About This Project

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What is the context of this research?

Posttraumatic stress disorder (PTSD) is a predominant form of anxiety disorders (ADs), with a particularly high prevalent rate in returning veterans or victims of traumatic early-life bad experience such as sexual abuse, maltreatment, and neglect. Clinically, it is featured by three core symptoms, including reexperiencing of previous traumatic events, persistent avoidance/numbing, and hyperarousal. Frequent expression of these symptoms, or the comorbidity of other psychiatric entities such as depression, will dramatically disable victims’ mental life. Despite extensive studies, however, the underlying pathogenic mechanism is still not clear, nor is an effective therapy currently available. Recently clinical evidence has indicated that morphological changes in the hippocampus, a critical brain region that is essentially involved in fear response and cognition in the human, are critically involved in the development of PTSD. However, in human patients, it is very difficult to further understand how these morphological changes impact the pathogenic processing. Recently, we have developed a robust PTSD model in the mouse by combining genetic manipulation and adolescent trauma. This mouse model shows many behavioral phenotypes that resemble to symptoms of human PTSD patients. With this powerful model, we have recently further identified that a significant morphological change at the synaptic level in the hippocampus is associated with the development of behavioral phenotypes. Therefore, it is of a significant interest to further study how these morphological changes are related to behavioral abnormalities in these PTSD mice.

What is the significance of this project?

In this project, we will determine whether a manipulation of an endocrine system, namely CRF, in the brain during the stage of trauma exposure is able to prevent the development of PTSD-like behavior in our PTSD mouse model. In order to further elucidate the neuronal mechanism, efforts will be made on the effect of this manipulation on synaptic morphological changes in this model. Multiple experimental approaches will be employed, and the outcome from these studies will elucidate how the morphological changes in the hippocampus are involved in both the pathogenesis and therapeutic aspects. Most importantly, through these studies, we will be able to define a specific time window during which we can dramatically decrease the effect of trauma, so that we will be able to develop the paradigm that is able to prevent the development of PTSD. Once our concept is approved in our PTSD animal model, we will move to human studies, and once it is demonstrated to be effective for human subjects too, it is expected that our new strategy will have a significant impact for most PTSD patients, especially for those who have exposed to traumatic insults.

What are the goals of the project?

In this project, we will have the following goals:

1. We will determine in which stage, e.g. trauma exposure, post-trauma "incubation", and the expression of PTSD-like symptom, the manipulation of the CRF system in the brain effectively prevents the development of PTSD-like symptoms in these PTSD mice. We will treat mice with a CRF antagonist during the different stages as described above, and then PTSD-liek symptoms will be evaluated by using a battery of behavioral tests such as fear-conditioning, etc. It is well known that a long-term treatment with CRF antagonist will produce some side effect. Therefore, a stage-specific treatment will be most valuable for our goal to fight against PTSD. Such a goal can only be first tested in the PTSD animal models.

2. We will determine the effect of these CRF manipulations on the morphological changes in the hippocampus of PTSD mice, in order to further understand what is the relationship between the morphological changes and behavioral phenotypes, and between the morphological changes and therapeutic revenue, and between the behavioral changes and CRF system and the pathogenesis of PTSD. Synaptic morphology, such as spine density and spine shape will be our focus. Gene-gun-based morphological approach and Camera-based lucida analysis will be used.