Section Major depression is a subjective emotional state resulting in decreased mood, loss of ability to cope with stressful life events and reduced ability to experience pleasure. The incidence of major depression is increasing worldwide, and a significant proportion of patients suffering from major depression have an underlying comorbid condition of an activated innate immune system. Clinical data have already shown that symptoms of depressed mood are elicited by cytokine administration. Also, preclinical models show that physiological stressors, including psychological stress or infection, induce the production of inflammatory cytokines followed by depression-like behaviors. It is now generally accepted that symptoms of depression are associated with systemic inflammation. Negative affect, anhedonia and fatigue are all symptoms of depression that are induced by inflammatory events. However, these criteria possess distinct psychopathological constructs, suggesting discrete inflammation-dependent pathways responsible for specific symptoms. To date, the biological underpinnings of these symptom-dependent pathways have eluded characterization. The experiments in this proposal will build on our discovery that tryptophan is metabolized through divergent indolamine 2,3-dioxygenase (IDO)-dependent pathways that are uniquely responsible for deficits in motivated behavior (anhedonia and fatigue) and induction of negative affect (helplessness/despair). Three overlapping areas will be investigated to define the role of tryptophan metabolism in specific symptoms of depression.
In Aim 1, we will use preclinical genetic and pharmacological Ido floxed mouse models to characterize the tryptophan metabolizing pathways necessary for negative affect.
In Aim 2, floxed mice will then be used to clarify the role of tryptophan metabolism in motivated behaviors.
In Aim 3, we will define the regulation of tryptophan metabolism within specific brain regions relative to specific symptoms of depression, focusing on the striatum and hippocampus. These exciting and novel experiments will be the first to integrate neuroimmune regulation of tryptophan metabolism with specific symptoms of major depression. This effort is the first step toward the development of new targets to treat depression based on symptomology.

Public Health Relevance

The proposed research will significantly advance mental health research efforts based on our discovery of a new link between emotional states and the physiological stress induced by an activated innate immune system by showing a cause-effect relationship between inflammation-inducible tryptophan-degrading enzymes (IDOs) and specific symptoms of depression. This link will be determined for the first time and our proposed experiments are novel because they will identify specific pathways responsible for specific symptoms of depression. This information has eluded psychobiologists, but it is absolutely necessary to develop therapeutic profiles based on symptomology and thereby make a major contribution to the mission of the National Institute of Mental Health by developing a new approach to improve mental well-being and enhance quality of life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH101145-01A1
Application #
8759230
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Desmond, Nancy L
Project Start
2014-08-06
Project End
2017-06-30
Budget Start
2014-08-06
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$611,054
Indirect Cost
$225,774
Name
University of Illinois Urbana-Champaign
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820