Inflammation and neurological disease-related genes are differentially expressed in depressed patients with mood disorders and correlate with morphometric and functional imaging abnormalities

Abstract

Depressed patients show evidence of both proinflammatory changes and neurophysiological abnormalities such as increased amygdala reactivity and volumetric decreases of the hippocampus and ventromedial prefrontal cortex (vmPFC). However, very little is known about the relationship between inflammation and neuroimaging abnormalities in mood disorders. A whole genome expression analysis of peripheral blood mononuclear cells yielded 12 protein-coding genes (ADM, APBB3, CD160, CFD, CITED2, CTSZ, IER5, NFKBIZ, NR4A2, NUCKS1, SERTAD1, TNF) that were differentially expressed between 29 unmedicated depressed patients with a mood disorder (8 bipolar disorder, 21 major depressive disorder) and 24 healthy controls (HCs). Several of these genes have been implicated in neurological disorders and/or apoptosis. Ingenuity Pathway Analysis yielded two genes networks, one centered around TNF with NFKβ, TGFβ, and ERK as connecting hubs, and the second network indicating cell cycle and/or kinase signaling anomalies. fMRI scanning was conducted using a backward-masking task in which subjects were presented with emotionally-valenced faces. Compared with HCs, the depressed subjects displayed a greater hemodynamic response in the right amygdala, left hippocampus, and the ventromedial prefrontal cortex to masked sad versus happy faces. The mRNA levels of several genes were significantly correlated with the hemodynamic response of the amygdala, vmPFC and hippocampus to masked sad versus happy faces. Differentially-expressed transcripts were significantly correlated with thickness of the left subgenual ACC, and volume of the hippocampus and caudate. Our results raise the possibility that molecular-level immune dysfunction can be mapped onto macro-level neuroimaging abnormalities, potentially elucidating a mechanism by which inflammation leads to depression.

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

“…These include a genome-wide expression study of peripheral blood mononuclear cells that identified increased TNF expression in depression (Savitz et al, 2013), and a post mortem brain tissue microarray study reporting increased expression of proinflammatory and anti-inflammatory cytokine pathway genes in the mPFC in depression (Shelton et al, 2011). Specific evidence for increased density or activation of microglia was not obtained in the present study.…”

“…Importantly, these same regions exhibit altered structure-function-molecular genetic changes in depression e.g. (Disner et al, 2011;Mayberg, 2003;Price and Drevets, 2010;Savitz et al, 2013;Sibille et al, 2009). The 23 experiment was conducted using next-generation sequencing, and genes that were expressed above a threshold level and were significantly altered in their expression in CSD versus CON mice were subjected to pathway analysis to identify the processes and pathways with which they are most commonly associated and their upstream regulators.…”

“…Next generation sequencing and canonical pathway analysis were applied to conduct a hypothesis-free, transcriptome-level analysis of effects of CSD on gene expression in specific brain regions. The regions selected for study, ventral hippocampus, medial prefrontal cortex, and central and basolateral nuclei of amygdala, are fundamental to the neurocircuitries underlying the behaviours under study here (Amat et al, 2005;Maren et al, 2013;Moscarello and LeDoux, 2013) as well as the corresponding depression psychopathologies (Capuron et al, 2007;Disner et al, 2011;Mayberg, 2003;Price and Drevets, 2010;Savitz et al, 2013;Sibille et al, 2009;Strigo et al, 2008). 7…”

Neuropathological and neuromorphometric abnormalities in bipolar disorder: View from the medial prefrontal cortical network

“…The reciprocal relationship between the vagus nerve and the mPFC may have implications for the regulation of the immune system, which is putatively disturbed in mood disorders (Dantzer et al, 2008;Irwin and Cole, 2011;Miller et al, 2009;Padmos et al, 2008;Savitz et al, 2013a). The vagus nerve modulates immune function via its effect on the hypothalamic-pituitary-adrenal (HPA) axis and peripheral leukocytes (Rosas-Ballina and Tracey, 2009).…”

“…Another gap in the literature is the paucity of studies evaluating microglia and/or infiltrating macrophages in mood disorders. Given emerging evidence for the role of immune dysregulation in affective illness (Dantzer et al, 2008;Miller et al, 2009;Padmos et al, 2008;Savitz et al, 2013a), postmortem studies of microglia would be an important addition to the literature. One immunohistological study has reported evidence for increased levels of microglia in depressed suicide victims (Steiner et al, 2008).…”