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. 2015 Feb 18;35(7):3022-33.
doi: 10.1523/JNEUROSCI.3028-14.2015.

Microglial Activation Enhances Associative Taste Memory Through Purinergic Modulation of Glutamatergic Neurotransmission

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Free PMC article

Microglial Activation Enhances Associative Taste Memory Through Purinergic Modulation of Glutamatergic Neurotransmission

Jean-Christophe Delpech et al. J Neurosci. .
Free PMC article

Abstract

The cerebral innate immune system is able to modulate brain functioning and cognitive processes. During activation of the cerebral innate immune system, inflammatory factors produced by microglia, such as cytokines and adenosine triphosphate (ATP), have been directly linked to modulation of glutamatergic system on one hand and learning and memory functions on the other hand. However, the cellular mechanisms by which microglial activation modulates cognitive processes are still unclear. Here, we used taste memory tasks, highly dependent on glutamatergic transmission in the insular cortex, to investigate the behavioral and cellular impacts of an inflammation restricted to this cortical area in rats. We first show that intrainsular infusion of the endotoxin lipopolysaccharide induces a local inflammation and increases glutamatergic AMPA, but not NMDA, receptor expression at the synaptic level. This cortical inflammation also enhances associative, but not incidental, taste memory through increase of glutamatergic AMPA receptor trafficking. Moreover, we demonstrate that ATP, but not proinflammatory cytokines, is responsible for inflammation-induced enhancement of both associative taste memory and AMPA receptor expression in insular cortex. In conclusion, we propose that inflammation restricted to the insular cortex enhances associative taste memory through a purinergic-dependent increase of glutamatergic AMPA receptor expression at the synapse.

Keywords: AMPA; ATP; cytokines; lipopolysaccharide; neuroinflammation.

Figures

Figure 1.
Figure 1.
LPS induces a localized inflammatory reaction. A, Schematic representation of the experimental design. Proinflammatory and anti-inflammatory cytokine expression was measured by Bioplex in insular cortices or blood samples, 30 min (saline: n = 5; LPS: n = 7), 1 h (saline: n = 5; LPS: n = 6), or 1h30 (saline: n = 5; LPS: n = 7) after saline or LPS infusion. B–D, Tissue concentrations (relative fold change) of the proinflammatory cytokines IL-1β (B), TNF-α (C), and IL-10 (D). E, Tissue concentrations of ATP (in μm). F–H, Blood concentrations (relative fold change) of the proinflammatory cytokines IL-1β (F), TNF-α (G), and IL-10 (H). I, Effect of intrainsular infusion of either vehicle (n = 8) or LPS (n = 8) on body weight 2 d before and 2 d after conditioned taste aversion acquisition. J, Effect of intrainsular infusion of either vehicle (n = 12) or LPS (n = 13) on corticosterone concentration in plasma 2h15 after LPS infusion. *p < 0.05. ***p < 0.001.
Figure 2.
Figure 2.
LPS modulates glutamatergic receptors expression in the insular cortex with no effect on incidental taste memory. A, Schematic representation of the experimental design. Rats were infused 1h30 before a novel (saccharin) or a familiar (water) taste consumption and killed 30 min later. After decapitation, insular cortices were punched and protein expression measured by Western blot in total or synaptoneurosomal fractions. B–E, Expression levels of GluN2B (B), phospho-GluN2B (C), GluA1 (D), and GluA2 (E) in total extracts. Familiar taste-saline: n = 5; familiar taste-LPS: n = 6; novel taste-saline: n = 5; novel taste-LPS: n = 5. F, G, Expression levels of GluA1 (F) and GluA2 (G) in synaptoneurosomal fractions (saline: n = 5; LPS: n = 4). H, I, Kinetics of expression of GluA1 and GluA2 30 min (saline: n = 5; LPS: n = 4), 1h (saline: n = 5; LPS: n = 5), and 1h30 (saline: n = 4; LPS: n = 6) after LPS infusion in the insular cortex. J, Schematic representation of the experimental design for incidental taste memory evaluation. Two groups of rats were infused either with saline (n = 7) or LPS (n = 8) in the insular cortex 1h30 before the first saccharin presentation (acquisition). K, Saccharin consumption measured daily over the 3 d of test as a percentage of water intake at baseline. Saccharin consumption is significantly increased in both saline- and LPS-treated animals at T1 compared with acquisition day. *p < 0.05. **p < 0.01.
Figure 3.
Figure 3.
LPS enhances associative taste memory. A, Schematic representation of the experimental design. B, Effect of LPS infusion in the insular cortex on conditioned taste aversion acquisition induced by a moderate dose of LiCl (0.15 m). Left, Kinetics of saccharin consumption over the 3 d of test (T1–T3). Two groups of rats were infused with either saline (n = 9) or LPS (n = 10) in the insular cortex before conditioned taste aversion acquisition. *(apposed to bracket), LPS increased aversion strength over the 3 d of extinction tests (significant LPS effect and no interaction with time). Right, Averaged saccharin consumption of rats over the 3 d of test. Red dotted line indicates the level of saccharin consumption on the acquisition day. C, Effect of LPS infusion in the insular cortex on conditioned taste aversion acquisition induced by a low dose of LiCl (0.075 m). Left, Kinetics of saccharin consumption over the 3 d of test (T1–T3). Two groups of rats were infused either with saline (n = 9) or LPS (n = 8) in the insular cortex before conditioned taste aversion acquisition. *(apposed to bracket), LPS increased aversion strength over the 3 d of extinction tests (significant LPS effect and no interaction with time). Right, Averaged saccharin consumption of rats over the 3 d of test. Red dotted line indicates the level of saccharin consumption on the acquisition day. D, Schematic representation of the experimental design. E, Effect of intrainsular LPS infusion on retrieval of conditioned taste aversion. Three days after pairing of saccharin with a moderate dose of LiCl (0.15 m), LPS was infused 1h30 before exposure to saccharin on the first retrieval test. Left, Kinetics of saccharin consumption over the 3 d of test (T1-T3). Two groups of rats were infused with either saline (n = 9) or LPS (n = 8) in the insular cortex. F, Schematic representation of the experimental design. G, Effect of GluA2 AMPAR trafficking blocking peptide (pepR845A) on conditioned taste aversion induced by a moderate dose of LiCl (0.15 m). Left, Kinetics of saccharin consumption over the 3 d of extinction test (T1-T3). Three groups of rats were infused with saline (n = 9), low dose of peptide (80 ng/μl, n = 8), or high dose of peptide (8 μg/μl, n = 9) in the insular cortex before conditioned taste aversion acquisition. Right, Averaged saccharin consumption of rats over the 3 d of test. Red dotted line indicates the level of saccharin consumption on the acquisition day. H, Effect of pepR845A on LPS-induced conditioned taste aversion enhancement. Left, Kinetics of saccharin consumption over the 3 d of extinction test (T1-T3). Four groups of rats were infused with saline-saline (n = 5), saline-LPS (n = 5), pepR845A-saline (n = 6), or pepR845A-LPS (n = 7) in the insular cortex before conditioned taste aversion acquisition. Right, Averaged saccharin consumption of rats over the 3 d of test. Red dotted line indicates the level of saccharin consumption on the acquisition day. *p < 0.05. **p < 0.01.
Figure 4.
Figure 4.
ATP, but not proinflammatory cytokines, is the main inflammatory mediator of LPS-induced associative taste memory enhancement. A, Schematic representation of the experimental design. B, Averaged saccharin consumption of rats over the 3 d of test after infusion of TNF-α (100 ng), IL-1β (100 ng), or a mix of TNF-α and IL-1β (50 ng each) in the insular cortex. C, Averaged saccharin consumption of rats over the 3 d of test after infusion of ATP (10 mm) in the insular cortex. D, Schematic representation of the experimental design. Conditioned taste aversion acquisition in rats infused either with saline or suramin (20 μg/0.5 μl/side) in the insular cortex as a pretreatment, followed by infusion of either saline or LPS (100 ng/0.5 μl/side) as a treatment (saline-saline: n = 7; saline-LPS: n = 7; suramin-saline: n = 6; suramin-LPS: n = 7). E, Left, Kinetics of saccharin consumption over the 3 d of extinction test (T1-T3). Right, Averaged saccharin consumption of rats over the 3 d of test. Red dotted line indicates the level of saccharin consumption on the acquisition day. F, Schematic representation of the experimental design. GluA2 AMPAR expression levels in punched insular cortices of rats infused either with saline or suramin (20 μg/0.5 μl/side) in the insular cortex as a pretreatment, followed by infusion of either saline or LPS (100 ng/0.5 μl/side) as a treatment (saline-saline: n = 4; saline-LPS: n = 5; suramin-saline: n = 4; suramin-LPS: n = 6). G, Expression levels of GluA2 in total fractions. *p < 0.05. #p = 0.06.

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