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：
8344687
负责人：
ANDREW HOLMES
金额：
$ 128.5万
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/8344687
关键词：
Alcohols Amygdaloid structure Animal Model Anxiety Behavior Behavior Control Behavioral Behavioral Genetics Behavioral Sciences Biological Models Brain Chronic Cognitive Collaborations Development Discrimination Learning Disease Drug Delivery Systems Emotional Emotional disorder Emotions Endocannabinoids Enzymes Ethanol Exposure to Extinction (Psychology)Fright Future Genes Genetic Genetic Engineering Glutamates Goals Human Hypnosis Individual Individual Differences Knockout Mice Laboratories Laboratory mice Learning Measures Mediating Mediation Mediator of activation protein Mental Depression Modeling Mouse Strains Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate Pharmaceutical Preparations Pharmacology Play Prefrontal Cortex Prevention Process Proteins Publications Recovery Research Research Design Reversal Learning Rewards Risk Role Sedation procedure Series Stress System Testing Therapeutic Time Trauma Traumatic Stress Disorders Variant Visual Work addiction alcohol effect alcohol sensitivity drug of abuse executive function experience fatty acid amide hydrolase flexibility information gathering insight interest mouse model mutant neglect neural circuit neuropsychiatry neurotransmission novel postnatal programs psychologic receptor research study

项目摘要

Overview. In this year (October, 2010 to September, 2011) the Section on Behavioral Science and Genetics continued a program of research designed 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 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 controled 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 functions. 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 fear extinction across 8 genetically-distinct mouse strains. The aim was to gather information on which strains are suitable for studies of fear inhibition and at the same time provide insight into genetic factors modulating of this process. Study 2 assessed knockout mice lacking the NR2B receptor subunits on tests for pairwise visual discrimination and reversal learning. This will inform as to the role of NR2B-containing receptors in mediating prefrontal cortex mediated cognitive flexibility. 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 effects of chronic exposure to ethanol on NMDAR-related behavioral and electrophysiological endpoints. For the behavioral experiments, a combination of pharmacological (NR2B antagonists) and gene mutant (NR2B KO mice) was employed. Study 2 examined the differential contribution of the NMDA receptor anchoring protein to mediation of ethanol sensitivity and the ability of NMDA receptor-blockade to potentiate ethanol sensitivity (as measured by sedation/hypnosis). Another project examined the role of endocannabinoids as a mechanism underlying individual differences in fear extinction a form of inhibitory learning that aids recovery from psychological trauma. Working in close collaboration with the laboratory of Dr. George Kunos, we tested the effects of a novel drug that boosts brain endocannabinoid levels (via prevention of degradation by the enzyme fatty acid amide hydrolase). Our preliminary work has found that either systemic or intra-amygdala delivery of this drug facilitates fear extinction in a mouse strain with impaired extinction. Supporting the amygdala as effect-locus, AM3506s extinction-facilitating effects were blocked by intra-amygdala CB1R antagonism and recapitulated by intra-amygdala AM3506. These findings reveal a new potential therapeutic approach to treating trauma and have been submitted for publication.

概述。在今年（2010年10月至2011年9月）的行为科学和遗传学部分继续进行了一项研究计划，旨在开发情绪障碍和成瘾的老鼠模型，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，尚不清楚这些神经精神疾病的应力如何增加后期的风险。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，研究人类严格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老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功能产生可靠的影响。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是对8种遗传学的小鼠菌株中恐惧灭绝的影响的比较。目的是收集有关哪些菌株适合于恐惧抑制作用的信息，同时洞悉调节该过程的遗传因素。研究2评估了对成对视觉歧视和逆转学习的测试中缺乏NR2B受体亚基的基因敲除小鼠。这将告知含NR2B受体在介导前额叶皮层介导的认知灵活性中的作用。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研究了慢性暴露于乙醇对NMDAR相关行为和电生理终点的影响。对于行为实验，采用了药理学（NR2B拮抗剂）和基因突变体（NR2B KO小鼠）的组合。研究2研究了NMDA受体锚定蛋白对乙醇敏感性介导的差异贡献以及NMDA受体阻滞对增强乙醇敏感性的能力（如通过镇静/催眠测量）。另一个项目研究了内源性大麻素作为恐惧消灭中个体差异的一种机制的作用，一种抑制性学习的形式，有助于从心理创伤中恢复。与乔治·库诺斯（George Kunos）博士的实验室密切合作，我们测试了一种新型药物的作用，该药物促进了脑内源性大麻素水平（通过预防酶脂肪酸酰胺水解酶的降解）。我们的初步工作发现，这种药物的全身性或杏仁核内递送都有助于恐惧在灭绝受损的小鼠菌株中灭绝。支持杏仁核作为效应 - 稳定性，AM3506S灭绝 - 促液化效应被-Amygdala CB1R拮抗作用阻止，并被杏仁核内AM3506概括。这些发现揭示了一种新的潜在治疗方法来治疗创伤，并已提交出版。