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Function-specific serotonergic neurons, discrete brain targets, and addiction

功能特异性血清素能神经元、离散大脑目标和成瘾

基本信息

批准号：
8828655
负责人：
Susan M. Dymecki
金额：
$ 20.56万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8828655
关键词：
Amygdaloid structure Area Attenuated Axon Behavior Behavior assessment Behavioral Behavioral Assay Biological Assay Biological Models Brain Brain region Cells Classification Cocaine Cocaine Dependence Corpus striatum structure Development Discipline Dopamine Dopamine Receptor Drug Addiction Engineering Gene Combinations Gene Expression Profile Genetic Genetic Techniques HTR2A gene Health Hippocampus (Brain)Incentives Interneurons Link Maps Medial Mediator of activation protein Memory Molecular Genetics Molecular Probes Molecular Profiling Morphology Mus Names Nature Neurons Nucleus Accumbens Outcomes Research Output Pharmacogenetics Pharmacology Phenotype Physiological Population Prefrontal Cortex Presynaptic Terminals Prevention Procedures Prosencephalon Proteins Public Health Receptor Signaling Relapse Relative (related person)Research Resolution Role Serotonin Serotonin Receptor 5-HT2C Signal Transduction Structure Substance abuse problem Synapses System Therapeutic Tissue-Specific Gene Expression Ventral Tegmental Area addiction area striata drug relapse genetic approach genome-wide immunoreactivity in vivo innovation mesolimbic system motivated behavior nerve supply neural circuit novel novel therapeutics paired stimuli postsynaptic preference receptor receptor expression relating to nervous system response tool transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Serotonin (5-HT)-producing neurons are recognized as key modulators of cocaine-seeking behavior. As cocaine-seeking behavior reflects the incentive motivational effect of stimuli paired with cocaine, 5-HT is thought to contribute to the formation of addiction-related memory that underlies relapse. Alteration of 5-HT commands is an emerging therapeutic direction for addiction treatment, with efforts focusing largely on receptor manipulations. Here we propose a novel, complementary approach that focuses presynaptically, on the 5-HT neurons themselves. Guided by recent research showing that cocaine seeking involves opposing activity of 5-HT at 5-HT2A and 5-HT2C receptors, which are key modulators of dopamine (DA) output, we will determine to what degree different subtypes of 5-HT neurons in mice differentially modulate the incentive motivational effects of stimuli paired with cocaine via the conditioned place preference procedure (Aim 1) and will explore their forebrain projection targets, especially as relates to postsynaptic 5-HT2A and 5-HT2C receptor expression (Aim 2). Our starting point is an emerging structure-function-connectivity map of the serotonergic neural system being assembled by the Dymecki lab, in which 5-HT neurons are classified by their expression of unique gene combinations and thus likely unique functionalities. They are further typed by their axonal target regions and by assessment of behavioral and physiological deficits following their selective silencing in vivo. Here we propose probing these 5-HT neuron subtypes for their role in addiction-related behavior, focusing first on 5-HT neuron subtypes that innervate brain regions implicated in enhancing or suppressing cocaine-seeking behavior. Three 5-HT neuron subtypes stand out: the r1-En1 5-HT neuron subtype, named by its origin in rhombomere (r) 1 and expression of the transcription factor Engrailed1; r2-Hoxa2 subtype, defined by its origin in r2 and expression of the transcription factor Hoxa2; and the Drd1a 5-HT neuron subtype, by expression of the type 1a DA receptor. Because the latter two show more restricted innervation profiles within the addiction-relevant mesolimbic system, perhaps suggestive of specialized roles in behavior modulation, these two will be explored first in this R21 application. Our approach of partnering molecular genetic techniques with a well-established behavioral assay in mice is both technically and conceptually innovative. The integration of these distinct disciplines is made possible only now through development of intersectional genetic tools that make molecularly distinct subtypes of 5-HT neurons apparent and accessible in mice for behavioral probing and genome-wide molecular profiling. Identifying the key 5-HT neuron subtypes involved and the nature of their effects on addiction-related behavior, along with having molecular genetic tools for their selective isolation and molecular probing is foundational for discovering new, possibly behaviorally-selective, therapeutic leads.

描述（由申请人提供）：产生5-羟色胺（5-HT）的神经元被认为是可卡因寻求行为的关键调节剂。由于可卡因寻求行为反映了与可卡因配对的刺激的激励动机效应，5-HT被认为有助于形成成瘾相关记忆，这是复发的基础。5-HT指令的改变是成瘾治疗的新兴治疗方向，其努力主要集中在受体操纵上。在这里，我们提出了一种新的，互补的方法，重点突触前，对5-HT神经元本身。最近的研究表明，可卡因寻求涉及5-HT在5-HT 2A和5-HT 2C受体上的相反活性，这是多巴胺（DA）输出的关键调节剂，我们将通过条件性位置偏爱程序（Aim 1）确定小鼠中不同亚型的5-HT神经元在多大程度上差异性地调节与可卡因配对的刺激的激励动机效应。并将探索其前脑投射靶点，特别是与突触后5-HT 2A和5-HT 2C受体表达相关的靶点（目的2）。我们的出发点是Dymecki实验室正在组装的多巴胺能神经系统的新兴结构-功能-连接图，其中5-HT神经元通过其独特基因组合的表达进行分类，因此可能具有独特的功能。通过它们的轴突靶区域以及通过在它们体内选择性沉默后评估行为和生理缺陷来进一步分型它们。在这里，我们建议探测这些5-HT神经元亚型在成瘾相关行为中的作用，首先关注5-HT神经元亚型，这些神经元亚型支配与增强或抑制可卡因寻求行为有关的脑区。三种5-HT神经元亚型脱颖而出：r1-En 1 5-HT神经元亚型，因其起源于菱形节（r）1和转录因子Engrailed 1的表达而命名; r2-Hoxa 2亚型，由其起源于r2和转录因子Hoxa 2的表达定义;和Drd 1a 5-HT神经元亚型，由1a型DA受体的表达定义。因为后两个在成瘾相关的中脑边缘系统中显示出更受限制的神经支配概况，可能暗示了行为调制中的专门作用，所以这两个将首先在R21应用中进行探索。我们将分子遗传学技术与成熟的小鼠行为检测方法相结合的方法在技术上和概念上都是创新的。这些不同学科的整合是现在才有可能通过交叉遗传工具的发展，使分子不同亚型的5-HT神经元明显和可访问的小鼠行为探测和全基因组分子分析。确定所涉及的关键5-HT神经元亚型及其对成瘾相关行为的影响的性质，沿着具有用于其选择性分离和分子探测的分子遗传工具，是发现新的、可能具有行为选择性的治疗线索的基础。