Defining Roles of Synapse-Organizing SynCAM Molecules in Drug Addiction

定义突触组织 SynCAM 分子在药物成瘾中的作用

基本信息

批准号：
8402489
负责人：
Thomas Biederer
金额：
$ 20.74万
依托单位：
YALE UNIVERSITY
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/8402489
关键词：
Addictive Behavior Affect Behavior Behavioral Behavioral Paradigm Binding Biochemical Biological Assay Brain Brain region Cell Adhesion Molecules Choline O-Acetyltransferase Cocaine Communications Media Complex Confocal Microscopy Data Development Drug Addiction Elements Excitatory Synapse Exposure to Family Functional disorder Generations Goals Gray unit of radiation dose Habenula Health Hippocampus (Brain)Human Human Genetics Knockout Mice Learning Link Measurement Mediating Memory Methods Motor Activity Mus Names Neurodevelopmental Disorder Neurologic Neurons Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Positioning Attribute Predisposition Process Proteins Public Health Reagent Research Rewards Rodent Role Schizophrenia Shapes Site Structure Synapses Synaptic Cleft Synaptic plasticity Testing Therapeutic Intervention Time Transgenic Mice Vertebral column Work addiction base behavior test cocaine exposure density drug of abuse mouse model nectin novel overexpression postsynaptic preference presynaptic programs promoter protein degradation protein expression psychostimulant research study response reward processing synaptic function synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Neurons communicate with each other in the brain through specialized junctions, called synapses. Drugs of abuse can change synapse structure and function together with behavioral responses related to addiction. Select molecules induce and organize synapses in the developing brain, but their functional roles during the response to drugs of abuse have not been tested. Such roles can be hypothesized based on the morphological changes of synapses in addiction as well as due to human genetic studies. One class of proteins that organize synapses are SynCAMs (also named nectin-like molecules), a family of adhesion molecules that connect pre- and postsynaptic sites. SynCAM 1 induces new, fully functional excitatory synapses in the developing brain and its expression regulates learning and memory. The objective of this application is to define to which extent the synapse-organizing protein SynCAM 1 controls synapse number and structure in brain regions affected by drugs of abuse, and how its functions impact behavioral responses to the psychostimulant cocaine. The central hypothesis of this application is that differences in synapse organization in brain regions affected by addictive drugs impact drug susceptibility, and that these drugs alter synaptogenic pathways. To attain the objective of this application, two specific aims will be pursued. The first aim of this application is to analyze whether synapse organization by SynCAM 1 impacts synapses in the nucleus accumbens and the addiction-related behaviors to which this region contributes. Second, it will be tested how altered synapse organization in the habenula, a brain region involved in reward learning, affects responses to drugs of abuse. These experiments involve the morphometric analysis of spines, the postsynaptic elements of excitatory synapses, in brain regions affected by drugs of abuse. Biochemical studies will determine effects of addictive drugs on the expression of synapse organizing proteins. Functional analyses will be performed using assays of addiction-related behaviors. In addition, a transgenic mouse model will be developed to target excitatory synaptic connectivity in the habenula. Achieving these goals is important for human health, as this application will test to which extent altered synapse organization affects the re-wiring of neuronal circuits during addiction. In summary, this application aims to identify the molecular interactions involved in synapse organization during the first response to drugs of abuse and the subsequent development of addiction. The progress under this application will allow testing to which extent differences in synapse-organizing processes predict vulnerability to drugs of abuse and whether these pathways represent novel points of therapeutic intervention. PUBLIC HEALTH RELEVANCE: Nerve cells in the brain communicate with each other through specialized junctions, called synapses. Changes in synapse formation and function impair the wiring of the brain and can contribute to neurological and behavioral dysfunction, including addiction to drugs of abuse. This research program is relevant to public health because it will analyze how addictive drugs alter the way nerve cells connect with each other, allowing us to understand what steps go wrong when substances are abused.

描述（由申请人提供）：神经元通过专门的连接（称为突触）在大脑中相互通信。滥用药物可以改变突触的结构和功能，以及与成瘾有关的行为反应。精选分子在发育中的大脑中诱导和组织突触，但是它们在对滥用药物的反应过程中的功能作用尚未进行测试。可以根据成瘾中突触的形态变化以及人类遗传研究的形态变化来假设这种作用。一类组织突触的蛋白质是syncams（也称为nectin样分子），这是连接前和突触后位点的粘附分子家族。 Syncam 1在发育中的大脑及其表达中诱导新的，功能齐全的兴奋性突触可调节学习和记忆。该应用的目的是定义突触组织蛋白Syncam 1在多大程度上控制受滥用药物影响的大脑区域的突触数和结构，以及其功能如何影响对心理刺激可卡因的行为反应。该应用的中心假设是，受成瘾性药物影响的大脑区域突触组织的差异会影响药物的敏感性，并且这些药物改变了突触源性途径。为了实现本申请的目标，将实现两个具体的目标。该应用的第一个目的是分析Syncam 1的突触组织是否影响伏隔核的突触以及该区域贡献的与成瘾相关的行为。其次，将测试它如何改变与奖励学习的大脑区域Habenula的突触组织如何影响对滥用药物的反应。这些实验涉及对受滥用药物影响的大脑区域的刺的形态分析，刺激突触的突触后元素。生化研究将确定成瘾性药物对突触组织蛋白质表达的影响。功能分析将使用与成瘾相关的行为进行测定。另外，将开发一个转基因小鼠模型，以靶向Habenula中的兴奋性突触连通性。实现这些目标对于人类健康很重要，因为该应用将测试突触组织改变在成瘾过程中影响神经元电路的程度。总而言之，该应用旨在确定对滥用药物的首次反应以及随后的成瘾发展，涉及突触组织中涉及的分子相互作用。该应用下的进展将允许测试突触组织过程的差异预测滥用药物的脆弱性，以及这些途径是否代表了治疗干预的新颖点。公共卫生相关性：大脑中的神经细胞通过称为突触的专门连接处相互通信。突触形成和功能的变化会损害大脑的接线，并可能导致神经和行为功能障碍，包括对滥用药物的成瘾。该研究计划与公共卫生有关，因为它将分析上瘾的药物如何改变神经细胞之间的连接方式，从而使我们了解滥用物质时出了什么步骤。