：利用超声引导的子宫移植来绘制四个不同的胚胎端脑祖细胞区（内侧、外侧、尾侧神经节突起和皮质纹状体边界）的命运图谱，我们将验证这些区域在发育的不同时期为成熟的伏隔核和杏仁核提供独特的神经元亚型群的假设。具体目标2：使用分子命运定位技术，我们将验证皮质纹状体边界是两个独立祖细胞群来源的假设，这些祖细胞群将在成熟的伏隔核和杏仁核中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：使用体外和体内方法的结合，我们将验证来自皮质纹状体边界的两个不同的祖细胞群体通过差异链和径向迁移模式迁移到发育中的伏隔核和杏仁核的假设。

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.