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

PTSD 小鼠模型海马体积和功能的 MRI 评估

• 批准号: 8513417
• 负责人: Gregory G Brown
• 金额: $ 22.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-18 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513417
• 关键词: Adult; Aftercare; Animal Model; Animals; Anxiety Disorders; Behavior Therapy; Behavioral; Biological Markers; Blood flow; Brain; Brain Stem; Cerebellum; Cerebrospinal Fluid; Chronic Post Traumatic Stress Disorder; Corticotropin-Releasing Hormone; Development; Disease; Doctor of Philosophy; Doxycycline; Etiology; Exhibits; Feasibility Studies; Functional disorder; Future; General Population; Genetic; Health Status; Hippocampus (Brain); Hormones; Human; Image; Impairment; Interdisciplinary Study; Intervention; Learning; Left; Link; Magnetic Resonance Imaging; Manganese; Memory; Mental disorders; Messenger RNA; Modeling; Mus; Mutant Strains Mice; National Institute of Mental Health; Neurobiology; Neurons; Neuropeptides; Occupational; Pathology; Peptides; Performance; Perfusion Weighted MRI; Pharmaceutical Preparations; Pharmacotherapy; Play; Post-Traumatic Stress Disorders; Prevalence; Prophylactic treatment; Prosencephalon; Protocols documentation; Recovery; Regulation; Relative (related person); Research; Research Design; Residual state; Role; Severities; Strategic Planning; Stress; Structure; Symptoms; System; Technology; Testing; Tetanus Helper Peptide; Therapeutic; Time; Time Study; Tissues; Transgenes; Transgenic Mice; Translating; behavioral impairment; biological adaptation to stress; brain volume; design; effective therapy; imaging modality; improved; longitudinal design; manganese chloride; mouse model; novel; prevent; social; stress disorder; therapy development; transgene expression; ultra high resolution

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.

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，但目前许多治疗慢性 PTSD 的药物疗法留下了残留症状。治疗和/或预防 PTSD 的改进治疗方法的开发可能源于对 PTSD 神经生物学的更好理解，而这种理解可以从动物模型的完善中获得。为了创建用于治疗和机制研究的 PTSD 病理学模型，我们建议检查与 PTSD 症状严重程度相关的两个一致生物标志物之间的关联：(1) 海马结构和功能的破坏，以及 (2) 脑脊液 (CSF) 中 CRF 水平的增加。该项目旨在确定 CRF 超信号传导是否足以诱导海马体改变以及这些影响是否可逆。 该项目采用超高分辨率锰增强磁共振成像 (MEMRI) 与灌注 MRI 的新颖整合来研究 PTSD 转基因小鼠模型的海马体积和血流。该研究的具体目的是检查前脑中促肾上腺皮质激素释放因子（CRFOE）短暂过度表达之前和之后的海马体积和功能。在组间纵向设计中，将用强力霉素（Camk2a-rTta2“dox-on”系统与tet-o-CRF转基因组合）治疗时暂时过度表达CRF的24只转基因小鼠与24只未治疗的小鼠进行基线比较，实验组进行一个月的强力霉素治疗后以及终止强力霉素治疗后100天。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 表达具有时间和区域控制。用多西环素饲料治疗3周的突变小鼠，海马和皮质中的CRF mRNA增加了2-3倍，海马中的CRF肽显着增加，而小脑、脑干和其他非前脑区域保持不变。这些小鼠在海马依赖性记忆任务上也表现出行为障碍。加州大学圣地亚哥分校双转基因小鼠模型的建立以及超高分辨率 MEMRI 和小鼠 MRI 灌注方案的实施证明了该研究的可行性。该研究设计利用了 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。该研究符合 NIMH 战略计划的目标 3，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，作为研究可能保护或逆转 PTSD 中观察到的海马功能障碍的干预措施时机的手段。这些时间信息应该有助于优化动物治疗研究，并可以提供有关一般应激障碍（特别是创伤后应激障碍）中海马功能障碍的病因学的信息。

项目成果

DTI-identified microstructural changes in the gray matter of mice overexpressing CRF in the forebrain.

• DOI: 10.1016/j.pscychresns.2020.111137
• 发表时间: 2020-10-30
• 期刊: Psychiatry research. Neuroimaging
• 作者: Deslauriers J;Toth M;Scadeng M;McKenna BS;Bussell R;Gresack J;Rissman R;Risbrough VB;Brown GG
• 通讯作者: Brown GG