Putting habenula pathways on the map

将缰核路径绘制在地图上

• 批准号: 8444531
• 负责人: Eric E. Turner
• 金额: $ 36.1万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-10 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444531
• 关键词: Address; Anatomy; Area; Attention; Behavior; Behavioral; Bioinformatics; Brain; Brain Mapping; Brain Stem; Brain region; Cell Nucleus; Characteristics; Clinical; Cognition Disorders; Cognitive; Collaborations; Complex; Disease model; Dopamine; Dorsal; Epithalamic structure; Fiber; Functional disorder; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Models; Genomics; Goals; Habenula; Heterogeneity; Human; Institutes; LacZ Genes; Lateral; Learning; Maps; Medial; Mediating; Mental Depression; Methods; Midbrain structure; Molecular; Molecular Profiling; Mood Disorders; Moods; Motivation; Mus; Neural Pathways; Neurons; Nicotine; Output; Pain; Pathway interactions; Perception; Play; Population; Primates; Process; Prosencephalon; Punishment; Rattus; Reporter; Reproductive Behavior; Rewards; Rodent; Role; Schizophrenia; Septal Nuclei; Serotonin; Sleep Wake Cycle; System; Tegmentum Mesencephali; Testing; Thalamic Nuclei; Thalamic structure; Time; Transgenic Mice; Transgenic Organisms; Work; addiction; base; biological adaptation to stress; cell type; cost effective; design; gamma-Aminobutyric Acid; genetic manipulation; interpeduncular nucleus; mesolimbic system; molecular marker; monoamine; neural circuit; nutrition; research study; response; tool; transcription factor

DESCRIPTION (provided by applicant): This is a new R01 proposal addressing neural pathways and gene expression in habenula- midbrain circuits. The habenula is a dorsal thalamic nucleus consisting of medial (MH) and lateral (LH) subnuclei that participate in distinct neural pathways. The MH and LH both send their output fibers to the ventral midbrain via the prominent fasciculus retroflexus (FR), but only the LH directly innervates midbrain dopamine (DA) and serotonin (5HT) systems, while the MH projects first to the interpeduncular nucleus (IP), which in turn projects to ventral midbrain. Recent behavioral experiments suggest strong functional interactions between the habenula-midbrain pathway and the monoamine systems, with major implications for mood disorders, cognitive disorders, and addiction. Using microarrays and bioinformatic approaches, we have recently shown that molecular markers identify subpopulations of neurons in the MH and LH which suggest functional heterogeneity within these nuclei. Further progress in understanding habenula function will require a much better understanding of these distinct molecular classes of habenula neurons, including their anatomic and functional connectivity, which are not accessible to conventional tract-tracing methods. Here we propose three Specific Aims that will explore habenula circuits and rapidly delineate the connections of defined populations of neurons in the MH, LH and IP. These experiments are planned in a short time-frame (3 years) and with cost-effective use of existing tools, including genomic and bioinformatic assets from the Gensat and Allen Brain Institute brain mapping projects. Aim 1. Test the hypothesis that specific subpopulations of MH and LH neurons participate in distinct neural pathways. Use transgenic mice with LacZ, GFP, and Cre reporters to trace the projections of genetically defined classes of MH, LH, and IP neurons to the midbrain. Available lines target the Brn3a, Gpr151, Tac2/SK, Slc18a3, Chrnb4, Prokr2, Chrna5, Tac1/SP, and Chat genes. Aim 2. Test the hypothesis that the LH provides input to the mesolimbic DA system via GABAergic neurons of the mesopontine rostromedial tegmental nucleus (RMTg) in mice as it does in rats. Localize the mouse RMTg using cFos induction, anterograde tract tracing from the LH, and GABA marker expression. Identify the LH subpopulations projecting to the RMTg using transgenic tracing. Aim 3. In collaboration with the Allen Institute, use bioinformatic analysis to test the hypothesis that key nodes of the habenula pathway, specifically the forebrain septal nuclei, LH, IP and RMTg, have distinctive gene expression profiles, as previously demonstrated for the MH. These gene expression profiles will form the basis for the genetic manipulation of habenula pathways in future studies.

描述（由申请人提供）：这是一个新的R01提案，涉及Habenula中脑电路中神经途径和基因表达。 Habenula是一种由内侧（MH）和侧（LH）亚核的背丘脑核，参与不同的神经途径。 MH和LH都通过突出的筋膜反射（FR）将其输出纤维发送到腹中脑，但只有LH直接支配中脑多巴胺（DA）和5-羟色胺（5HT）系统，而MH则首先投影到跨岩体核（IP），在转向中间脑中脑中脑中的核核（IP）。最近的行为实验表明，Habenula-Midbrain途径与单胺系统之间的强烈功能相互作用，对情绪障碍，认知障碍和成瘾具有重大影响。 使用微阵列和生物信息学方法，我们最近表明，分子标记鉴定了MH和LH中神经元的亚群，这表明这些核中的功能异质性。了解Habenula功能的进一步进展将需要更好地理解这些独特的分子类神经元的分子类别，包括它们的解剖和功能连通性，而这些连通性无法访问传统的沟通方法。 在这里，我们提出了三个特定目标，这些目标将探索Habenula电路，并迅速描述MH，LH和IP中定义的神经元种群的连接。这些实验计划在短时间（3年）中计划，并使用具有成本效益的现有工具（包括Gensat的基因组和生物信息学资产）和艾伦脑研究所脑图项目。 目标1。检验以下假设：MH和LH神经元的特定亚群参与不同的神经途径。将转基因小鼠与LACZ，GFP和CRE记者使用转基因，将MH，LH和IP神经元的遗传定义类别的投影传播到中脑。可用的线目标是BRN3A，GPR151，TAC2/SK，SLC18A3，CHRNB4，PROKR2，CHRNA5，TAC1/SP和CHAT基因。 AIM 2。检验以下假设：LH通过小鼠中的中桥式膜中膜的GABA能神经元提供了对中侧的DA系统的输入，就像在大鼠中一样。使用CFOS诱导，从LH的地下图和GABA标记表达来定位小鼠RMTG。使用转基因跟踪确定向RMTG投射的LH亚群。 AIM 3。与艾伦研究所合作，使用生物信息学分析来检验以下假设：Habenula途径的关键节点，特别是前脑核中核，LH，IP和RMTG具有独特的基因表达谱，如先前证明的MH所示。这些基因表达谱将构成对未来研究中Habenula途径的基因操纵的基础。