Table_1_Alterations of the Innate Immune System in Susceptibility and Resilience After Social Defeat Stress.PDF

<p>Dysregulation of innate immune responses has frequently been reported in stress-associated psychiatric disorders such as major depression. In mice, enhanced circulating cytokine levels as well as altered innate immune cell numbers have been found after stress exposure. In addition, stress-induced recruitment of peripheral monocytes to the brain has been shown to promote anxiety-like behavior. However, it is yet unclear whether specific differences in the innate immune system are associated with stress susceptibility or resilience in mice. Utilizing chronic social defeat, a model of depression and stress vulnerability, we characterized peripheral and brain-invading myeloid cells in stress-susceptible and resilient animals. In all defeated animals, we found reduced percentages of CD11c⁺ dendritic cells (DCs) by flow cytometry in the spleen when compared to non-defeated controls. Exclusively in susceptible mice conventional DCs of the spleen showed up-regulated expression of MHC class II and co-stimulatory CD80 molecules pointing toward an enhanced maturation phenotype of these cells. Susceptible, but not resilient animals further exhibited an increase in inflammatory Ly6C^hi monocytes and higher numbers of spleen-derived CD11b⁺ cells that produced the proinflammatory cytokine tumor necrosis factor (TNF) upon lipopolysaccharide (LPS) stimulation. Increased percentages of peripheral CD45^hi CD11b⁺ cells immigrated into the brain of defeated mice, regardless of resilience or susceptibility. However, cellular infiltrates in the brain of susceptible mice contained higher percentages of CC chemokine receptor 2 (CCR2⁺) Ly6C^hi monocytes representing an inflammatory phenotype. Thus, we defined specific stress-related immune signatures involving conventional DCs and inflammatory Ly6C^hi monocytes in susceptible and resilient mice. Together, our findings suggest an impact of the innate immune system in vulnerability to stress-related disorders such as major depression.</p

QUOROM flow chart used to identify studies for review.

<p>QUOROM flow chart used to identify studies for review.</p

Brain areas involved in aversive conditioning according to the modality of the US.

<p>Different brain areas (with at least unilateral activation during aversive conditioning) are plotted against the x-axis. The number of studies out of 46 studies per brain region is plotted against the y-axis, taking into account US modality, which is tactile in 33 studies (such as electrical shocks), auditory in nine studies (such as noise), olfactory in one study (such as odors), or visual in three studies (such as aversive pictures).</p

Forty-six studies on aversive conditioning and/or extinction, with forty studies on delay conditioning (including seven studies on extinction), two studies on trace, and four studies on delay and trace conditioning, with focus on main results of acquisition and/or extinction of conditioned responses (in alphabetic order).

<p>Abbreviations: ACC: anterior cingulate cortex, ant: anterior; BA: Brodman area, cau: caudal, C: cortex, CR: conditioned response, CS: conditioned stimulus, dor: dorsal, DPFC: dorsal prefrontal cortex, DLPFC: dorsolateral prefrontal cortex, DMPFC: dorsomedial prefrontal cortex, EMG: electromyography, F: female, FOP: frontal operculum, G: gyrus, inf: inferior, IAPS: International Aversive Picture System, IPL: inferior parietal lobe, lat: lateral, L: left, Lo: lobule/lobe, M: male, med: medial, mid: middle, MFL: medial frontal lobe, MPFC: medial prefrontal cortex, MTL: medial temporal lobe, N: nucleus, No.: number, OFC: orbitofrontal cortex, post: posterior, PCC: posterior cingulate cortex, PFC: prefrontal cortex, PMA: premotor area, R: right, rCBF: regional cerebral blood flow, trans: transverse, RT: reaction time, ros: rostral, SCR: skin-conductance response, SCL: skin-conductance level, SI: primary somatosensory cortex, SII: secondary somatosensory cortex, SMA: supplementary motor area, S: sulcus; sup: superior, vent: ventral, VMPFC: ventromedial prefrontal Cortex, US: unconditioned stimulus.</p

Reaction times and accuracy rate.

<p>Reaction times (mean±standard error) and accuracy rate (percentage of correct answers, mean±standard error) of 25 subjects. Asterisks denote where pair-wise comparison is significant.</p

Main effects and Fischer LSD Post-hoc tests for mean activation changes during working memory task and subsequent rest.

<p>Main effects and Fischer LSD Post-hoc tests for mean activation changes during working memory task and subsequent rest.</p

Mean of activation in the DMN.

<p>Mean of activation in the DMN were calculated for each n-back (lower values: 0-back, 1-back, 2-back) and subsequent resting block (upper values: R0-back, R1-back, R2-back). x-Axis: working memory load, y-Axis: activation as extracted by TICA for the selected component (which can differ in scaling and mean).</p

Default-mode network extracted by TICA.

<p>Top: sagittal, coronal and transversal view (Image displayed in radiological convention). Bottom: rendered 3d-view with transparent voxeldata from frontal-left- (left) and behind-left-view (right). Major clusters with coordinates, Z-score and Brodman area (BA) are: PCC (−4, −32, 28), Z = 5.86, BA 31 and (−6, −52, 12), Z = 3.87, BA 30; Precuneus (−8, −72, 28), Z = 6.44, BA 31; Cuneus (10, −74, 30), Z = 7.50, BA 18; Culmen (−8, −48, −4), Z = 3.09, BA 19; vACC (4, 16, −12), Z = 2.86, BA 25; Middle Frontal Gyrus (4, 60, −4), Z = 3.33, BA 10. Clusters exist left and right in similar size.</p

Region of interest analysis of the amygdala.

<p>Left: bar graphs depicting the mean contrast value for negative, SP-related, and positive versus neutral words extracted from x = −18, y = 0, z = −24. Error bars, SEM. Right: coronal view (y = 0), depicting the significant group x word category interaction in the bilateral amygdala.</p

Mean differences for patients with social phobia (SP) and healthy controls (HC) concerning age, verbal intelligence, depression (BDI), Trait- and State anxiety (STAI-T and STAI-S) and social phobia symptoms (SPS/SIAS).

<p><i>M</i> =  Mean; SD  =  standard deviation. BDI, Beck Depression Inventory; STAI-T, State-Trait Anxiety Inventory, Trait version; STAI-S, State-Trait Anxiety Inventory, State version; SPS, Social Phobia Scale; SIAS, Social Interaction Anxiety Scale.</p>a<p>Assessed with the Mehrfachwahl-Wortschatz-Intelligenztest <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109949#pone.0109949-Lehrl1" target="_blank">[47]</a>.</p><p>Mean differences for patients with social phobia (SP) and healthy controls (HC) concerning age, verbal intelligence, depression (BDI), Trait- and State anxiety (STAI-T and STAI-S) and social phobia symptoms (SPS/SIAS).</p