Abstract
Depression symptoms following immune response to a challenge have been reported after the recovery from sickness. A RNA-Seq study of the dysregulation of the microglia transcriptome in a model of inflammation-associated depressive behavior was undertaken. The transcriptome of microglia from mice at day 7 after Bacille Calmette Guérin (BCG) challenge was compared to that from unchallenged Control mice and to the transcriptome from peripheral macrophages from the same mice. Among the 562 and 3,851 genes differentially expressed between BCG-challenged and Control mice in microglia and macrophages respectively, 353 genes overlapped between these cells types. Among the most differentially expressed genes in the microglia, serum amyloid A3 (Saa3) and cell adhesion molecule 3 (Cadm3) were over-expressed and coiled-coil domain containing 162 (Ccdc162) and titin-cap (Tcap) were under-expressed in BCG-challenged relative to Control. Many of the differentially expressed genes between BCG-challenged and Control mice were associated with neurological disorders encompassing depression symptoms. Across cell types, S100 calcium binding protein A9 (S100A9), interleukin 1 beta (Il1b) and kynurenine 3-monooxygenase (Kmo) were differentially expressed between challenged and control mice. Immune response, chemotaxis, and chemokine activity were among the functional categories enriched by the differentially expressed genes. Functional categories enriched among the 9,117 genes differentially expressed between cell types included leukocyte regulation and activation, chemokine and cytokine activities, MAP kinase activity, and apoptosis. More than 200 genes exhibited alternative splicing events between cell types including WNK lysine deficient protein kinase 1 (Wnk1) and microtubule-actin crosslinking factor 1(Macf1). Network visualization revealed the capability of microglia to exhibit transcriptome dysregulation in response to immune challenge still after resolution of sickness symptoms, albeit lower than that observed in macrophages. The persistent transcriptome dysregulation in the microglia shared patterns with neurological disorders indicating that the associated persistent depressive symptoms share a common transcriptome basis.
Highlights
Studies of behavioral and molecular changes in response to a challenge have exposed the relationship between brain inflammation and incidence of depression-like symptoms [1,2]
Bacille Calmette-Guérin (BCG)-challenged and Control mice suggests the capacity of microglia to restrain or quickly resolve transcriptomic dysregulation relative to macrophages
The differential expression of kynurenine 3-monooxygenase (Kmo) in microglia between BCG-challenged and Control mice suggests that Kmo is a potential target of pro-inflammatory cytokines in the kynurenine pathway and a potential factor of depressive-like symptoms that remain after sickness symptoms subside
Summary
Studies of behavioral and molecular changes in response to a challenge have exposed the relationship between brain inflammation and incidence of depression-like symptoms [1,2]. Peripheral infections can alter inflammatory cytokines elicited by microglia, the innate immune cells located in the brain. This alteration of cell signaling dysregulates pathways such as tryptophan metabolism that has been associated with depression-like behaviors. After peripheral challenge with Bacille Calmette-Guérin (BCG) mice display depressive-like behaviors 7 days to 1 month post challenge, well-past sickness recovery. Despite the recovery from sickness symptoms, depression-like behaviors including significant increase in the duration of immobility measured using the tail suspension test and the Porsolt forced swim test at day 6 and decrease in sucrose ingestion in the sucrose preference test at day 7 were recorded in mice challenged with BCG relative to control mice [3,4,5]
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