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，许多目前的药物治疗慢性创伤后应激障碍留下残留症状。对创伤后应激障碍神经生物学的更好理解可以从动物模型的改进中获得，这可能会导致治疗和/或预防创伤后应激障碍的改进治疗方法的发展。为了创建一个创伤后应激障碍的病理模型，用于治疗和机制研究，我们建议检查与创伤后应激障碍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；(2)脑脊液（CSF）中CRF水平的增加。该项目旨在确定CRF高信号传导是否足以诱导海马改变，以及这些影响是否可逆。

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.