Necessity for ERK Activation for Mammalian Learning

As described in section two of this book, two paradigms that have been used extensively in studying learning are the conditioned fear task6 and the Morris water task.74 In fear conditioning, animals learn to associate neutral stimuli with a foot shock. In the spatial learning version of the Morris water task, animals learn to utilize various distal visual cues to navigate through a pool of water to locate a hidden escape platform. Lesions of the hippocampus has previously been shown to impair learning in variants of both of these tasks in mice.62 Evidence from studies of hippocampal synaptic plasticity and of the behaving animal suggests that activation of protein kinases may contribute to the formation of these types of memories, however, the underlying signal transduction mechanisms remain largely unknown.1,2,3,8,85,91,102

In early studies, we found that the ERK MAPK cascade is required for fear conditioning in the rat,8 as has also been observed subsequently by Schafe et al. In the study by Atkins et al,8 hippocampal ERK activation increased 1 hour after training with a fear conditioning protocol. This increased ERK activation was prevented by injection of the NMDA antagonist MK801, a drug that blocks both LTP and fear conditioning.18,25 The NMDA receptor-mediated activation of ERK was required for learning, as inhibiting ERK activation by intraperitoneal administration of SL327 blocked both contextual and cue learning in the rat.

Due to the emergence of mice as the standard genetic and behavioral model, we examined the role of ERK in fear learning in mice (Fig. 4). In these studies, SL327 injected systemically crossed the blood-brain barrier at concentrations sufficient to inhibit basal levels of ERK acti-

Figure 4. SL327 blocks contextual fear conditioning and attenuates cue learning following 1 CS-US pairing. A) Freezing responses during the training phase are shown. A tone (solid bar) was paired with a foot shock (ft) between minutes 3 and 4. Baseline behavior (before presentation of the tone) and shock response (after the foot shock) were similar for all groups. B) Mice given SL327 (10 mg/kg, n = 5 or 30 mg/kg, n = 7) demonstrated significant reductions in freezing to the context 24 hours after receiving one pairing of tone and shock as compared to animals injected with vehicle (n = 6), left. Administration of10 or 30 mg/kg SL327 was also sufficient to significantly attenuate freezing to the cue (CS - PreCS), right. There was no difference between the PreCS values for any of the groups. **represents p < 0.01, ^represents p < 0.05.

Figure 4. SL327 blocks contextual fear conditioning and attenuates cue learning following 1 CS-US pairing. A) Freezing responses during the training phase are shown. A tone (solid bar) was paired with a foot shock (ft) between minutes 3 and 4. Baseline behavior (before presentation of the tone) and shock response (after the foot shock) were similar for all groups. B) Mice given SL327 (10 mg/kg, n = 5 or 30 mg/kg, n = 7) demonstrated significant reductions in freezing to the context 24 hours after receiving one pairing of tone and shock as compared to animals injected with vehicle (n = 6), left. Administration of10 or 30 mg/kg SL327 was also sufficient to significantly attenuate freezing to the cue (CS - PreCS), right. There was no difference between the PreCS values for any of the groups. **represents p < 0.01, ^represents p < 0.05.

vation, and could effectively eliminate contextual learning in mice as it did in rats.8 SL327 administration also significantly attenuated cue learning, although these drug-treated mice did display considerable freezing in response to the white noise following its pairing with a foot shock. More intense training paradigms consisting of more than a single CS-US pairing rescued the deficit observed in cue learning.

Of course, a number of other laboratories also investigated the ERK cascade in associative learning in a wide variety of systems. ERK is activated in response to a novel taste, and infusion of PD098059 into the insular cortex of rats attenuates conditioned taste aversion.14 Genetic manipulations of upstream members of the cascade that leads to ERK MAPK activation also engender learning impairments. For example, the Drosophila mutant Leonardo which lacks 14-3-3, a protein important in the activation of Raf-1 (MAPKKK) by Ras, shows learning-related impairments.22 In addition, mice lacking Ras-GRF, a guanine-nucleotide exchange factor that induces Ras activation, display impairments in cue fear conditioning and abnormal amygdalar LTP.21 However, these mice show normal hippocampal function and no significant deficits in spatial learning.

Figure 5. SL327 impairs performance during training on the hidden platform version of the Morris water maze. Average escape latency during training on the hidden platform task. Performance for mice injected with vehicle (n = 13) improved over the course of the training. Mice treated with 30 mg/kg SL327 (n = 11) took significantly longer to locate the escape platform. The dark vertical line between blocks 10 and 11 represents the drug switch on day 6. On that day, SL327-trained mice (■) received DMSO (n = 9), while vehicle-trained animals (O) received SL327 (n = 11).

Figure 5. SL327 impairs performance during training on the hidden platform version of the Morris water maze. Average escape latency during training on the hidden platform task. Performance for mice injected with vehicle (n = 13) improved over the course of the training. Mice treated with 30 mg/kg SL327 (n = 11) took significantly longer to locate the escape platform. The dark vertical line between blocks 10 and 11 represents the drug switch on day 6. On that day, SL327-trained mice (■) received DMSO (n = 9), while vehicle-trained animals (O) received SL327 (n = 11).

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