Posttraumatic stress disorder (PTSD) is one of the most common war-related illness and is highly comorbid with other anxiety disorders. Veterans from the recent Iraq and Afghanistan wars (Operation Enduring Freedom/Operation Iraqi Freedom) have a particularly high incidence of PTSD and other mental disorders such as anxiety and mood disorders. A significant problem for the treatment of PTSD is the lack of an appropriate pharmacological or biological intervention to treat the illness. Indeed, current medications for PTSD are used to treat associated symptoms such as depression or sleep problems and there in no formulation that effectively treat PTSD. Recent studies indicate that T lymphocytes are protective against the development of posttraumatic stress and anxiety as suggested by studies in mice. These studies show that boosting T cell mediated responses confer protection against the development of anxiety and startle responses to stress after acute exposure to predator odor. These studies further indicate that mice deficient of T cell responses are more susceptible to the effects of stress. This is in agreement with our preliminary results suggesting that other mice models of T cell deficiency are more susceptible to the development of anxiety after acute stress exposure and that reconstitution with CD4+ T cells from wild type restore adaptive responses to stress. The objective of the present application is to validate and establish a mice model of T cell function in anxiety and stress-related disorders to study the role of T cells in conferring protection against posttraumatic stress and anxiety. The central hypothesis is that T cells will confer protection to psychogenic stress by trafficking into the brain where they will stimulate the production of neurotrophic factors. It is further hypothesized that polarized T helper type 2 (TH2) cells will mediate these effects while TH1 will favor the development of pathological stress responses. To test, we will employ the RAG2-/- deficient mice which lack functional T and B cells and reconstitution of T cells by adoptive transfer from BALB/c wild type mice in 2 behavioral models of PTSD. In vitro differentiation of T cells will be applied to test the role of TH2 vs TH1 lymphocytes on posttraumatic stress and anxiety. BALB/c wild type, RAG2-/- and RAG2-/- mice reconstituted with differentiated T cells will be evaluated in the exposure to predator odor paradigm or in the extinction of conditioned Pavlovian fear responses. The first paradigm models acute exposure to psychogenic stress and later responses to stress and anxiety and the second paradigm models maladaptive fear responses. These 2 paradigms model key aspects of brain function which are affected in PTSD. Real-time RT-PCR will be used to compare cytokine mRNA expression in the brain to evaluate brain inflammatory responses and the effects of T cell treatment. These responses will be compared with peripheral levels of cytokines determined by ELISA. Immunohistochemistry and confocal microscopy will be employed to analyze the presence of T cells in the brain and the expression of neurotrophic factors.
In specific aim #1 we will compare behavioral, immunological and neurochemical responses between BALB/c wild type and RAG2-/- mice.
In specific aim #2 we will test the effects of reconstituting RAG2-/- mice with differentiated TH2 cells and in specific aim #3 we will test the effects of reconstituting RAG2-/- mice with differentiated TH1 cells in behavioral, immunological and neurochemical responses. The experiments and studies proposed in this application are aimed at establishing a pre-clinical model of neuroimmune function in PTSD and to test the role of differentiated T cells in psychogenic traumatic stress and anxiety. These studies may provide insight into cellular mechanisms of resilience to psychogenic stress that when stimulated may provide regenerative and repair functions in the brain and restore normal stress responses and behavior. This will assist in the development of new and more effective strategies of intervention for the treatment of PTSD and anxiety-related disorders.

Public Health Relevance

Posttraumatic stress disorders (PTSD) are highly prevalent in veterans of the Iraq and Afghanistan war zones. Current pharmacological treatments with psychotropic medications display poor efficacy and are generally aimed at treating associated symptoms rather than the illness. The present studies will evaluate if processes mediated by T cells confer protection against the development of posttraumatic stress and anxiety. It is hypothesized that TH2 cells will traffic to the brain after exposure to acute stress where they will stimulate the release of neurotrophic factors conferring protection against deleterious effects of stress. These studies are based upon recent findings suggesting that T cells may prevent the development of anxiety and exaggerated stress responses in a mice model of PTSD. These studies are aimed at establishing an animal model to test the efficacy of treatments with T cells to restore normal stress responses and protect against PTSD and anxiety disorders.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Mental Health and Behavioral Science A (MHBA)
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Baltimore VA Medical Center
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Song, Chang; Nicholson, James D; Clark, Sarah M et al. (2016) Expansion of brain T cells in homeostatic conditions in lymphopenic Rag2(-/-) mice. Brain Behav Immun 57:161-172
Clark, Sarah M; Soroka, Jennifer A; Song, Chang et al. (2016) CD4(+) T cells confer anxiolytic and antidepressant-like effects, but enhance fear memory processes in Rag2(-/-) mice. Stress 19:303-11