Table 1.
Effects of PAMPs and other microbial metabolites on emotional-affective and cognitive behavior.
| PAMP/metabolite | Main receptor | Dose | Species (sex) | Behavioral effects | Additional effects | Reference |
|---|---|---|---|---|---|---|
| MALP-2 FSL-1 |
TLR2/6 | 100 µg/kg IP | Wistar rats (male) | Sickness behavior: anorexia, adipsia, hypoactivity | Hypo- and hyperthermia, upregulated levels of proinflammatory cytokines in plasma | (137) |
| Pam3CSK4 | TLR2/1 | 200 ng/2 μl in mice, 1 μg/3 μl in rats, ICV | Mice and rats (male) | Sickness behavior: anorexia, hypoactivity | Hypothalamic inflammation and microglia activation, increased POMC neuron activity, hyperthermia | (138) |
| LTA | TLR2 | 20 mg/kg IP | C57BL/6N mice (male) | No effect 3 h after LTA injection | Upregulated levels of proinflammatory cytokines in plasma (proteins) and brain (mRNA), decreased expression of tight junction-associated proteins in the brain, increased circulating corticosterone levels | (97) |
| LPS | TLR4 | 0.83 mg/kg IP | C57BL/6 mice (male) | Acute sickness (6 h) and delayed depression (24 h) | Expression of acute (c-Fos) and chronic (ΔFosB) cellular reactivity markers | (13) |
| Crl:CD1 mice (male) | Depression-like behavior prevented by minocycline or IDO antagonist 1-MT | Enhanced kynurenine/tryptophan ratio in plasma and brain normalized by minocycline or 1-MT | (191) | |||
| 0.8 ng/kg IV | Healthy human volunteers (male) | Anxiety, depressed mood, and decreased memory performance | Increased circulating levels of IL-6, TNF-α, soluble TNF receptors, IL-1 receptor antagonist and cortisol, mild increase in rectal temperature | (87) | ||
| 0.4 ng/kg IV | Healthy human volunteers (male, female) | Anxiety, depressed mood, sickness symptoms | Increase in circulating proinflammatory cytokines and cortisol higher in females than males | (90) | ||
| 1.0 ng/kg IV | Healthy human volunteers (male) | Sickness symptoms | Microglial activation throughout the brain, increased circulating levels of proinflammatory cytokines | (91) | ||
| FK565, MDP, LPS | NOD1, NOD2, TLR4 | 3, 3, 0.1 mg/kg IP | C57BL/6 mice (male) | NOD agonists alone without effect, synergism with LPS in eliciting sickness | Hypothermia, upregulated levels of proinflammatory cytokines in plasma (proteins) and brain (mRNA), increased circulating corticosterone levels | (10) |
| Poly I:C | TLR3 | 6 mg/kg IP | Sprague–Dawley rats (male) | Reduced locomotor activity (6 h), anxiety-like behavior (24 h), reduced saccharin preference (24–72 h) | Decreased body weight gain (24 h), molecular changes in frontal cortex and hippocampus: increased proinflammatory cytokine and IDO expression (mRNA, 6 h), reduced BDNF and TrkB expression (mRNA, 6, 24, 48 h), increased tryptophan (6, 24, 48 h), and kynurenine (24, 48 h) levels | (174) |
| 2, 6, 12 mg/kg IP | C57BL/6 mice (female) | Dose-dependent acute sickness observed in OFT (4, 8, 12 h) and burrowing (6, 10, 26 h) | Upregulation of proinflammatory cytokines in plasma (protein) and brain (mRNA), biphasic core body temperature change | (96) | ||
| 12 mg/kg IP | C57BL/6J mice (male) | Deficit in contextual memory consolidation (24 h) | Diminished BDNF mRNA expression (4 h) | (176) | ||
| 4-EPS | 30 mg/kg IP for 3 weeks | C57BL/6N mice | Increased anxiety and startle reflex | Increase in 4-EPS levels in response to maternal immune activation by Poly I:C | (57) | |
| SCFAs | GPR41 | 25 mM sodium propionate, 40 mM sodium butyrate plus 67.5 mM sodium acetate in drinking water for 7 weeks | BDF1 mice overexpressing α-synuclein | Motor deficits | α-Synuclein-mediated neuroinflammation | (82) |
| GPR43 | 25 mM sodium propionate, 40 mM sodium butyrate plus 67.5 mM sodium acetate in drinking water for 4 weeks | Germ-free C57BL/6 mice (male and female) | Normalization of microglia density, morphology and immaturity (altered in germ-free mice) | (26) | ||
| Sodium butyrate | GPR41 | 1 g/kg by oral gavage for 3 days | Germ-free C57BL/6J mice (male) | Normalization of blood–brain barrier permeability which is enhanced in germ-free mice | Normalization of occludin expression in frontal cortex which is decreased in germ-free mice, increase of histone acetylation in brain lysates | (28) |
| GPR43 | 1.2 g/kg IP in single injection or for 4 weeks | C57BL/6J mice | Antidepressant-like effect | Increase of histone acetylation in hippocampus | (83) | |
| 1.2 g/kg IP | Aged (24 months) Wistar rats (male) | Rescue of aging-associated memory impairment | (84) | |||
| Propionic acid | GPR41 | 4 µl of 0.26 M solution, ICV | Adolescent (41 days) Long–Evans rats (male) | Restricted behavioral interest in a specific object, impaired social behavior, impaired reversal in T-maze task | Neuroinflammatory response | (85) |
| GPR43 | 4 µl of 0.26 M solution ICV for 8 days | Long-Evans rats | Increase of locomotor activity | Change in molecular phospholipid species in blood and brain | (86) | |
BDNF, brain-derived neurotrophic factor; 4-EPS, 4-ethyl phenol sulfate; FSL-1; fibroblast-stimulating lipopeptide-1; ICV, intracerebroventricular; IDO, indoleamine 2,3-dioxygenase; IL, interleukin; IP, intraperitoneal; IV, intravenous; LTA, lipoteichoic acid; LPS, lipopolysaccharide; MALP-2, macrophage-activating lipopeptide-2; MDP, muramyl dipeptide; 1-MT, 1-methyltryptophan; NOD, nucleotide-binding and oligomerization domain; OFT, open field test; PAMP, pathogen-associated molecular pattern; poly I:C, polyinosinic:polycytidylic acid; POMC, proopiomelanocortin; SCFA, short-chain fatty acid; TLR, Toll-like receptor; TNF, tumor necrosis factor; TrkB, tropomyosin-related kinase B.