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. 2001 Aug 1;21(15):5513-9.
doi: 10.1523/JNEUROSCI.21-15-05513.2001.

The p38 mitogen-activated protein kinase is involved in associative learning in rabbits

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The p38 mitogen-activated protein kinase is involved in associative learning in rabbits

X Zhen et al. J Neurosci. .

Abstract

This study examined the role of the mitogen-activated protein kinase (MAPK) family during acquisition of the rabbit's classically conditioned eye-blink response. Eye-blink conditioning produced a significant, bilateral activation of both extracellular signal-regulated protein kinases (ERKs) and p38 MAPK in the anterior cerebellar vermis. There was also a significant bilateral activation of ERKs in the dorsal hippocampus with no change in p38 MAPK. These changes were seen at 2 min after the last conditioning session, were maintained for at least 180 min, and occurred without any change in the protein expression of either ERKs or p38 MAPK. There were no changes in ERKs or p38 MAPK in frontal cortex, in cerebellar hemispheral lobule VI, or in a section of brainstem containing the inferior olive. Moreover, the stress-related protein kinase Jun N-terminal kinase (JNK), another subfamily of MAPKs, was not altered in any of the brain regions examined. Animals receiving explicitly unpaired presentations of a conditioned stimulus and an unconditioned stimulus did not acquire conditioned responses (CRs) and did not demonstrate any changes in ERKs, p38 MAPK, or JNK. The intraventricular injection of SB203580, a selective p38 MAPK inhibitor, significantly retarded CR acquisition and blocked the learning-related increases in p38 MAPK activity in the anterior vermis. PD98059, a selective MAPK kinase inhibitor, had a smaller and only marginally significant effect on CR acquisition, although it did block the learning-related increases in ERK activity in both the hippocampus and anterior vermis. These results indicate that p38 MAPK is activated during associative learning and may play a role in the transcriptional events that lead to memory consolidation.

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Figures

Fig. 1.
Fig. 1.
Acquisition of CRs to the tone CS during delay eye-blink conditioning. Data are expressed as the mean percentage of CS-elicited responses for rabbits receiving 3 d of either paired CS–US training (paired; n = 4) or explicitly unpaired presentations of CS and US (unpaired; n = 4). Thepoints above A are the percentage of responses during an adaptation session when no stimuli were presented. Error bars represent ±1 SEM.
Fig. 2.
Fig. 2.
Learning-related activation of MAPKs in four brain regions. Animals of Figure 1 were decapitated at 180 min after the third conditioning day, and activities of MAPKs were measured byin vitro immune complex kinase assay using MBP as substrate. The radioactivity incorporated into MBP was determined by scintillation counting. The results are presented as a ratio of the values obtained in normal controls that had not been exposed to any conditioning procedure (see Materials and Methods). Each mean is based on four to seven determinations and represents values for the left hippocampus (B), frontal cortex (C), left cerebellar vermis (A), and a bilateral section of brainstem containing the inferior olive (D). Error bars represent ±1 SEM (*p < 0.05 compared with control; #p < 0.05 compared with paired CS–US group).
Fig. 3.
Fig. 3.
Conditioning does not alter JNK activity and MAPK protein levels. A, Representative autoradiographs of JNK activities in various brain areas (left) and summary data of densitometric scans (in relative density units) obtained from at least four animals in each group (right).B, Summary of densitometric scans for ERK2 (top left) and p38 MAPK (top right) expression and representative Western blots of ERK (bottom left) and p38 MAPK (bottom right) protein levels. Tissue was obtained from controls and from animals of Figure 1 that had been decapitated at 180 min after the last training session. JNK activity was measured by in vitro immune complex kinase assay using c-Jun GST as substrate. The radioactivity incorporated into c-Jun was determined by autoradiography. ERK and p38 MAPK protein levels were detected by Western blotting using anti-ERK2 and p38 MAPK antibody, respectively. The experiments of A and Bwere repeated three to four times with similar results.c, Control; Cereb., anterior vermis of cerebellum; FCX, frontal cortex; HP, dorsal hippocampus; IO, section of brainstem containing the inferior olive; p, paired; up, unpaired.
Fig. 4.
Fig. 4.
Time course for learning-induced ERK and p38 MAPK activation. Animals were decapitated at designated times after the last conditioning session. ERK and p38 MAPK activities were determined in both the left (B) and right (A) dorsal hippocampus and anterior vermis of the cerebellum (C, D) as described in Figure 2. The results are presented as a ratio of the values obtained in normal controls (C) that had not been exposed to any conditioning procedure. Each value is the mean ± 1 SEM of determinations obtained from three to nine animals (*p < 0.05; **p < 0.01, compared with control).
Fig. 5.
Fig. 5.
Associative learning does not induce MAPK activation in hemispheral lobule VI of the cerebellum. The ERK and p38 MAPK activities in hemispheral lobule VI (right, A; left, B) were measured at 2 and 30 min after the last conditioning session. Data are presented as described in Figures 2 and4, and each value is the mean of three to nine determinations.
Fig. 6.
Fig. 6.
The p38 MAPK inhibitor SB203580 attenuates acquisition of CRs. Rabbits were injected with DMSO vehicle (n = 19), 40 μg of SB203580 (n = 11), or 40 μg of PD98059 (n = 17) into the left lateral ventricle 15–20 min before each of the three conditioning sessions. Data are presented as the mean percentage of CRs. The points aboveA are the percentage of responses during an adaptation session when no stimuli were presented. Error bars represent ±1 SEM.
Fig. 7.
Fig. 7.
Intraventricular administration of MAPK inhibitors blocked the learning-associated activation of MAPKs. Rabbits were injected with DMSO or inhibitors as described in Figure 6. Animals were decapitated at 2 min after the last conditioning session. ERK (bottom) and p38 MAPK (top) activities were determined in both the left (HP) and right (data not shown) dorsal hippocampus and anterior vermis of the cerebellum (AV) as described in Figure 2. The results are presented as a ratio of the values obtained in basal controls that had not been exposed to any conditioning procedure. Each value is the mean ± 1 SEM of determinations obtained from four to eight animals (*p < 0.01 compared with basal; #p < 0.01 compared with vehicle injection).

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References

    1. Aloyo VJ, Romano AG, Harvey JA. Evidence for an involvement of the mu-type of opioid receptor in the modulation of learning. Neuroscience. 1993;55:511–519. - PubMed
    1. Atkins CM, Selcher JC, Petraitis JJ, Trzaskos JM, Sweatt JD. The MAPK cascade is required for mammalian associative learning. Nat Neurosci. 1998;1:602–609. - PubMed
    1. Bailey CH, Kaang BK, Chen M, Martin KC, Lim CS, Casadio A, Kandel ER. Mutation in the phosphorylation sites of MAP kinase blocks learning-related internalization of apCAM in Aplysia sensory neurons. Neuron. 1997;18:913–924. - PubMed
    1. Berman DE, Hazvi S, Rosenblum K, Seger R, Dudai Y. Specific and differential activation of mitogen-activated protein kinase cascade by unfamiliar taste in the insular cortex of the behaving rat. J Neurosci. 1998;18:10037–10044. - PMC - PubMed
    1. Blum S, Moore AN, Adams F, Dash PK. A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. J Neurosci. 1999;19:3535–3544. - PMC - PubMed

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