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：
10248091
负责人：
ANDREW HOLMES
金额：
$ 235.98万
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/10248091
关键词：
Address Alcohol abuse Alcohols Amygdaloid structure Animal Model Antidepressive Agents Anxiety Anxiety Disorders Behavior Behavioral Behavioral Sciences Biological Models Brain CNR1 gene Chronic Clinical Cognitive Collaborations Data Discrimination Learning Drug Delivery Systems Emotional disorder Endocannabinoids Enzymes Ethanol 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 Science of genetics Serotonergic System Stimulus Stress Structure System Testing Therapeutic Training Trauma Trauma recovery Work addiction alcohol use disorder base behavioral genomics behavioral impairment comorbid depression comorbidity 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, 2017 to September, 2018) 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。行为和基因组神经科学实验室在今年（2017年10月至2018年9月）继续进行一项研究计划，旨在开发情绪障碍和成瘾的小鼠模型，其重点仍然集中在皮质层状电路上。受到极端形式的创伤和忽视形式的人更容易患有与酒精使用障碍合并的情绪障碍，例如焦虑和抑郁症。尚不清楚酗酒如何增加以后对这些神经精神疾病的风险。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，可以研究由于遗传赋予小鼠菌株的可用性和工程基因突变体的能力而导致的神经因素调节行为。行为科学和遗传学的部分旨在开发认知异常和酒精使用障碍的小鼠模型。该实验室进行了研究，该研究旨在阐明确定慢性酒精对皮质纹状体系统及其行为产量的影响的作用。我们采用了通过EtOH蒸气进行慢性间歇性ETOH（CIE）暴露的程序。我们的数据表明，CIE暴露在我们在其他研究中发现的同一皮质层状区域中产生了明显的结构和功能改变。我们在CIE后在DLS中观察到的明显结构和功能变化将支持DLS异常的某些作用。为了测试慢性ETOH对任务性能的影响，我们在歧视学习之前或在逆转之前将小鼠暴露于CIE。这些实验表明，CIE暴露在逆转后学习或重新学习期间犯的错误数量显着减少。值得注意的是，CIE引起的重新学习促进仅限于训练的后期，其促进方式类似于我们在前额叶皮层病变后早些时候发现的。根据上面概述的计划，这增加了增强逆转的可能性是由CIE诱导的PL功能性病变以及在包括DLS在内的地区介导的刺激结合学习中导致的竞争丧失。但是，目前尚不清楚CIE之后的这些变化是否一定会导致DLS对性能贡献的增益而不是损失。为了更好地解释CIE的行为影响，正在采取进一步的工作来定义DLS的作用。一个主要项目研究了内源性大麻素作为恐惧消灭中个体差异的基础机制的作用，这种抑制性学习形式有助于从心理创伤中恢复。与乔治·库诺斯（George Kunos）博士合作，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治疗创伤的新潜在治疗方法。目前，我们正在研究有关涉及的精确机制的研究，重点是与杏仁核5-羟色胺系统和抗抑郁药氟西汀的相互作用。另一个主要项目测试了CIE对各种行为的后果，包括强迫性Etoh的恐惧灭绝。我们的发现提出了一种方案，通过ETOH诱导的NMDAR介导的皮质神经元爆发的损失编码灭绝以损害行为。更普遍地，这些观察结果提供了新的证据表明，慢性EtoH如何破坏皮质型乳糖功能，并预测其他取决于该电路的行为（例如强迫性吸毒）将受到慢性ETOH的不利影响。从临床上讲，我们的发现可能对了解合并音频和焦虑的神经基础具有影响。例如，灭绝皮层调节的损失可能会损害心理创伤和基于灭绝的疗法的疗效，从而增加患焦虑症（例如PTSD）的风险。持续的焦虑反过来可能会促进进一步的酒精滥用，从而导致滥用的恶性循环并逐渐削弱前额叶功能。同样，可以改善从创伤中恢复的治疗方法（例如，内源性大麻素靶向）可以帮助减少焦虑和酗酒。