Organization and Function of the Asymmetric Habenular Nuclei

描述（申请人提供）：缰核是从边缘系统到中脑的进化保守的传导途径的一部分。尽管habenulae与多种行为和各种神经系统疾病有关，但对其组织和功能之间的关系尚缺乏详细的了解。斑马鱼是一个有价值的系统，研究其结构和连通性，由于其易受转基因方法。此外，斑马鱼的缰状核为研究大脑的左右差异提供了一个独特的模型。左右habenulae由两个解剖学上不同的核组成，在大小、神经细胞密度和基因表达上表现出明显的差异，但这种不对称与亚核组织的关系也不清楚。本研究的总体目标是更详细地描述斑马鱼缰的组织和连通性，并分析缰组织的功能相关性。Habenular亚区将通过制作详细的基因表达和神经元投影图来定义。新的转基因系将从不同缰核或不对称亚域表达的基因调控区域开发，利用Brainbow绘制单个神经元的投影，并在行为研究中选择性地破坏或抑制给定的缰核区域。行为测试将测试缰背核在焦虑和恐惧回避测试中的作用。了解缰状组织的功能意义将有助于深入了解这一临床上重要的大脑区域如何调节行为，并为理解侧化信息的处理提供一个独特的模型。

DESCRIPTION (provided by applicant): The habenular nuclei are part of an evolutionarily conserved conduction pathway from the limbic system to the midbrain. Although the habenulae have been implicated in diverse behaviors and in a variety of neurological disorders, a detailed understanding of the relationship between their organization and function is lacking. Zebrafish are a valuable system to study habenular structure and connectivity due to their amenability to transgenic approaches. Moreover, the zebrafish habenulae provide a unique model for studying left-right differences in the brain. The right and left habenulae consist of two anatomically distinct nuclei and show pronounced differences in size, neuropil density and gene expression, but how this asymmetry relates to subnuclear organization is also unclear. The overall goals of the proposed study are to characterize the organization and connectivity of the zebrafish habenulae in greater detail, and to analyze the functional relevance of habenular organization. Habenular subregions will be defined by the production of detailed gene expression and neuronal projection maps. New transgenic lines will be developed from the regulatory regions of genes expressed in distinct habenular nuclei or asymmetric subdomains to map projections of individual neurons using Brainbow and to selectively disrupt or inhibit a given habenular regions in behavioral studies. Behavioral assays will test the role of the dorsal habenular nucleus in anxiety and fear-avoidance assays. Understanding the functional significance of habenular organization will provide insight into how this clinically important brain region regulates behavior, as well as provide a unique model to understand the processing of lateralized information. PUBLIC HEALTH RELEVANCE: Habenular dysfunction has been implicated in a range of psychiatric disorders including depression, schizophrenia and drug addiction. The proposed experiments using a genetic model system, the zebrafish, will increase our knowledge of how habenular organization relates to function in this conserved yet poorly understood brain region.