Mouse models of stress disorders and addiction

应激障碍和成瘾小鼠模型

基本信息

批准号：
9569182
负责人：
ANDREW HOLMES
金额：
$ 241.41万
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/9569182
关键词：
Address Alcohol abuse Alcohols Amygdaloid structure Animal Model Antidepressive Agents Anxiety Anxiety Disorders Behavior Behavioral Behavioral Genetics Behavioral Sciences Biological Models Brain CNR1 gene Chronic Clinical Cognitive Collaborations Comorbidity Data Discrimination Learning Drug Delivery Systems Emotional disorder Endocannabinoids Enzymes Exposure to Extinction (Psychology)Fluoxetine Fostering Fright Genetic Genetic Engineering Genetic study Goals Human Impairment Individual Individual Differences Laboratories Laboratory mice Learning Lesion Mediating Mouse Strains Mus Neurons Neurosciences Output Pattern Performance Pharmaceutical Preparations Pharmacology Play Post-Traumatic Stress Disorders Prefrontal Cortex Prevention Procedures Recovery Research Risk Role Scheme Serotonergic System Stimulus Stress System Testing Therapeutic Training Trauma Trauma recovery Work addiction alcohol use disorder base behavioral genomics behavioral impairment comorbid depression design drug of abuse executive function experience experimental study fatty acid amide hydrolase improved inter-individual variation interest mouse model mutant neglect neural circuit neuropsychiatric disorder novel novel therapeutics programs psychological trauma relating to nervous system stress disorder vapor

项目摘要

Overview. The Laboratory of Behavioral and Genomic Neuroscience continued a program of research in this year(October, 2015 to September, 2065) designed to develop mouse models of emotional disorders and addiction, with focus remaining on corticostriatal circuits. Individuals exposed to extreme forms of trauma and neglect are more prone to suffer from emotional disorders, such as anxiety and depression, that are comorbid with alcohol use disorders. It is far from clear exactly how alcohol abuse increases 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 neural 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 cognitive abnormalities and alcohol use disorders. The laboratory was engaged in studies that addressed the goal of elucidating the role of to determine the effects of chronic alcohol on corticostriatal systems and their behavioral output. We employed a procedure of chronic intermittent EtOH (CIE) exposure via EtOH vapors. Our data show that CIE exposure produced marked structural and functional alterations in the same corticostriatal regions we had found in other studies to cognitive behavior. The marked structural and functional changes we observed in the DLS after CIE would support some role for DLS abnormalities. In order to test for effects of chronic EtOH on performance in the task, we exposed mice to CIE either prior to discrimination learning or before reversal. These experiments showed that CIE exposure produced a significant decrease in the number of errors made during either learning or relearning after reversal. Notably, CIE-induced facilitation of relearning was limited to the late stage of training, in a pattern of facilitation analogous to that we had earlier found after prefrontal cortex lesions. According to the scheme outlined above, this raises the possibility that enhanced reversal was caused by a CIE-induced functional lesion of the PL and a resultant loss of competition on stimulus-bound learning mediated by regions, including the DLS. However, it remains unclear at present whether these changes after CIE would necessarily results in gain, rather than loss, of a DLS contribution to performance. Further work is being undertaken to define the role of the DLS in order to better explain the behavioral effects of CIE. One major 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 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 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. We are currently following this work up with studies on the precise mechanisms involved, with a focus on interactions with the amygdala serotonin system and the antidepressant drug, fluoxetine. Another major project tested the consequences of CIE for various behaviors including compulsive EtOH-seeking fear extinction. Our findings suggested a scheme whereby EtOH-induced loss of NMDAR-mediated cortical neuronal bursting disrupts encoding of extinction to impair the behavior. More generally, these observations provide novel evidence of how chronic EtOH disrupts corticoamygdala function, and predict that other behaviors dependent on this circuitry, such as compulsive drug-taking, will be adversely impacted by chronic EtOH. Clinically , our findings could have implications for understanding the neural basis of comorbid AUDs and anxiety. For example, loss of cortical modulation of extinction could impair recovery from psychological trauma and the efficacy of extinction-based therapies, increasing risk for anxiety disorders such as PTSD. Persistent anxiety could in turn foster further alcohol abuse, leading to a vicious cycle of abuse and progressively weakening prefrontal function. By the same token, treatments (e.g., endocannabinoid-targeting) that improve recovery from trauma could help break this cycle to reduce anxiety and alcohol abuse.

概述。行为与基因组神经科学实验室今年（2015年10月至2065年9月）继续开展一项研究计划，旨在开发情绪障碍和成瘾的小鼠模型，重点仍然是皮质纹状体回路。遭受极端形式的创伤和忽视的人更容易患上与酒精使用障碍共存的情绪障碍，例如焦虑和抑郁。目前尚不清楚酗酒究竟如何增加这些神经精神疾病的日后风险。另一个悬而未决的问题是，为什么有些人对压力的影响特别敏感，而另一些人则具有弹性。这种个体间的差异表明，遗传学在调节压力方面发挥着重要作用，这一观点得到了最近对人类的研究的支持。不幸的是，在严格控制的条件下研究遗传和环境对人类行为的影响存在固有的局限性。动物模型提供了一个有价值的替代方案。由于基因上不同的小鼠品系的可用性和工程基因突变体的能力，实验室小鼠可能提供一个优秀的模型系统来研究调节行为的神经因素。行为科学和遗传学部分致力于开发认知异常和酒精使用障碍的小鼠模型。该实验室从事的研究旨在阐明长期饮酒对皮质纹状体系统及其行为输出的影响。我们采用了通过乙醇蒸气进行慢性间歇性乙醇 (CIE) 暴露的程序。我们的数据表明，CIE 暴露在我们在其他认知行为研究中发现的相同皮质纹状体区域中产生了显着的结构和功能改变。我们在 CIE 后观察到的 DLS 中显着的结构和功能变化将支持 DLS 异常的某些作用。为了测试慢性乙醇对任务表现的影响，我们在辨别学习之前或逆转之前将小鼠暴露于 CIE。这些实验表明，CIE 暴露显着减少了学习或逆转后重新学习过程中所犯的错误数量。值得注意的是，CIE 诱导的再学习促进仅限于训练的后期，其促进模式类似于我们之前在前额皮质损伤后发现的模式。根据上述方案，这提出了一种可能性，即增强的逆转是由 CIE 引起的 PL 功能损伤以及由此导致的由区域（包括 DLS）介导的刺激限制学习的竞争丧失引起的。然而，目前尚不清楚 CIE 后的这些变化是否一定会导致 DLS 对性能的贡献增加而不是损失。正在开展进一步的工作来定义 DLS 的作用，以便更好地解释 CIE 的行为影响。一个主要项目研究了内源性大麻素作为消除恐惧个体差异的机制的作用，恐惧消除是一种有助于从心理创伤中恢复的抑制性学习形式。我们与 George Kunos 博士的实验室合作，测试了一种提高大脑内源性大麻素水平的新药的效果（通过防止脂肪酸酰胺水解酶的降解）。我们的工作发现，全身或杏仁核内递送这种药物可促进消退受损的小鼠品系的恐惧消退。支持杏仁核作为效应位点，AM3506 的消退促进作用被杏仁核内 CB1R 拮抗作用所阻断，并被杏仁核内 AM3506 重演。这些发现揭示了治疗创伤的新的潜在治疗方法。我们目前正在跟进这项工作，研究所涉及的精确机制，重点是杏仁核血清素系统和抗抑郁药物氟西汀的相互作用。另一个主要项目测试了 CIE 对各种行为的影响，包括强迫性寻求乙醇的恐惧消退。我们的研究结果表明，EtOH 诱导的 NMDAR 介导的皮质神经元爆发丧失会破坏消退的编码，从而损害行为。更一般地说，这些观察结果提供了慢性乙醇如何破坏皮质杏仁核功能的新证据，并预测依赖于该回路的其他行为，例如强迫性吸毒，将受到慢性乙醇的不利影响。在临床上，我们的研究结果可能对理解 AUD 和焦虑共病的神经基础具有重要意义。例如，皮质消退调节的丧失可能会损害心理创伤的恢复和基于消退的疗法的功效，从而增加患创伤后应激障碍（PTSD）等焦虑症的风险。持续的焦虑反过来可能会促进进一步的酗酒，导致滥用的恶性循环并逐渐削弱前额叶功能。出于同样的原因，改善创伤恢复的治疗（例如内源性大麻素靶向）可能有助于打破这一循环，从而减少焦虑和酗酒。