MRI Assessment of Hippocampal Volume and Function in a Mouse Model of PTSD

描述（由申请人提供）：尽管创伤后应激障碍（PTSD）的常见和衰弱的影响，许多目前的慢性PTSD的药物治疗留下残留症状。用于治疗和/或预防PTSD的改进的治疗方法的发展可能是由于对PTSD的神经生物学的更好理解，可以从动物模型的改进中获得。为了建立一个用于治疗和机制研究的PTSD病理模型，我们建议检查与PTSD症状严重程度相关的两个一致的生物标志物之间的关联：（1）海马结构和功能的破坏和（2）脑脊液（CSF）中CRF水平的增加。该项目旨在确定CRF高信号是否足以诱导海马改变，以及这些影响是否可逆。 该项目使用超高分辨率锰增强磁共振成像（MEMRI）与灌注MRI的新集成来研究PTSD转基因小鼠模型中的海马体积和血流。这项研究的具体目的是检查前脑促肾上腺皮质激素释放因子（CRFOE）短暂过度表达前后海马的体积和功能。在组间纵向设计中，将24只在用多西环素治疗时瞬时过表达CRF的转基因小鼠（Camk 2a-rTta 2“dox-on”系统与tet-o-CRF转基因组合）与24只在基线、实验组多西环素治疗一个月后和多西环素治疗终止后100天的未治疗小鼠进行比较。先前的研究表明，所提出的转基因小鼠模型通过Camk 2a-rTta 2转基因技术对CRF表达具有时间和区域控制。用多西环素食物处理3周的突变小鼠在海马和皮质中表现出高达2-3倍的CRF mRNA增加，海马中CRF肽的稳健增加，而小脑、脑干和其他非前脑区域保持不变。这些小鼠还表现出依赖于大脑的记忆任务的行为障碍。通过在UCSD建立双转基因小鼠模型以及在UCSD实施超高分辨率、MEMRI和小鼠MRI灌注方案，证明了该研究的可行性。研究设计利用了MRI的可重复性，并将涉及直接转化为人类PTSD研究的成像协议。该研究与NIMH战略计划的目标3一致，即为精神疾病患者开发新的更好的干预措施。该研究的潜在影响与CRF过度表达的时间控制有关，作为研究干预措施时机的一种手段，可能会保护或逆转在PTSD中观察到的海马功能障碍。这一时间信息应有助于优化动物治疗研究，并可提供有关应激障碍，特别是创伤后应激障碍的海马功能障碍的病因学信息。

DESCRIPTION (provided by applicant): Despite the common and debilitating effects of post-traumatic stress disorder (PTSD), many current drug therapies for chronic PTSD leave residual symptoms. The development of improved therapeutic approaches for treating and/or preventing PTSD is likely to result from the better understanding of the neurobiology of PTSD that can be gained from animal model refinement. To create a model of PTSD pathology for treatment and mechanistic studies we propose to examine the association between two consistent biomarkers linked to PTSD symptom severity: (1) disruptions in hippocampal structure and function and (2) increases in CRF levels in cerebrospinal fluid (CSF). The project aims to determine if CRF hypersignaling is sufficient to induce hippocampal alterations and if these effects are reversible. The project uses a novel integration of ultra high- resolution, manganese-enhanced magnetic resonance imaging (MEMRI) with perfusion MRI to study hippocampal volume and blood flow in a transgenic mouse model of PTSD. The study's specific aim is to examine hippocampal volume and function before and after transient over expression of corticotropin releasing factor (CRFOE) in the forebrain. In a between group, longitudinal design, 24 transgenic mice that transiently over-express CRF when treated with doxycycline (Camk2a-rTta2 "dox-on" system combined with tet-o-CRF transgene) will be compared with 24 untreated mice at baseline, following one month of doxycline treatment for the experimental group and 100 days following termination of doxycycline treatment. Previous research has shown that the proposed transgenic mouse model has temporal and regional control over CRF expression via the Camk2a-rTta2 transgene technology. Mutant mice treated for 3 weeks with doxycycline chow exhibit an up to 2-3 fold increase in CRF mRNA in hippocampus and cortex, robust increases in CRF peptide in hippocampus, while cerebellum, brainstem and other non-forebrain regions remain unchanged. These mice also exhibit behavioral impairments on hippocampal-dependent memory tasks. The feasibility of the study is demonstrated by the establishment of the dual transgenic mouse model at UCSD and by the implementation at UCSD of an ultra high-resolution, MEMRI and mouse MRI perfusion protocols. The study design takes advantage of the repeatability of MRI and will involve imaging protocols that directly translate into human PTSD studies. The study is consistent with Objective 3 of the NIMH strategic plan to develop new and better interventions for people with mental illnesses. The potential impact of the study is related to the temporal control of CRF over-expression as a means to study the timing of interventions that might protect or reverse the hippocampal dysfunction observed in PTSD. This timing information should aid in the optimization of animal treatment studies and could provide information about the etiology of hippocampal dysfunction in stress disorders in general and PTSD in particular.