Putting habenula pathways on the map

将缰核路径绘制在地图上

基本信息

批准号：
8083850
负责人：
Eric E. Turner
金额：
$ 39万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/8083850
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 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 Pattern 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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Recent studies in rodents, primates and humans have implicated a poorly understood brain region, the habenula, in the perception of punishment or the absence of an expected reward. Circuits from the habenula to the midbrain, mediating these responses, may play a role in depression and addiction. The habenula is a complex brain region, containing multiple types of neurons, and cannot be understood as a single unit. We propose to use transgenic mice to show how distinct kinds of habenula neurons are "wired" to the regions of the brainstem regulating reward, motivation and mood.

描述（由申请人提供）：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。缰核是丘脑背核，由参与不同神经通路的内侧 (MH) 和外侧 (LH) 亚核组成。 MH 和 LH 都通过突出的反屈束 (FR) 将其输出纤维发送到腹侧中脑，但只有 LH 直接支配中脑多巴胺 (DA) 和血清素 (5HT) 系统，而 MH 首先投射到脚间核。 IP），进而投射到腹侧中脑。最近的行为实验表明，缰核-中脑通路和单胺系统之间存在强大的功能相互作用，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可以识别 MH 和 LH 中的神经元亚群，这表明这些细胞核内的功能异质性。了解缰核功能的进一步进展将需要更好地了解缰核神经元的这些不同分子类别，包括它们的解剖和功能连接，这是传统的束追踪方法无法实现的。在这里，我们提出了三个具体目标，将探索缰核回路并快速描绘 MH、LH 和 IP 中定义的神经元群的连接。这些实验计划在很短的时间内（3 年）进行，并以具有成本效益的方式使用现有工具，包括来自 Gensat 和艾伦脑研究所脑图项目的基因组和生物信息资产。目标 1. 检验 MH 和 LH 神经元的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遗传定义的 MH、LH 和 IP 神经元类别到中脑的投射。可用的细胞系针对 Brn3a、Gpr151、Tac2/SK、Slc18a3、Chrnb4、Prokr2、Chrna5、Tac1/SP 和 Chat 基因。目标 2. 检验以下假设：小鼠 LH 通过中桥脑内侧被盖核 (RMTg) 的 GABA 能神经元向中脑边缘 DA 系统提供输入，就像在大鼠中一样。使用 cFos 诱导、LH 的顺行道追踪和 GABA 标记表达来定位小鼠 RMTg。使用转基因追踪识别投射到 RMTg 的 LH 亚群。目标 3. 与艾伦研究所合作，利用生物信息学分析来检验以下假设：缰核通路的关键节点，特别是前脑间隔核、LH、IP 和 RMTg，具有独特的基因表达谱，正如之前针对 MH 所证明的那样。这些基因表达谱将构成未来研究中缰核途径遗传操作的基础。公共卫生相关性：最近对啮齿动物、灵长类动物和人类的研究表明，人们对缰核这一大脑区域知之甚少，它与惩罚感知或预期奖励缺乏有关。从缰核到中脑的回路调节这些反应，可能在抑郁和成瘾中发挥作用。缰核是一个复杂的大脑区域，包含多种类型的神经元，不能被理解为一个单一的单元。我们建议使用转基因小鼠来展示不同种类的缰核神经元如何“连接”到脑干调节奖赏、动机和情绪的区域。