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.

Public Health Relevance

Despite the common and debilitating effects of post-traumatic stress disorder (PTSD), many current drug therapies for chronic PTSD leave residual symptoms. The proposed study aims to validate a mouse model of PTSD that uses magnetic resonance imaging to assess hippocampal tissue volume and blood flow before and following the transient release of corticotropin releasing factor, a neuropeptide involved in the regulation of the stress response. If successful, the mouse model could serve as a neurobiological platform for testing new interventions that protect against and/or treat PTSD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Meinecke, Douglas L
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University of California San Diego
Schools of Medicine
La Jolla
United States
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