Live imaging of brain circuitry in mouse models of PTSD

创伤后应激障碍 (PTSD) 小鼠模型脑回路的实时成像

基本信息

批准号：
8481583
负责人：
ELAINE L BEARER
金额：
$ 49.65万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
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：
2012-07-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8481583
关键词：
Address Adult Affect Alleles American Anatomy Animal Model Animals Anxiety Disorders Arousal Behavior Behavioral Biological Biological Assay Biological Neural Networks Brain Brain imaging Cholecystokinin Cocaine Computer software Coupled Custom Data Set Diagnosis Diagnostic Diagnostic tests Dissection Early-life trauma Event Exposure to Extinction (Psychology)Fright Future Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genotype Gulf War Histology Human Image Image Analysis Individual Knock-in Mouse Knock-out Knockout Mice Life Life Stress Limbic System Link Location Longevity Magnetic Resonance Imaging Maintenance Manganese Maps Measures Medical Mental disorders Metabolism Methods Minisatellite Repeats Mission Molecular Mood Disorders Mus Mutation National Institute of Mental Health Neurons Numbness Odors Pattern Pharmaceutical Preparations Phenotype Post-Traumatic Stress Disorders Predisposition Promoter Regions Protocols documentation Psyche structure Psychopathology Public Health Publications Regulation Reporting Research Resolution Risk Rodent Rodent Model Role Selective Serotonin Reuptake Inhibitor Serotonin Staging Stimulus Stress Structure Symptoms Synaptic Cleft System Technology Testing Text Therapeutic Intervention Time Transgenic Mice Transgenic Organisms Variant Veterans Work base cohort combat design drug of abuse early experience empowered experience frontal lobe human subject mouse model mutant neural circuit neural patterning neurobehavioral preclinical study psychologic relating to nervous system research study response serotonin transporter tool

项目摘要

DESCRIPTION (provided by applicant): Live imaging of brain circuitry in mouse models of PTSD Post-traumatic stress disorder (PTSD) occurs after experiencing a life-threatening event and is predicted to affect many returning veterans, yet a major unmet medical need is for reliable methods of prediction, diagnosis and treatment. People with PTSD display alterations in brain functional anatomy and in brain structures, and many experience relief from selective serotonin reuptake inhibitors, linking anatomical changes in PTSD to the serotonergic system. Genetic studies show an association with polymorphisms in the serotonin transporter (SERT, 5-HTT) gene with risk of affective disorders including PTSD. Evidence that serotonin metabolism underlies stress-activated psychopathologies comes from three lines of research: 1) Rodent models, with genetic alterations of SERT or after fear provocation with predator odor; 2) Genetic dissection of human SERT, SLC6A4, and association of alleles with behavior; and 3) Magnetic resonance imaging (MRI), both functional and structural, of human subjects and mouse models. Our working hypothesis is that fear evokes neural activity that in some individuals continues long after the traumatic event resolves, leading to changes in functional anatomy of the mesolimbic cortical circuit. We further hypothesize that persistent activity occurs when SERT levels are low and/or in adults who experienced trauma early in life. Our specific aims are to: (1) Map and measure the intensity and duration of neural responses to fear in wild-type and SERT mutants; (2) Measure the impact of fear on functional circuitry; and (3) Quantify effects of early life trauma on neural activity and mesocortical limbic circuitry in the adult. We will measure the neural activity and circuitry changes before and after fear with time-lapse, quantitative manganese-enhanced MRI of living mice at 11.7T giving 90¿m3 voxel resolution, and the effects on anatomy with DTI and histology. Transgenic mice, including the validated mouse model of PTSD (SERT knock-out), and new transgenics in which 50kb of the mouse SERT locus has been replaced with human SERT alleles (long or short variants), will be imaged and compared with wild-type littermates. Predator odor will be used to provoke fear responses. To reveal whether SERT mutants affect a common neural network, cholecystokinin knock-out mice with a behavioral phenotype similar to SERT mutants will be imaged and analyzed in parallel. Datasets of 3D whole brain MR images from cohorts of each genotype will be analyzed statistically on a voxel-wise basis with custom-designed computational software. This study is the first to link genetics, functional and structural MRI with fear responses in this new transgenic mouse model carrying human gene alleles of the serotonin transporter. The successful completion of this proposed preclinical study will provide information necessary to address the unmet need by identifying: a) genetic susceptibilities for prediction of risk; and b) sequence of functional changes in the brain during progression to PTSD for design of stage-specific diagnoses and therapeutic interventions.

描述（由适用提供）：在经历了威胁生命的事件后，发生了PTSD创伤后应激障碍（PTSD）小鼠模型中脑电路的实时成像，并预计会影响许多退伍军人，但是对于可靠的预测，诊断和治疗方法，主要的未满足医疗需求是对可靠的医疗需求。患有PTSD的人在脑功能解剖结构和大脑结构中显示改变，许多人可以缓解选择性5-羟色胺再摄取抑制剂，将PTSD的解剖学变化与5-羟色胺能系统联系起来。遗传研究表明，在5-羟色胺转运蛋白（SERT，5-HTT）基因中与包括PTSD在内的情感障碍风险的多态性相关。 5-羟色胺代谢是压力激活的心理病理学基础的证据来自三项研究：1）啮齿动物模型，SERT的遗传改变或恐惧挑衅以捕食者气味而改变； 2）人类SERT，SLC6A4和等位基因与行为的关联的遗传解剖； 3）人类受试者和小鼠模型的功能和结构的磁共振成像（MRI）。我们的工作假设是，恐惧唤起了神经活动，在某些人发生创伤事件后很长一段时间内，恐惧会导致中唇皮质回路功能解剖结构的变化。我们进一步假设，当Sert水平较低和/或生命早期经历创伤的成年人时，持续活动就会发生。我们的具体目的是：（1）地图并测量野生型和SERT突变体恐惧的神经反应的强度和持续时间；（2）衡量恐惧对功能电路的影响；（3）量化早期生命创伤对成年人神经元活性和中皮层回路的影响。我们将通过延时，定量锰增强小鼠的MRI在11.7T的恐惧之前和之后的神经元活性和电路变化，得出90®M3Voxel分辨率，以及对DTI和组织学的解剖结构的影响。转基因小鼠，包括经过验证的PTSD的小鼠模型（SERT敲除），将成像50kb的小鼠SERT基因座（长或短变体）代替50kb，与野生型垃圾倍人相比。捕食者气味将用于引起恐惧反应。为了揭示SERT突变体是否影响通用的神经网络，将成像和平行分析具有类似于SERT突变体的行为表型的胆囊动蛋白敲除小鼠。来自每个基因型队列的3D全脑MR图像的数据集将使用自定义设计的计算软件以统计范围进行统计分析。这项研究是第一个将遗传学，功能和结构MRI与恐惧反应联系起来的，该反应在这种新的转基因小鼠模型中，载有5-羟色胺转运蛋白的人类基因等位基因。这项拟议的临床前研究的成功完成将提供必要的信息来通过识别：a）预测风险的遗传敏感性； b）在阶段特异性诊断和治疗干预措施设计过程中，大脑的功能变化序列。