A significant number of studies report that individuals suffering from chronic inflammatory diseases including allergic and autoimmune diseases have a higher incidence of psychiatric complications related to increased emotional reactivity and poor coping responses to stress. Such mental complications including depression and anxiety disorders impose a great burden to these patients which has been also related to the poor prognosis of the inflammatory condition. The reasons for this association are poorly understood and research on potential mechanisms is lacking. Results from our studies and those of our collaborator show that in experimentally controlled conditions, behavioral alterations indicative of increased emotional reactivity develop as a result of the activity of peripheral lymphocytes which are responsible for the initiation and maintenance of inflammatory diseases. There is however significant controversy if the activity of these immune cells is directly related with neurobehavioral mechanisms or if it is a phenomenon that develops in parallel with other neuroimmunological processes responsible for the manifestation of behavioral pathology. The present application will evaluate if activated T lymphocytes in the periphery are necessary and sufficient to induce emotional behavioral changes. Using state of the art methods in immunology by employing the RAG2-/- deficient mice which lacks mature T lymphocytes, we plan to assess if reconstitution by adoptive transfer of in vitro differentiated T cells is a condition capable of inducing altered emotional behavior and deficient responses to psychogenic stressors. RAG2-/- mice will be reconstituted with either in vitro differentiated TH1 or TH2 cells obtained from RAG2 D011.10 transgenic mice. These mice express the transgene for the T-cell antigen receptor that is specific for ovalbumin and therefore these animals do contain OVA specific T-cells. Groups of reconstituted mice will be then challenged with OVA antigen and evaluated in the open field, elevated plus maze, social interaction and sucrose preference tests. Control groups will consist of naive RAG2-/- mice under different immunization protocols and reconstituted RAG2-/- mice not immunized (not activated). Based on our recent studies about trafficking of activated T cells into the brain and their effects on cytokine expression, their presence in the brain will be studied by immunohistochemistry and cytokine mRNA expression by real-time RT-PCR. These experiments are proposed within the framework of an R21 application to test if differences on behavior under the different reconstitution strategies are quantifiable. These studies may provide a working model to further study the mechanisms by which lymphocytes exert specific effects on brain function and behavior and yield valuable information on neuroimmune mechanisms involving the adaptive arm of the immune response. This may advance the understanding of mind-body interaction and lead to the development of new strategies of interventions to improve the treatment of mental disorders in chronically ill patients.
Chronic inflammatory diseases including allergic and autoimmune diseases are highly prevalent in the U.S. Studies have documented that individuals suffering from these conditions have a high incidence of anxiety and depressive disorders. However, the mechanisms underlying this relationship are poorly understood. The present studies will evaluate if the activity of differentiated lymphocytes are responsible for neurobehavioral alterations during peripheral inflammation. The results of the proposed experiments may lead to new strategies of intervention for balancing emotions in chronically ill patients.
|Clark, Sarah M; Michael, Kerry C; Klaus, Joseph et al. (2015) Dissociation between sickness behavior and emotionality during lipopolysaccharide challenge in lymphocyte deficient Rag2(-/-) mice. Behav Brain Res 278:74-82|