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)具有常见且令人衰弱的影响，但许多目前治疗慢性PTSD的药物治疗会留下残余症状。治疗和/或预防创伤后应激障碍的改进治疗方法的发展可能源于对创伤后应激障碍的神经生物学的更好理解，这可以通过动物模型的改进而获得。为了建立一个用于治疗和机制研究的创伤后应激障碍病理模型，我们建议检查两个与创伤后应激障碍症状严重程度相关的一致生物标志物之间的关系：(1)海马区结构和功能的破坏；(2)脑脊液中CRF水平的升高。该项目旨在确定CRF过度信号是否足以诱导海马区改变，以及这些影响是否可逆。 该项目使用一种新的超高分辨率、锰增强磁共振成像(MEMRI)与灌注MRI相结合的方法来研究PTSD转基因小鼠模型的海马体体积和血流。本研究的具体目的是检测前脑短暂过度表达促肾上腺皮质激素释放因子(CRFOE)前后的海马体体积和功能。在一组间隔组的纵向设计中，24只在多西环素(Camk2a-rTta2“dox-on”系统结合tet-o-CRF转基因)治疗后瞬时过表达CRF的转基因小鼠将在基线时与24只未治疗的小鼠进行比较，实验组多西环素治疗一个月后，多西环素治疗终止100天后。先前的研究表明，所提出的转基因小鼠模型通过Camk2a-rTta2转基因技术对CRF的表达具有时间和区域控制。经多西环素治疗3周后，突变小鼠海马区和大脑皮层CRF基因表达增加2-3倍，海马区CRF多肽含量显著增加，而小脑、脑干和其他非前脑区域无明显变化。这些小鼠在海马区依赖的记忆任务中也表现出行为障碍。UCSD的双转基因小鼠模型的建立和UCSD的超高分辨率MEMRI和小鼠MRI灌注方案的实施证明了这项研究的可行性。这项研究设计利用了MRI的可重复性，并将涉及直接转化为人类创伤后应激障碍研究的成像方案。这项研究与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。这项研究的潜在影响与CRF过度表达的时间控制有关，作为一种手段，研究干预的时机可能保护或逆转PTSD所观察到的海马区功能障碍。这一时间信息应该有助于优化动物治疗研究，并可以提供关于应激障碍，特别是创伤后应激障碍的海马区功能障碍的病因的信息。

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.