TABLE 1.
Animal studies of immune regulation of spontaneous/conditioned fear.
| Model | PD-relevant phenotype and effect | Potential immune effectors | Brain region(s) implicated | References |
| Panic-relevant (spontaneous) | ||||
| CO2 Inhalation | Freezing, respiration, blood pressure | TDAG8, IL-1β, IL-1RA | SFO | Vollmer et al. (94) |
| Freezing, rearing | IL-1β, IL-1R1, IL-1RA | SFO, mPFC, amygdala, PAG | McMurray et al. (152) | |
| Microglia | Nucleus tractus solitarius, locus coeruleus | Marques et al. (169) | ||
| Panic-relevant (conditioned fear) | ||||
| Fear conditioning (FC) (without prior stress; no follow up behavior) | Conditioned fear (freezing), extinction (freezing) | IL-6 | Young et al. (76) | |
| Contextual extinction acquisition (freezing) | TNF-α | Whole brain and hippocampus | Yu et al. (203) | |
| Auditory extinction acquisition (freezing) | IFN- α, IL-1β, TNF-α | Amygdala | Bi et al. (215) | |
| Extinction acquisition (freezing) | IL-6 | Amygdala | Hao et al. (202) | |
| Contextual fear extinction (Freezing); Open field (center duration), Elevated Plus Maze (open arm time) | Nlrp3 inflammasome: cleaved Casp1, IL-1β, and TNFα | Hippocampus | Dong et al. (204) | |
| Models of panic vulnerability (stressors exacerbating later panic-relevant outcomes) | ||||
| Early life stressor: neonatal maternal separation | Impaired response to influenza infection: IL-1, IL-6, IL-12, IFN-g, and TNFa mRNA in lung (IL-1, TNFa and IFNg only in females) corticosterone | Avitsur et al. (228) | ||
| Open field (center time), forced swim test (immobility) | CD8+ T cells, spleen T cell CD4/CD8 ratio, thymocytes, corticosterone | Roque et al. (229) | ||
| CD8/CD4 cell ratio, natural killer cells, lymphocytes (monkeys) | Lubach Coe and Ershler (230) | |||
| Cardio/respiratory control | Synaptic pruning via microglia | Medulla, Nucleus tractus solitarius, dorsal motor nucleus of vagus | Baldy et al. (168) | |
| CO2 sensitivity: respiratory response to 6% CO2 inhalation | N/A | Luchetti et al. (164), Cittaro et al. (163), Giannese et al. (166), Battaglia et al. (126), D’Amato et al. (65), Giannese et al. (166) | ||
| Early life stressor: repeated cross fostering | CO2 sensitivity: respiratory response to 5% CO2 inhalation | N/A | Genest et al. (167) | |
| Neonatal dexamethasone treatment increases susceptibility to experimental autoimmune encephalomyelitis in adult rats corticosterone, TNFα, IL-1β release Changes peripheral T cell Vbeta repertoire | Peritoneal macrophages | Bakker et al. (231), Bakker et al. (232) | ||
| changes in microbiota | Daft et al. (233) | |||
| Anxiety-relevant behaviors in males | Bartolomucci et al. (234) | |||
| Fear conditioning (freezing) | IL-1β (Astrocytes) | Hippocampus | Jones et al. (208), Jones et al. (210), Jones et al. (210) | |
| Stress-enhanced fear learning (SEFL) | N/A | IL-1β, IL-18, IL-6, IL-10, monocyte chemotactic protein (MCP-1), DAMPs (uric acid and Hsp72) | Plasma | Maslanik et al. (235) |
| Inescapable shocks | Fear memory | peripheral T lymphocytes | Clark et al. (205) | |
| Predator stress | Fear conditioning acquisition (freezing), 2-way Avoidance/Escape (active responding, escape failures), motor activity, fatigue | plasma TNF; corticosterone; dysregulated immune pathway gene expression | PFC, Amygdala, Periphery (plasma/spleen) | Azzinnari et al. (236) |
| Social defeat/chronic social stress | Anxiety-relevant behavior (Open field test, elevated plus maze) | Monocytes, macrophages, IL-1β | Spleen, whole brain | Lisboa et al. (182) |
| Tachycardia, heart rate variability | Morais-Silva et al. (192) | |||
| Anxiety-relevant behavior (open field test, light-dark preference) | IL-1β, IL-1R1, TNFα, IL-6 | Brain | Wohleb et al. (184) | |
| Social defeat/chronic social stress restraint stress | Social exploration | IL-1R1 | Hippocampus | DiSabato et al. (185) |
| Inescapable shocks | Anxiety-relevant (Open field test) | IL-1β, monocytes | McKim et al. (186) | |
| Predator stress | Anxiety-relevant (light-dark preference) | Macrophages, IL-1b, IL-6, TNFa | Brain | Wohleb et al. (187) |
| Social defeat/chronic social stress | Monocyte-derived microRNA106b∼25 | Pfau et al. (188) | ||
| IL-6 | periphery | Hodes et al. (189) | ||
| Social interaction | Dihydrocaffeic acid (DHCA) and malvidin-3′-O-glucoside (Mal-gluc), IL-6 | Wang et al. (190) | ||
| IL-6 | Nucleus accumbens | Menard et al. (191) | ||
| Bradypnea | Dorsal medial hypothalamus, nucleus of the solitary tract | Brouillard et al. (194) | ||