Table 1.
Microglial activation profile induced by SD stress and related behavioral outcomes.
| Defeated subjects | Age | Stressor | Source of microglia | Microglia changes | Behavioral outcomes | Reference |
|---|---|---|---|---|---|---|
| ♂ICR mice | 8–10 w | CSD (20 days) | HPC (DG) mPFC |
↓ hippocampal microglial numbers, process lengths and soma areas No changes in microglia numbers in PFC ↓ expression levels of Iba-1 and CD11b |
↑ immobility in the TST and FST ↓ in sucrose consumption in the SPT ↓ time in the center in the OFT |
Tong et al. (2017) |
| ♂C57BL/6J mice ♂CX3CR1wt/gfp mice |
8–10 w | Acute RSD (3 days) Chronic RSD (14 days) |
Infralimbic ctx Prelimbic ctx Anterior cingulate ctx Piriform ctx Nucleus accu. Dorsal DG Basolateral AMY |
Chronic SD microglia phagocytosed more labeled material ↑ numbers of CD68hi microglia in chronic SD mice vs HC and ASD ↑ microglial phagocytosis ex vivo ↑ microglial proliferation after ASD |
↓ marking preference in the USM task in CSD CX3CR1wt/gfp mice ↓ SI in CSD mice |
Lehmann et al. (2016) |
| ♂C57BL/6 mice | 6–8 w | RSD (6 days) | HPC (DG) | ↑ soma size, shorter and thicker cell processes ↑ microglial Iba-1 immunoreactivity, augmented in caudal HPC ↑ IL-1β mRNA |
↑ latency and distance to reach the platform of the MWM ↑ time in the outer annulus of the MWM ↓ time in the target quadrant of the MWM ↑ latency to find the escape hole in the BM ↑ number of errors to reach the escape hole in the BM |
McKim et al. (2016a) |
| ♂C57BL/6 mice | 6–8 w | RSD (6 days) | Whole brain homogenates | ↑ microglia gene expression of IL-1β, IL-6, TNF-α ↑ microglia activation markers TLR-4, CCL2 and CX3CR1 |
↓ number of center entries in the OFT ↑ time to first enter the center in the OFT ↓ time spent in the interaction zone in the SAT |
Ramirez and Sheridan (2016) |
| ♂C57BL/6 mice | 6–8 w | RSD (6 days) | HPC HPT Whole brain homogenates |
↑ microglia gene expression and mRNA expression of IL-1β, IL-6, TNF-α ↑ microglia activation markers TLR-4, CCL2 and CX3CR1 |
↓ number of center entries in the OFT ↑ time to first enter the center in the OFT ↓ time spent in the interaction zone in the SAT |
Ramirez et al. (2016) |
| Donors: ♂C57BL/6 mice Recipients: ♂Rag2−/− mice |
10–13 w | CSD–(14 days) | Whole brain homogenates (-cerebellum) | Stressed/lymphocytes donors: ↑ basal gene expression of the M1 microglia cytokines IL-1β and IL-6. ↓ basal expression of the M2 marker MRC1 and muted ARG response to IL-4 Non-stressed/lymphocytes recipients: skewed microglia to a M2-like phenotype. ↑ ARG expression (basal and IL-4 stimulated) and a generally muted response of IL-1β and IL-6 to LPS stimulation |
SD → Rag mice on C57BL/6 background: ↑ transitions in the L/D box ↑ center time in the OFT ↑ interaction in the SI test ↑ time mobile in the TST SD → Rag mice on 129 background: ↑ transitions in the L/D box ↑ travel in the OFT ↑ center time in the OFT ↑ marking preference in the USM |
Brachman et al. (2015) |
| ♂C57BL/6 mice | 6–8 w | RSD (6 days) | Whole brain homogenates | ↑ microglia gene expression of IL-6 ↑ gene expression of IL-1β, IL-6, and TNF-α in ex vivo LPS stimulated microglia from RSD mice ↑ relative gene expression of IL-6 in microglia 24 days after stress cessation |
↓ time spent in the interaction zone in the SAT ↑ time spent in the corners in the SAT |
Ramirez et al. (2015) |
| ♂C57BL/6 WT mice ♂IL-1R1Ko mice ♂IL-1R1Kd mice |
6–10 w | RSD (6 days) | Whole brain homogenates | Robust change in the morphology of microglia in WT mice after RSD ↑ surface expression of the activation marker CD14 Altered gene expression of inflammatory-related genes in brain CD11b+ cells De-ramified morphology in WT and IL-1R1Kd mice with increased Iba-1 proportional area |
WT: ↑ thigmotaxis in the OFT ↑ latency to enter the center in the OFT ↓ time spent in the center in the OFT ↓ time to enter the dark zone in the L/D box ↑ time spent in the dark zone of the L/D box |
Wohleb et al. (2014b) |
| ♂C57BL/6 WT mice | 6–10 w | ASD (1 day) RSD (6 days) |
PFC AMY HPC (CA3 and DG) Whole brain homogenates |
ASD altered microglia morphology in stress sensitized mice ↑ Iba-1 proportional area in PFC, AMY and HPC (CA3 and DG) in RSD mice ↑ mRNA levels of IL-1β, TNF-α and CD14, 5 days after RSD ↓ CX3CR1 after RSD |
↑ latency to enter the center in the OFT at 0.5 and 8 days ↓ time spent in the center in the OFT at 0.5 days ↓ time spent in the interaction zone in the SAT at 0.5, 8 and 24 days ↑ time spent in the corners in the SAT at 0.5 and 24 days ↓ % time spent in the interaction zone in the SAT |
Wohleb et al. (2014a) |
| ♂C57BL/6 mice | 6–10 w | SSD (1 day) RSD (3 or 6 days) |
PFC HPC (DG) |
↑ Iba-1 immunoreactivity after RSD ↑ microglial activation (de-ramified morphology) in PFC and DG after RSD Microglia recruit peripheral myeloid cells to the brain |
↑ latency to enter the center in the OFT after RSD (3 and 6 days) ↓ time spent in the center in the OFT after RSD (3 and 6 days) ↓ time to enter the dark zone in the L/D box after RSD (6 days) ↓ time spent in the light zone in the L/D box after RSD (6 days) |
Wohleb et al. (2013) |
| ♂C57BL/6 mice | 6 w | RSD (6 days) | PFC HPC PVN AMY Whole brain homogenates |
↑ mRNA levels of IL-1β, TNF-α, iNOS and CD14 ↑ IL-1β and TNF-α mRNA levels after LPS injection Hypertrophic microglia with shorter and thicker processes ↑ inflammatory response of brain CD11b+ cells following a peripheral LPS challenge ↑ activated morphology of microglia (Iba-1+) in the PFC, AMY, PVN, and HPC Amplified surface expression of CD14 after LPS injection |
↓ social exploratory behavior ↓ time spent in the center in the OFT ↑ latency to enter the center in the OFT |
Wohleb et al. (2012) |
| ♂C57BL/6 mice ♂IL-1R1−/− mice |
6–8 w | SSD (1 day) RSD (3 days) RSD (6 days) |
AMY PFC HPC |
↑ de-ramified (shorter and thicker processes by Iba-1) microglia in MeAMY, PFC and HPC ↑ surface markers CD14, CD68 and TLR-4 after RSD (6d) ↑ mRNA expression of interleukin IL-1β ↓ levels of glucocorticoid responsive genes (GILZ and FKBP51) ↑ ex vivo levels of IL-6, TNF-α and MCP-1 following LPS stimulation |
WT mice: ↓ time to enter the dark zone in the L/D box after RSD (6 days) ↑ time spent in the dark zone in the L/D box after RSD (6 days) |
Wohleb et al. (2011) |
Abbreviations: ASD, Acute Social Defeat; AMY, Amygdala; BM, Barnes Maze; CCL2, Chemokine (C-C motif) ligand 2; CSD, Chronic Social Defeat; Ctx, cortex; CXCL2, Chemokine (C-X-C motif) ligand 2; d, days; DG, Dentate Gyrus; FKBP51, FK506 binding protein 51; FST, Forced Swimming Test; GILZ, Glucocorticoid-induced leucine zipper; HPC, Hippocampus; Iba-1, Ionized Calcium-Binding Adapter Molecule 1; IL-1R1Kd, IL-1 receptor type-1 knock-down; IL-1R1Ko, IL-1 receptor type-1 knock-out; L/D, Light/Dark; LPS, Lipopolysaccharide; MCP-1, monocyte chemoattractant protein-1; mPFC, medial Pre-Frontal Cortex; MWM, Morris Water Maze; OFT, Open-Field Test; PFC, Pre-Frontal Cortex; PND, Post-Natal Day; PVN, Paraventricular Nucleus; RSD, Repeated Social Defeat; SAT, Social Avoidance Test; SI, Social Interaction; SSD, Single Social Defeat; Tg, Transgenic; TST, Tail Suspension Test; USM, Urine Scent Marking; w, weeks; WT, Wild-Type.