This K23 proposal is designed to provide the applicant with protected time, resources and a supervised research experience that will facilitate the development of an independent research career at the interface of behavioral immunology and neuroimaging. Neuropsychiatric disorders including depression in the medically ill are of significant public health concern, occurring in up to 50% of patients and having a major impact on treatment adherence, quality of life, morbidity and mortality. Mounting data indicate that peripheral immune system activation/inflammation and the associated release of inflammatory cytokines may play a role in the development of neuropsychiatric disorders including depression in the medically ill as well as in medically healthy individuals. Nevertheless, few studies have examined the impact of peripherally elaborated cytokines on the brain, especially the metabolism of relevant CNS cell types including both neurons and glia. The long- term objective of the proposed research and career development plan is to utilize neuroimaging technologies such as magnetic resonance spectroscopy (MRS) to measure the consequences of peripheral inflammation on brain metabolism during depression. To accomplish this goal, the applicant proposes a training plan which encompasses: a) a comprehensive set of didactics in behavioral neuroscience, neuroimaging and immunology, b) one-on-one supervision with a primary mentor and consultants, and c) a hands-on supervised research experience. The research project aims to study the association between inflammatory cytokines and behavior and makes use of the model of neuropsychiatric symptoms precipitated by the inflammatory cytokine, interferon (IFN)-alpha. Previous work in the mentor's laboratory has established that administration of IFN-alpha to humans reliably causes symptoms of depression while inducing a CNS inflammatory response. Thus, IFN-alpha provides a unique model system for testing neuroimaging strategies such as MRS to identify metabolic processes that may participate in behavioral changes that occur in the context of inflammation. The primary aim of the proposed research is to test the hypothesis that IFN-alpha-induced behavioral and cognitive changes will be associated with increased markers of glial activation and excitatory neurotransmission, accompanied by decreased markers of neuronal viability. These CNS metabolic changes in turn will be associated with activation of CNS inflammatory responses and cytokine-induced increases in excitotoxic kynurenine metabolites, including quinolinic acid. To test these hypotheses, 50 adult patients with hepatitis C will be studied pre- and post-IFN-alpha. Concentrations of biomarkers of glial activation, excitotoxicity and neuronal dysfunction in relevant brain regions including the basal ganglia will be measured by single voxel proton MRS and correlated with blood and cerebrospinal fluid biomarkers of immune activation and kynurenine metabolism. Aside from providing important insight into the mechanism by which cytokines influence behavior, these data will provide a foundation for the applicant's elaboration of an independent research program.
This K23 proposal is designed to promote the career development of the applicant, while also exploring novel brain imaging methods to investigate the impact of the immune system on the brain. Cytokines released by an activated immune system have been associated with the development of depression in both medically ill and medically healthy individuals. The proposed research will explore the mechanism of these effects by using advanced neuroimaging strategies to measure brain metabolism before and after cytokine administration and relate changes in brain metabolism to cytokine-induced changes in behavior.
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