Inflammation-Induced Behavioral Alterations: A Psychogenomic Approach

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DESCRIPTION (provided by applicant): Major depression is the second largest burden of disease in the developed world and a leading cause of disability. The role of inflammation in depression has been established, yet a more complete understanding of the molecular mechanisms and biological processes associated with inflammation-induced depression requires an investigation of possibilities that lie "outside the box" of individual candidate systems. The rationale of this application is to fill the void that currently exists through a genome-wide functional analysis and network reconstruction of the mechanisms of inflammation-induced depression. We will integrate our well-validated and accepted murine model of Bacillus Calmette-Guerin (BCG) induced inflammation and our indoleamine 2,3 dioxygenase knock-out (IDO KO) mice to answer two important and rate-limiting questions: Aim 1) What genes are differentially expressed in innate immune cells in BCG-induced depression? Aim 2) What are the biological functions and networks of the BCG-induced depression genes? Aim 1 will be addressed by characterizing the transcriptome profile of innate immune cells measured using RNA-Seq. We have demonstrated the three pivotal cornerstones for this proposal. First, BCG inoculation induces long-lasting depression-like behaviors that persist for at least 3 weeks. Second, BCG-induced depression is mediated by IDO activation and IDO KO mice develop inflammation just as wild-type mice, although they do not display depression-like behaviors. Third, lung and brain macrophages play a crucial role in mounting inflammatory behavioral response. Therefore, a randomized 2x2 factorial design including two treatments (BCG-challenge and saline control) and two mice strains (wild type and IDO KO) will be used. Lung macrophages and brain microglia from 12 mice per challenge-strain group, based on power analysis, will be collected 2 weeks after challenge. Subtractive and differential expression contrasts between groups will permit identification of inflammation-induced depression genes that are expressed in a long-lasting model of depression-like behavior and: 1) are independent of changes in inflammation and immunity that may contribute to recovery, and 2) are independent of baseline strain differences. Aim 2 will be addressed using abstractionist functional analyses of the genes identified in Aim 1 and gene network reconstruction. In addition to knowledge discovery, we will test concrete hypotheses on the functional signature of depression, including: serotonin, guanine-tetrahydrobiopterin nitric oxide, and energy metabolism pathways and transcription factors. Key transcripts will be confirmed using Real Time Quantitative PCR. A multidisciplinary team with expertise in neuroscience, behavior, immunity, transcriptome analysis and bioinformatics has been assembled to accomplish the proposed research. This application is submitted to the R21 program because a targeted RNA-Seq "exploratory experiment" and innovative comparison of pathways and networks are proposed. The outcomes of the proposed research are: 1) identification of molecular mechanisms including immune pathways and regulatory motifs that underlie inflammation-induced depression, 2) elucidation of the relationship between inflammation and depression, and 3) insights on related processes such as age-dependent inflammation-induced depression and other inflammation-associated neurological disorders, including anxiety, autism, schizophrenia, Alzheimer's disease and dementia caused by human immunodeficiency virus, and addictions to alcohol and drugs.