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Evidence for inflammation-mediated memory dysfunction in gastropods: putative PLA2 and COX inhibitors abolish long-term memory failure induced by systemic immune challenges.

Hermann PM, Park D, Beaulieu E, Wildering WC - BMC Neurosci (2013)

Bottom Line: This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein.This effect dissipated within 24 hrs after treatment.Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB T2N 1N4, Canada.

ABSTRACT

Background: Previous studies associate lipid peroxidation with long-term memory (LTM) failure in a gastropod model (Lymnaea stagnalis) of associative learning and memory. This process involves activation of Phospholipase A2 (PLA2), an enzyme mediating the release of fatty acids such as arachidonic acid that form the precursor for a variety of pro-inflammatory lipid metabolites. This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein.

Results: Systemic immune challenges by means of β-glucan laminarin injections induced elevated H2O2 release from L. stagnalis circulatory immune cells within 3 hrs of treatment. This effect dissipated within 24 hrs after treatment. Laminarin exposure has no direct effect on neuronal activity. Laminarin injections disrupted LTM formation if training followed within 1 hr after injection but had no behavioural impact if training started 24 hrs after treatment. Intermediate term memory was not affected by laminarin injection. Chemosensory and motor functions underpinning the feeding response involved in this learning model were not affected by laminarin injection. Laminarin's suppression of LTM induction was reversed by treatment with aristolochic acid, a PLA2 inhibitor, or indomethacin, a putative COX inhibitor, but not by treatment with nordihydro-guaiaretic acid, a putative LOX inhibitor.

Conclusions: A systemic immune challenge administered shortly before behavioural training impairs associative LTM function in our model that can be countered with putative inhibitors of PLA2 and COX, but not LOX. As such, this study establishes a mechanistic link between the state of activity of this gastropod's innate immune system and higher order nervous system function. Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.

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Long-term memory assessments after laminarin injection. A1. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. A2. LTM assessment in animals injected 1 hr before training. There was a robust response to conditioning in vehicle injected animals. In contrast, none of the unconditioned animals or the laminarin treated conditioned animals responded with significant feeding movements in the post-training test. These results indicate LTM impairment in snails treated with laminarin 1 hr before training. B1. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. B2. LTM assessment in animals treated 24 hrs before training. Both laminarin and vehicle treated conditioned animals showed a significant increase in the Δrasp values in the post-training test compared to their unconditioned peers suggesting that laminarin has no adverse effect on LTM performance when injected a day before training. * = P < 0.05, *** = p < 0.001, ns = non-significant.
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Figure 3: Long-term memory assessments after laminarin injection. A1. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. A2. LTM assessment in animals injected 1 hr before training. There was a robust response to conditioning in vehicle injected animals. In contrast, none of the unconditioned animals or the laminarin treated conditioned animals responded with significant feeding movements in the post-training test. These results indicate LTM impairment in snails treated with laminarin 1 hr before training. B1. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. B2. LTM assessment in animals treated 24 hrs before training. Both laminarin and vehicle treated conditioned animals showed a significant increase in the Δrasp values in the post-training test compared to their unconditioned peers suggesting that laminarin has no adverse effect on LTM performance when injected a day before training. * = P < 0.05, *** = p < 0.001, ns = non-significant.

Mentions: To assess laminarin’s impact on the formation of appetitive long term memory (LTM) animals randomly assigned to four test groups were injected with, respectively, laminarin or vehicle-only either 1 or 24 hours before their first training session and tested for the presence of conditioned feeding responses ~24 hrs after their last training session (Figures 3A1 and 3B1). These experiments revealed a prominent suppression of conditioned feeding responses in animals that received treatment with laminarin 1 hr prior to the first training session but not in any of the other three test groups (c.f., Figures 3A2 and 3B2; ANOVA interaction training × treatment; F1,126 = 7.475, p = 0.007 for animals trained 1 hr after injection and ANOVA interaction training × treatment; F1,32 = 0.0093, p = 0.92 for animals trained 24 hrs after injection). Notably, both vehicle-injected conditioned test groups (CS-UCS) displayed robust conditioned feeding responses compared to their non-conditioned peers whether they were injected 1 hr or 24 hrs prior to their training (F1,126 = 26.596 p < 0.0001 and F1,32 = 5.476 p = 0.03, respectively). In the case of laminarin-injected animals statistically significant conditioned feeding responses were only observed in animals trained 24 hrs after they received their injections (1 hr: F1,126 = 3.743 p = 0.06; 24 hr F1,32 = 6.209, p = 0.02). While the statistic suggests near significance of the effect of behavioural conditioning in animals treated with laminarin 1 hr prior to training the results leave no doubt (see Figure 3A2) that, in contrast to the animals trained 24 hrs after treatment, the impact of training in this group is drastically reduced compared to their vehicle-injected counterparts (F1,126 = 22.481, p < 0.0001 for animals trained 1 hr post-treatment and F1,32 = 0.001, p = 0.98 for animals trained 24 hrs post-treatment).


Evidence for inflammation-mediated memory dysfunction in gastropods: putative PLA2 and COX inhibitors abolish long-term memory failure induced by systemic immune challenges.

Hermann PM, Park D, Beaulieu E, Wildering WC - BMC Neurosci (2013)

Long-term memory assessments after laminarin injection. A1. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. A2. LTM assessment in animals injected 1 hr before training. There was a robust response to conditioning in vehicle injected animals. In contrast, none of the unconditioned animals or the laminarin treated conditioned animals responded with significant feeding movements in the post-training test. These results indicate LTM impairment in snails treated with laminarin 1 hr before training. B1. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. B2. LTM assessment in animals treated 24 hrs before training. Both laminarin and vehicle treated conditioned animals showed a significant increase in the Δrasp values in the post-training test compared to their unconditioned peers suggesting that laminarin has no adverse effect on LTM performance when injected a day before training. * = P < 0.05, *** = p < 0.001, ns = non-significant.
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Related In: Results  -  Collection

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Figure 3: Long-term memory assessments after laminarin injection. A1. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. A2. LTM assessment in animals injected 1 hr before training. There was a robust response to conditioning in vehicle injected animals. In contrast, none of the unconditioned animals or the laminarin treated conditioned animals responded with significant feeding movements in the post-training test. These results indicate LTM impairment in snails treated with laminarin 1 hr before training. B1. Protocol indicating timing of injection and start of pre- and post training tests with respect to the start of the first training session for both the conditioned (CS-UCS) and control (CS-DS) animals. B2. LTM assessment in animals treated 24 hrs before training. Both laminarin and vehicle treated conditioned animals showed a significant increase in the Δrasp values in the post-training test compared to their unconditioned peers suggesting that laminarin has no adverse effect on LTM performance when injected a day before training. * = P < 0.05, *** = p < 0.001, ns = non-significant.
Mentions: To assess laminarin’s impact on the formation of appetitive long term memory (LTM) animals randomly assigned to four test groups were injected with, respectively, laminarin or vehicle-only either 1 or 24 hours before their first training session and tested for the presence of conditioned feeding responses ~24 hrs after their last training session (Figures 3A1 and 3B1). These experiments revealed a prominent suppression of conditioned feeding responses in animals that received treatment with laminarin 1 hr prior to the first training session but not in any of the other three test groups (c.f., Figures 3A2 and 3B2; ANOVA interaction training × treatment; F1,126 = 7.475, p = 0.007 for animals trained 1 hr after injection and ANOVA interaction training × treatment; F1,32 = 0.0093, p = 0.92 for animals trained 24 hrs after injection). Notably, both vehicle-injected conditioned test groups (CS-UCS) displayed robust conditioned feeding responses compared to their non-conditioned peers whether they were injected 1 hr or 24 hrs prior to their training (F1,126 = 26.596 p < 0.0001 and F1,32 = 5.476 p = 0.03, respectively). In the case of laminarin-injected animals statistically significant conditioned feeding responses were only observed in animals trained 24 hrs after they received their injections (1 hr: F1,126 = 3.743 p = 0.06; 24 hr F1,32 = 6.209, p = 0.02). While the statistic suggests near significance of the effect of behavioural conditioning in animals treated with laminarin 1 hr prior to training the results leave no doubt (see Figure 3A2) that, in contrast to the animals trained 24 hrs after treatment, the impact of training in this group is drastically reduced compared to their vehicle-injected counterparts (F1,126 = 22.481, p < 0.0001 for animals trained 1 hr post-treatment and F1,32 = 0.001, p = 0.98 for animals trained 24 hrs post-treatment).

Bottom Line: This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein.This effect dissipated within 24 hrs after treatment.Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB T2N 1N4, Canada.

ABSTRACT

Background: Previous studies associate lipid peroxidation with long-term memory (LTM) failure in a gastropod model (Lymnaea stagnalis) of associative learning and memory. This process involves activation of Phospholipase A2 (PLA2), an enzyme mediating the release of fatty acids such as arachidonic acid that form the precursor for a variety of pro-inflammatory lipid metabolites. This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein.

Results: Systemic immune challenges by means of β-glucan laminarin injections induced elevated H2O2 release from L. stagnalis circulatory immune cells within 3 hrs of treatment. This effect dissipated within 24 hrs after treatment. Laminarin exposure has no direct effect on neuronal activity. Laminarin injections disrupted LTM formation if training followed within 1 hr after injection but had no behavioural impact if training started 24 hrs after treatment. Intermediate term memory was not affected by laminarin injection. Chemosensory and motor functions underpinning the feeding response involved in this learning model were not affected by laminarin injection. Laminarin's suppression of LTM induction was reversed by treatment with aristolochic acid, a PLA2 inhibitor, or indomethacin, a putative COX inhibitor, but not by treatment with nordihydro-guaiaretic acid, a putative LOX inhibitor.

Conclusions: A systemic immune challenge administered shortly before behavioural training impairs associative LTM function in our model that can be countered with putative inhibitors of PLA2 and COX, but not LOX. As such, this study establishes a mechanistic link between the state of activity of this gastropod's innate immune system and higher order nervous system function. Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.

Show MeSH
Related in: MedlinePlus