Mouse models of stress disorders and addiciton

应激障碍和成瘾小鼠模型

基本信息

批准号：
7591947
负责人：
ANDREW HOLMES
金额：
$ 84.32万
依托单位：
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7591947
关键词：
Alcohols Animal Model Anxiety Behavior Behavior Control Behavioral Behavioral Sciences Biological Models Brain Cognition Condition Data Development Disease Emotional Emotional disorder Emotions Equipment Exposure to Fright Future Genes Genetic Genetic Engineering Glutamates Goals Hippocampus (Brain)Human Human Resources Hypnosis Illicit Drugs Individual Knockout Mice Laboratory mice Life Stress Measures Mediating Mediator of activation protein Mental Depression Modeling Mouse Strains Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate NR1 gene Pharmacology Play Research Rewards Risk Role Science of genetics Sedation procedure Series Stress System Testing Thinking Time Trauma Traumatic Stress Disorders Variant Visual addiction alcohol effect alcohol response alcohol sensitivity drug of abuse executive function experience human NR1 protein information gathering insight interest morris water maze mouse model mutant neglect neural circuit neuropsychiatry neurotransmission postnatal programs receptor research study restraint

项目摘要

Overview. In this year the Section on Behavioral Science and Genetics (October, 2006 to September, 2007) continued to be outfitted with personnel and equipment. A program of research was initiated to develop mouse models of emotional disorders and addiction, with focus on the glutamate system. Individuals exposed to extreme forms of trauma and neglect are more prone to suffer from emotional disorders, such as anxiety and depression, and more likely to develop addiction to alcohol and illicit drugs of abuse. However, it is far from clear exactly how early life stress increase later risk for these neuropsychiatric disorders. Another unresolved question is why some individuals appear especially sensitive to effects of stress, while others are resilient. This inter-individual variation suggests that genetics play a significant role in modulating stress, a notion supported by recent research in humans. Unfortunately, there are inherent limitations to the study of genetic and environmental influences on behavior under tightly controlled conditions in humans. Animal models provide a valuable alternative. The laboratory mouse potentially provides an excellent model system to study genetic factors modulating behavior due to the availability of genetically-distinct mouse strains and the capacity for engineering genetic mutants. The Section on Behavioral Science and Genetics seeks to develop mouse models of emotional abnormalities and addiction. A series of studies were conducted with the goal of a developing a mouse model of stress that produced reliable effects on emotional behaviors and executive fucntions. The long-term goal of these studies is to develop a model that can be applied to genetically-modified mice (including NMDA KO mice described below) to study gene x stress interactions underlying emotion and addiction. Study 1 was a comparison of the effects of restraint on a battery of tests for fear, anxiety and stress, across 8 genetically-distinct mouse strains. The aim was to gather information on which strains are suitable for studies of stress and at the same time provide insight into genetic factors modulating of stress. Study 2 assessed knockout mice lacking the NR2A or NR2B receptor subunits on tests for cognition such as the Morris water maze and the pairwise visual discrmination. These experiments will provide baseline phenotypic data guiding later studies on the effects of stress on these behaviors in these mice. The role of glutamate NMDA receptors in mediating emotional behaviors and the behavioral effects of ethanol. Glutamate neurotransmission via NMDA receptors plays a major role in brain development, in mediating the behavioral effects of ethanol and, it is increasingly thought, modulating emotional behaviors. Therefore, the NMDA receptor represents a potential mechanism underlying the effects of stress on subsequent changes in emotion- and reward-related behaviors. The goal of initial studies was to identify which NMDA receptor subtypes are critical mediators of NMDA receptor effects on ethanol sensitivity and emotional behavior in mice and, therefore, which subtypes should be the focus of future studies of the effects of postnatal stress on possible NMDA receptor-mediated changes in these behaviors. Study 1 examined the differential contribution of the NR2A-R and NR2B-R subtypes to the ability of NMDA receptor-blockade to potentiate ethanol sensitivity (as measured by sedation/hypnosis). A combination of pharmacological (NR2-R antagonists) and gene mutant (NR2A KO mice) was employed. Study 2 assessed whether exposure to stress altered behavioral response to ethanol and, whether NMDA receptors, mediated these alterations, again using both pharmacological (NR2-R antagonists) and gene mutant (NR2A KO mice, NR1 hippocampal CA3-specific KO mice) approaches.

概述。在今年，有关行为科学和遗传学的部分（2006年10月至2007年9月）继续配备人员和设备。启动了一项研究计划，以开发情绪障碍和成瘾的小鼠模型，重点是谷氨酸系统。受到极端形式的创伤和忽视形式的人更容易患有情绪障碍，例如焦虑和抑郁，更有可能发展对酒精和非法虐待药物的成瘾。但是，尚不清楚早期压力如何增加这些神经精神疾病的后期风险。另一个尚未解决的问题是，为什么有些人看起来对压力的影响特别敏感，而另一些人则具有弹性。这种个体间的变化表明，遗传学在调节压力中起着重要作用，这是受到人类最近研究的支持。不幸的是，研究人类严重控制条件下对行为的影响存在固有的局限性。动物模型提供了一种有价值的替代方法。该实验室小鼠可能提供了一个出色的模型系统，可以研究遗传因素，从而调节遗传学的小鼠菌株的可用性和工程遗传突变体的能力。关于行为科学和遗传学的部分旨在开发情绪异常和成瘾的小鼠模型。进行了一系列研究，目的是开发压力的小鼠模型，该模型对情绪行为和执行企业产生可靠的影响。这些研究的长期目标是开发一个模型，该模型可以应用于遗传改性的小鼠（包括下面描述的NMDA KO小鼠），以研究基因X压力相互作用的情绪和成瘾。研究1是在8种遗传学的小鼠菌株中，约束对恐惧，焦虑和压力的一系列测试的影响的比较。目的是收集有关菌株适合压力研究的信息，同时提供了对压力调节的遗传因素的见解。研究2评估了缺乏NR2A或NR2B受体亚基的基因敲除小鼠，例如莫里斯水迷宫和成对视觉散发的认知。这些实验将提供基线表型数据指导以后对这些小鼠中压力对这些行为的影响的研究。谷氨酸NMDA受体在介导情绪行为和乙醇行为影响中的作用。通过NMDA受体通过NMDA受体的谷氨酸神经传递在大脑发育，介导乙醇的行为效应中起着重要作用，并且越来越多地认为，调节情绪行为。因此，NMDA受体代表了压力对随后的情绪和奖励相关行为变化的影响的潜在机制。初步研究的目的是确定哪些NMDA受体亚型是NMDA受体对小鼠乙醇敏感性和情感行为的影响的关键介体，因此，哪些亚型应成为未来研究对这些行为中NMDA受体介导的可能变化的未来研究的重点。研究1研究了NR2A-R和NR2B-R亚型对NMDA受体阻滞增强乙醇敏感性的能力的差异贡献（如通过镇静/催眠测量）。使用了药理学（NR2-R拮抗剂）和基因突变体（NR2A KO小鼠）的组合。研究2评估了承受压力改变对乙醇的行为反应是否改变，以及NMDA受体是否介导了这些改变，再次使用药理学（NR2-R拮抗剂）和基因突变体（NR2A KO小鼠，NR1 Hampocampal CA3特异性KO小鼠）方法。