Gene Expression and Drug Targets in the Rostromedial Tegmentum

鼻内侧被盖的基因表达和药物靶点

• 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
• 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

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，吻内侧被盖核（RMTg）。这些神经元通过向多巴胺神经元的密集投射，以及来自外侧缰核、延伸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、行为和成瘾中发挥关键作用。RMTg神经元是许多（但不是所有）与恐惧，焦虑，疼痛和药物戒断相关的厌恶行为所必需的。尽管最近关于RMTg解剖学、生理学和行为特征的知识快速增长，但这些神经元的遗传特性几乎完全未知。目前还不清楚它们含有什么神经递质（除了GABA），也不知道它们是否表现出受体，摄取转运蛋白或其他药物靶点，可以选择性地操纵它们的放电率。此外，RMTg区域在Nissl染色上缺乏清晰的边界，并且在没有神经示踪剂或立即早期基因诱导的情况下无法可视化，这些方法通常与其他实验范式不相容。因此，该区域的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，我们建议检查RMTg基因表达，首先使用荧光激活细胞分选（FACS），以隔离这些神经元从周围的结构，然后通过分析全基因组表达阵列，并在原位杂交，以确认候选基因的表达模式的结论。我们希望这些结果能够填补我们对这种新兴大脑结构的认识中的主要空白，同时也为临床前和临床使用提供新的工具。