Gene Expression and Drug Targets in the Rostromedial Tegmentum

鼻内侧被盖的基因表达和药物靶点

基本信息

批准号：
8473844
负责人：
THOMAS C JHOU
金额：
$ 7.08万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8473844
关键词：
Addictive Behavior Affect Amygdaloid structure Anatomy Animals Anxiety Basic Science Behavior Behavioral Brain Brain region Candidate Disease Gene Cell Nucleus Characteristics Clinical Clinical Research Cognition Collection DNA Microarray Chip Development Diffuse Drug Targeting Exhibits Fluorescence-Activated Cell Sorting Freezing Fright Gene Expression Genes Genetic Genome Glutamates Growth Habenula Human Immediate-Early Genes Immunohistochemistry In Situ Hybridization Individual Knowledge Label Lateral Lesion Mental Depression Methods Midbrain structure Molecular Molecular Genetics Mood Disorders Motivation Neurons Neuropeptide Receptor Neurotransmitter Receptor Neurotransmitters Pain Pattern Physiological Play Process Property Prosencephalon Protocols documentation Relative (related person)Research Role Site Slice Specificity Staining method Stains Stimulus Structure Techniques Tegmentum Mesencephali Testing Tracer Ventral Tegmental Area addiction dopaminergic neuron drug of abuse drug withdrawal frontal lobe gamma-Aminobutyric Acid gene induction interest learned behavior meetings motivated behavior nerve supply neurotransmitter uptake novel strategies optogenetics pre-clinical receptor relating to nervous system response tool uptake

项目摘要

DESCRIPTION (provided by applicant): In 2009, we and others recently identified a previously overlooked brain region, the rostromedial tegmental nucleus (RMTg). These neurons play key roles in aversive learning, behavior, and addiction, via their dense projections to dopamine neurons, and major inputs from the lateral habenula, extended amygdala, and other regions implicated in affect and motivation. RMTg neurons are critically required for many (though not all) aversive behaviors related to fear, anxiety, pain, and drug withdrawal. Despite the rapid recent growth of knowledge regarding RMTg anatomic, physiological, and behavioral characteristics, the genetic properties of these neurons are almost entirely unknown. It is unknown what neurotransmitters (besides GABA) they contain, nor whether they exhibit receptors, uptake transporters, or other drug targets that could selectively manipulate their firin rates. Furthermore, the RMTg region lacks sharp boundaries on Nissl stains, and cannot be visualized without neural tracers or immediate early gene induction, methods often incompatible with other experimental paradigms. Hence, further progress in basic science and clinical studies of this region requires development of molecular tools and drug targets that selectively identify and manipulate these neurons. To meet these needs, we propose to examine RMTg gene expression by first using fluorescence activated cell sorting (FACS) to isolate these neurons from surrounding structures, followed by analysis on whole-genome expression arrays, and concluding with in situ hybridization to confirm expression patterns of candidate genes. We expect the results to fill in major gaps in our knowledge of this emerging brain structure, while also producing new tools for preclinical and clinical use.

描述（由申请人提供）：2009 年，我们和其他人最近发现了一个以前被忽视的大脑区域，即嘴内侧被盖核 (RMTg)。这些神经元通过对多巴胺神经元的密集投射，以及来自外侧缰核、扩展杏仁核和其他与情感和动机有关的区域的主要输入，在厌恶性学习、行为和成瘾中发挥着关键作用。 RMTg 神经元对于许多（尽管不是全部）与恐惧、焦虑、疼痛和药物戒断相关的厌恶行为至关重要。尽管最近有关 RMTg 解剖学、生理学和行为特征的知识迅速增长，但这些神经元的遗传特性几乎完全未知。目前尚不清楚它们含有哪些神经递质（GABA 除外），也不知道它们是否表现出受体、摄取转运蛋白或其他可以选择性操纵其 firin 速率的药物靶标。此外，RMTg 区域在尼氏染色上缺乏清晰的边界，如果没有神经示踪剂或立即早期基因诱导，则无法可视化，而这些方法通常与其他实验范例不兼容。因此，该区域基础科学和临床研究的进一步进展需要开发选择性识别和操纵这些神经元的分子工具和药物靶点。为了满足这些需求，我们建议首先使用荧光激活细胞分选（FACS）将这些神经元与周围结构分离，然后对全基因组表达阵列进行分析，最后通过原位杂交来确认表达模式，以检查 RMTg 基因表达的候选基因。我们期望这些结果能够填补我们对这种新兴大脑结构的了解的主要空白，同时也产生用于临床前和临床使用的新工具。