Putting habenula pathways on the map

将缰核路径绘制在地图上

• 批准号: 8277883
• 负责人: Eric E. Turner
• 金额: $ 37.6万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277883
• 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(申请人提供)：这是一项新的R01提案，涉及缰核-中脑回路中的神经通路和基因表达。缰核是丘脑的背侧核，由参与不同神经通路的内侧(MH)和外侧(LH)亚核组成。MH和LH均通过突出的反折束(FR)向中脑腹侧投射纤维，但只有LH直接支配中脑多巴胺(DA)和5-羟色胺(5HT)系统，而MH首先投射到脚间核(IP)，后者再投射到中脑腹侧。最近的行为实验表明缰核-中脑通路和单胺系统之间有很强的功能相互作用，这与情绪障碍、认知障碍和成瘾有关。利用微阵列和生物信息学方法，我们最近已经证明分子标记识别MH和LH中的神经元亚群，这表明这些核团内的功能异质性。在了解缰核功能方面的进一步进展将需要更好地了解这些不同的缰核神经元分子类别，包括它们的解剖和功能连接，这是传统的束追踪方法无法获得的。在这里，我们提出了三个具体的目标，将探索缰核电路，并迅速描绘出确定的神经元群体在MH，LH和IP之间的联系。这些实验计划在很短的时间内(3年)，并经济高效地使用现有工具，包括来自Gensat和Allen Brain Institute大脑图谱项目的基因组和生物信息资产。目的1.验证MH和LH神经元特定亚群参与不同神经通路的假设。使用带有LacZ、GFP和Cre报告基因的转基因小鼠，追踪基因定义的MH、LH和IP神经元类别到中脑的投射。可利用的基因针对Brn3a、GPR151、Tac2/SK、Slc18a3、CHRNB4、PROKR2、CHRNA5、Tac1/SP和ChAT基因。目的2.验证黄体生成素通过中脑桥内侧被盖核(RMTg)GABA能神经元向中脑边缘DA系统提供信息的假说。使用CFOS诱导、来自黄体生成素的顺行追踪和GABA标记表达定位小鼠RMTg。利用转基因示踪法确定投射到RMTg的黄体生成素亚群。目的3.与Allen研究所合作，使用生物信息学分析来检验缰核通路的关键节点，特别是前脑隔核、黄体生成素、IP和RMTg具有独特的基因表达谱的假设，就像先前对MH所证明的那样。这些基因表达谱将为未来研究缰核通路的遗传操作奠定基础。