MAPK Establishes a Molecular Context That Defines Effective Training Patterns for Long-Term Memory Formation

A single 5 min 5HT exposure significantly increases the nuclear:cytoplasmic ratio of phosphorylated MAPK in tail sensory neurons at 45 min.

“5HT significantly increased the nuclear:cytoplasmic ratio of P-MAPK in tail SNs at 45 min (5HT: mean pixel intensity Ϯ SEM, 0.84 Ϯ 0.03, ASW: 0.65 Ϯ 0.03, p ϭ 0.038; Fig. 3).”

5HT-induced p90rsk phosphorylation is completely disrupted by U0126, demonstrating it is downstream of MAPK activity.

“Moreover, 5HT-induced p-p90rsk was completely disrupted by U0126, demonstrating that it is downstream of MAPK activity (U0126: n ϭ 6, 0.86 Ϯ 0.07 5HT/ASW ratio, p ϭ 0.063, U0124: n ϭ 4, 2.1 Ϯ 0.8, p ϭ 0.04).”

MAPK activity recruited by the initial training shock is required for the intertrial interaction during two-trial LTM induction.

“These data establish that MAPK activity recruited by the initial training shock is required for the intertrial interaction during two-trial LTM induction.”

• AssumptionRests on an assumption: A single training trial is not sufficient for LTM.

ApC/EBP induction is not observed at 1 h following 5HT treatment.

“Finally, ApC/EBP induction was not observed at 1 h following 5HT treatment (n ϭ 6, median Ϯ IQR, 1.0 Ϯ 1.25 control levels, W ϭ Ϫ1, p Ͼ 0.99, data not shown).”

ApC/EBP transcript levels are significantly increased at 45 min after a single 5HT treatment relative to control.

“We found that ApC/EBP message levels were significantly increased at 45 min after 5HT relative to a control, the S4 ribosomal subunit (n ϭ 10, median Ϯ IQR, 1.6 Ϯ 2.7, W ϭ 7, p ϭ 0.04, Wilcoxon matchedpairs signed rank test; Figure 4b).”

A single 5 min application of 50 μM 5HT to isolated pleural-pedal ganglia induces MAPK activation in tail sensory neurons that is significantly elevated at 45 min but not at 15 or 60 min post-treatment.

“An ANOVA of P-MAPK/T-MAPK ratios across the three groups indicated a temporally restricted activation of MAPK following 5HT treatment (F (2,24) ϭ 4.459, p ϭ 0.0226; Fig. 2a).”

• Also stated in: § The narrow temporal window of MAPK activation by behavioral training is also observed in vitro in response to exogenous 5HT application · plain

  “Within-group analyses also identified significant activation of MAPK above control levels at 45 min (n ϭ 11, 1 outlier, 1.3 Ϯ 0.08 p ϭ 0.0007, paired t test), but not at 15 min (n ϭ 8, 0.99 Ϯ 0.13, p ϭ 0.683) or 60 min (n ϭ 8, 1 outlier, 1.0 Ϯ 0.08, p ϭ 0.627).”

ApC/EBP induction at 45 min after 5HT requires MAPK activation, since it is significantly disrupted by U0126.

“ApC/EBP induction required MAPK activation since it was significantly disrupted by U0126 treatment (U0126: n ϭ 8, median Ϯ IQR, 0.95 Ϯ 0.4 control levels, W ϭ 10, p ϭ 0.55, U0124: n ϭ 7, 1.25 Ϯ 1.3, W ϭ Ϫ28, p ϭ 0.02).”

During sensitization of the T-TWR, a single training shock results in activation of MAPK in tail sensory neurons at 45 min.

“Consistent with this earlier observation, we found that during sensitization of the T-TWR, a single training shock results in the activation of MAPK in tail SNs at 45 min (n ϭ 7, 157 Ϯ 15% untrained phosphorylated-MAPK/total-MAPK ratio, p ϭ 0.0087 paired t test, see Fig. 5a, ASW).”

5HT-induced MAPK activation at 45 min requires MEK activity, since it is completely disrupted by the MEK inhibitor U0126.

“5HT-induced MAPK activation required MEK activity, since activation at 45 min was completely disrupted in the presence of the MEK inhibitor, U0126 (n ϭ 5, 92 Ϯ 10% 5HT-/ASW-treated, p ϭ 0.434 paired t test, data not shown).”

MAPK activation during or after training (or both) is required for the induction of two-trial LTM.

“Using a similar treatment strategy (CNS exposure to drug before, during and for 1 h after training), we first established that MAPK activation was required for the induction of two-trial LTM (U0124: n ϭ 4, 204 Ϯ 51% baseline T-TWR amplitude, U0126: n ϭ 4, 68 Ϯ 9% baseline T-TWR amplitude, p ϭ 0.04 unpaired t test, data not shown).”

MAPK activity is a necessary component of intertrial signaling during two-trial learning.

“Given that MAPK activity is a necessary component of the intertrial signaling during two-trial learning (Fig. 5)”

It is not until 45 min, when the MAPK-dependent molecular context in tail SNs has been established, that a second training shock can support LTM formation.

“It is not until 45 min, when the MAPK-dependent molecular context in tail SNs has been established, that a second training shock can support LTM formation (Fig. 6).”

The two-trial training interval for LTM induction in both T-SWR and T-TWR is restricted to 45 min, but not 15 min or 1 h, following an initial training shock.

“The two-trial training interval for LTM induction in both the T-SWR and the T-TWR is surprisingly narrow, restricted to 45 min (but not 15 min or 1 h) following an initial training shock (Fig. 1; Sutton et al., 2002;Philips et al., 2007).”

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cAMP/PKA activation is transient and is inactivated within 15 min following TS.

“cAMP/PKA activation is transient and is inactivated within 15 min following TS.”

By 45 min, MAPK has activated the CREB pathway as observed in increased phosphorylation of the CREB kinase p90rsk and increased ApC/EBP expression.

“By 45 min, MAPK has activated the CREB pathway as observed in the increased phosphorylation of the CREB kinase p90rsk and increased ApC/EBP expression.”

• Also stated in: § Two-trial training patterns provide a unique opportunity to study the spacing effect in LTM formation · plain

  “By 45 min, MAPK has activated the CREB pathway as observed in the increased phosphorylation of the CREB kinase p90rsk and increased ApC/EBP expression.”

Trial 1 MAPK established a molecular context of CREB signaling that included ApC/EBP induction, an essential requirement for LTM formation.

“In support of this notion, we found that Trial 1 MAPK established a molecular context of CREB signaling that included ApC/EBP induction (Fig. 4), an essential requirement for LTM formation.”

By 1 h, the MAPK-dependent molecular context has ended.

“By 1 h, the MAPK-dependent molecular context has ended.”

• Also stated in: § Two-trial training patterns provide a unique opportunity to study the spacing effect in LTM formation · plain

  “By 1 h, the MAPK-dependent molecular context has ended.”

In a preliminary investigation, 5HT-induced MAPK activation at 45 min could be disrupted with a blocking antibody against sensorin that antagonizes the autocrine signaling of sensorin at tail SNs.

“Consistent with this idea, in a preliminary investigation we observed that 5HT-induced MAPK activation at 45 min could be disrupted with a blocking antibody against sensorin that antagonizes the autocrine signaling of sensorin at tail SNs.”

Following both tail shock and 5HT treatment, single-trial MAPK activation is inactivated by 1 h.

“Strikingly, following both tail shock (Philips et al., 2007) and 5HT treatment (Fig. 2), single-trial MAPK activation is inactivated by 1 h.”

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Trial 1 MAPK activation required protein synthesis.

“We studied possible mechanisms for the activation of Trial 1 MAPK and found that it required protein synthesis (Fig. 2).”

MAPK is not activated in the somatic compartment of tail SNs of the reflex circuit until 45 min.

“and is not activated in the somatic compartment of tail SNs of the reflex circuit until 45 min”

Long-term memory for sensitization of the tail-elicited tail withdrawal reflex has a narrow temporal two-trial training window.

“Long-term memory for sensitization of the tail-elicited tail withdrawal reflex has a narrow temporal two-trial training window.”

Trial 1 MAPK translocates to the nucleus of tail sensory neurons.

“Trial 1 MAPK translocates to the nucleus of tail sensory neurons.”

Trial 1 MAPK activates the CREB kinase p90rsk.

“Trial 1 MAPK activates the CREB kinase p90rsk and increases transcription of the immediate early gene ApC/EBP.”

Trial 1 MAPK is necessary for the intertrial interaction during induction of LTM.

“Trial 1 MAPK is necessary for the intertrial interaction during induction of LTM.”

Trial 1 MAPK increases transcription of the immediate early gene ApC/EBP.

“Trial 1 MAPK activates the CREB kinase p90rsk and increases transcription of the immediate early gene ApC/EBP.”

Exposure to the protein synthesis inhibitor emetine for 30 min before 5HT treatment prevented the 5HT-induced MAPK activation at 45 min.

“Exposure to the protein synthesis inhibitor emetine (eme.) for 30 min before 5HT treatment prevented the 5HT-induced MAPK activation at 45 min.”

No MAPK activation was observed at 15 min or at 1 h following the same 5HT treatment.

“No activation was observed at 15 min or at 1 h following the same treatment.”

There is a significant increase in the nuclear/cytoplasmic ratio of P-MAPK immunofluorescence at 45 min post-5HT.

“Asterisk indicates a significant increase in the nuclear/cytoplasmic ratio at 45 min post-5HT.”

The specific disruption of Trial 1-induced MAPK activation during two-trial learning prevents LTM formation.

“The specific disruption of Trial 1-induced MAPK activation during two-trial learning prevents LTM formation.”

CNS exposure to U0126 for 40 min before, during and 15 min after a single training shock to behaving T-TWR preparations was sufficient to disrupt Trial 1 MAPK activation in tail SNs.

“CNS exposure to U0126 for 40 min before, during and 15 min after the administration of a single training shock to behaving T-TWR preparations was sufficient to disrupt Trial 1 MAPK activation in tail SNs (ASW vs I in summary histogram, right).”

In preparations trained with two shocks spaced by 45 min, responding at 18-22 h was enhanced over untrained controls.

“Asterisk indicates enhanced responding at 18 -22 h in 2ϫ45 trained animals over untrained controls (unpaired t test).”

Treatment with the inactive analog U0124 had no significant effect on p-p90rsk levels.

“Treatment with the inactive analog, U0124, had no significant effect.”

5HT increased levels of ApC/EBP (normalized to S4).

“Levels of ApC/EBP (normalized to levels of S4 ) were increased by 5HT.”

A 5 min 5HT exposure to isolated pleuralpedal ganglia induced significant MAPK activation in tail SNs at 45 min compared with paired ASW-treated control ganglia.

“A 5 min 5HT exposure to the isolated pleuralpedal ganglia induced significant MAPK activation in tail SNs at 45 min compared with paired ASW-treated control ganglia.”

Exposure to the MEK inhibitor U0126 disrupted the 5HT-induced increase in p-p90rsk.

“Exposure to the MEK inhibitor, U0126, disrupted the observed 5HT-induced increase in p-p90rsk.”

Trial 1 MAPK activation requires protein synthesis.

“Trial 1 MAPK activation requires protein synthesis which may account, at least in part, for its delayed activation.”

A single training trial, via the release of 5HT, recruits the temporally restricted nuclear translocation of activated MAPK in tail sensory neurons at 45 min.

“Collectively, these data support a model in which a single training trial, via the release of 5HT, recruits the temporally restricted nuclear translocation of activated MAPK in tail SNs at 45 min.”

MAPK is activated by the 5HT released during the initial training shock (Trial 1).

“The similar temporal profile of MAPK activation following training shock (Philips et al., 2007) and 5HT treatment strongly supports the hypothesis that MAPK is activated by the 5HT released during the initial training shock (Trial 1).”

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Much of the training pattern sensitivity during two-trial memory formation lies within the tail sensory neurons, which provide the input pathway for both the T-SWR and T-TWR reflexes.

“Collectively, the data support the hypothesis that much of the training pattern sensitivity lies within the tail SNs which are presynaptic to both central reflex circuits, and identifies a unique opportunity to study the mechanisms underlying the temporal specificity of the two-trial training interval in the T-TWR reflex where the pre-and post-synaptic elements which contribute to the reflex are w”

The kinetics of MAPK activation following individual experiences determines effective training intervals for LTM formation.

“These findings provide the first demonstration of a requirement for MAPK in the intertrial interactions during memory formation and suggest that the kinetics of MAPK activation following individual experiences determines effective training intervals for LTM formation.”

Trial 1 MAPK signals through a transient activation of the CREB kinase p90rsk at the 45 min two-trial training window.

“These data show that Trial 1 MAPK signals through a transient activation of the CREB kinase, p90rsk, at the 45 min two-trial training window.”

This study provides the first demonstration of a requirement for MAPK in the intertrial interactions during memory formation.

“These findings provide the first demonstration of a requirement for MAPK in the intertrial interactions during memory formation and suggest that the kinetics of MAPK activation following individual experiences determines effective training intervals for LTM formation.”

The T-TWR shares with the T-SWR a narrow two-trial training interval at 45 min for LTM induction.

“In sum, the T-TWR shares with the T-SWR (Philips et al., 2007) a narrow two-trial training interval at 45 min for LTM induction.”

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The kinetics for activation of MAPK in the cell body and nuclei of tail SNs following an initial training experience appears to determine the delayed 45 min two-trial training interval for LTM induction.

“Importantly, the kinetics for the activation of MAPK in the cell body and nuclei of tail SNs following an initial training experience appears to determine the delayed (45 min) two-trial training interval for LTM induction”

U0126 and U0124 had no effect on baseline responding as assessed through comparison with a third pretest 30 min into drug incubation.

“U0126/ U0124 had no effect on baseline responding as assessed through comparison with a third pretest 30 min into drug incubation.”

Sustained MAPK activation in tail sensory neurons following spaced training is necessary for LTM formation.

“We have previously shown that a sustained (1-3 h) MAPK activation develops in tail SNs following spaced training (4 or 5 spaced training shocks or pulses of 5HT; Sharma et al., 2003) and is necessary for LTM formation (Shobe et al., 2005).”

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The inhibition of MEK by U0126 could be readily reversed before the temporal window for the second training shock at 45 min, as evidenced by restoration of MAPK activation when a single shock was administered following 30 min of drug washout.

“Additionally, the inhibition of MEK could be readily reversed before the temporal window for the second training shock at 45 min, as evidenced by the restoration of MAPK activation when a single shock was administered to T-TWR preparations following 30 min of drug washout (n ϭ 6, 147 Ϯ 16% control, p ϭ 0.044; Fig. 5a,II).”

The phosphorylation and subsequent nuclear translocation of MAPK is thought to be an essential step in the activation of the transcription factor CREB and CREB-dependent immediate early gene transcription necessary for LTM induction.

“The phosphorylation and subsequent nuclear translocation of MAPK is thought to be an essential step in the activation of the transcription factor CREB, and CREB-dependent immediate early gene transcription necessary for LTM induction (Yin et al., 1994;Guzowski and McGaugh, 1997;Sharma and Carew, 2004;Lee et al., 2008).”

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• cites Guzowski and McGaugh, 1997Not checked yet

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• cites Sharma and Carew, 2004Not checked yet

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U0126 treatment until 15 min post-Trial 1 significantly disrupted Trial 1 MAPK activation observed at 45 min.

“This treatment significantly disrupted Trial 1 MAPK activation observed at 45 min (n ϭ 5, 82 Ϯ 17% control; Fig. 5a,I).”

The delay in MAPK activation may be sufficient to explain the failure of the 15 min training interval to induce LTM.

“the delay in MAPK activation may be sufficient to explain the failure of the 15 min training interval to induce LTM.”

The timing of the MAPK-dependent two-trial training interval is a reflection of the dependence of Trial 1 MAPK activation on new protein synthesis, perhaps the local synaptic translation of sensorin.

“Collectively, the data suggest that the timing of the MAPK-dependent two-trial training interval is a reflection of the dependence of Trial 1 MAPK activation on new protein synthesis (perhaps the local synaptic translation of sensorin).”

The intertrial dynamics of ERK/MAPK activation have been correlated with effective training patterns for LTM.

“The intertrial dynamics of ERK/MAPK activation have recently been correlated with effective training patterns for LTM.”

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Rapid inactivation of MAPK, and of the MAPK-dependent recruitment of CREB kinase and ApC/EBP expression, by 1 h may account for the failure of the longer training interval in two-trial LTM induction.

“This rapid inactivation of MAPK, and of the MAPK-dependent recruitment of CREB kinase and ApC/EBP expression, by 1 h may account for the failure of this longer training interval in two-trial LTM induction (Sutton et al., 2002;Philips et al., 2007).”

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The recruitment of a second, delayed phase of MAPK activation following training is important for the development of long-term memory following both multiple-trial spaced and single-trial training patterns.

“Finally, the recruitment of a second, delayed phase of MAPK activation following training has been shown to be important for the development of long-term memory following both multipletrial spaced (Atkins et al., 1998;Shobe et al., 2005) and single-trial (Cammarota et al., 2000;Michel et al., 2011) training patterns.”

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C/EBP is critical for long-term memory formation in Aplysia and other systems.

“C/EBP is critical for long-term memory formation in Aplysia and other systems (Alberini et al., 1994;Taubenfeld et al., 2001).”

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The recruitment of nuclear MAPK translocation, CREB kinase and ApC/EBP by a single training shock provides initial experimental evidence suggesting novel roles for CREB and ApC/EBP in the intertrial signaling important for LTM formation over spaced training trials.

“Given that a single training shock is not sufficient for LTM induction, the recruitment of nuclear MAPK translocation, CREB kinase and ApC/EBP is quite surprising, and provides initial experimental evidence suggesting novel roles for CREB and ApC/EBP in the intertrial signaling important for LTM formation over spaced training trials.”

• AssumptionRests on an assumption: A single training shock is not sufficient for LTM induction.

MAPK activates CREB indirectly through the cytoplasm-localized kinase p90rsk.

“MAPK is known to activate CREB indirectly through the cytoplasm-localized kinase p90rsk (RSK1/2; Arthur et al., 2004), and p90rsk phosphorylation (activation) is correlated with MAPK activation during learning (Sindreu et al., 2007).”

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The delayed onset of the MAPK-dependent molecular context may be sufficient to explain the failure of the short 15 min training interval to support LTM formation.

“The delayed onset of the MAPK-dependent molecular context may be sufficient to explain the failure of the short (15 min) training interval to support LTM formation.”

Parsons and Davis (2012) reported the recruitment at 1 h of a transient CREB phosphorylation in the amygdala of rats given a single training trial that was subthreshold for the induction of STM and LTM for a form of fear memory.

“Consistent with this notion, Parsons and Davis (2012) recently reported the recruitment at 1 h of a transient CREB phosphorylation in the amygdala of rats given a single training trial which, in itself, was subthreshold for the induction of STM and LTM for a form of fear memory.”

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Trial 1 MAPK activity establishes a unique molecular context within tail SNs by 45 min that is required for two-trial LTM formation.

“Trial 1 MAPK activity establishes a unique molecular context within tail SNs by 45 min that is required for two-trial LTM formation.”

• Also stated in: § Two-trial training patterns provide a unique opportunity to study the spacing effect in LTM formation · plain

  “Trial 1 MAPK activity establishes a unique molecular context within tail SNs by 45 min that is required for two-trial LTM formation.”

The temporal correlation between the appearance of activated MAPK in the cell bodies of tail SNs, cytoplasm and nucleus, and the permissive two-trial training interval suggests an important role for MAPK activity in this specific cellular compartment for intertrial signaling during LTM induction.

“The temporal correlation between the appearance of activated MAPK in the cell bodies of tail SNs (cytoplasm and nucleus) and the permissive two-trial training interval suggests an important role for MAPK activity in this specific cellular compartment for intertrial signaling during LTM induction.”

The delayed onset of the MAPK-dependent molecular context may be sufficient to explain the failure of the short (15 min) training interval to support LTM formation.

“The delayed onset of the MAPK-dependent molecular context may be sufficient to explain the failure of the short (15 min) training interval to support LTM formation.”

In humans, the determination of optimal training intervals for LTM formation depends heavily upon the retention interval examined.

“Finally, studies in humans have made clear that the determination of optimal training intervals for LTM formation depends heavily upon the retention interval examined (Donovan and Radosevich, 1999;Cepeda et al., 2006;Cepeda et al., 2008).”

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The optimal interval for two-trial memory induction may be determined by kinetics for the recruitment of MAPK following a wide range of training stimuli which will have their own unique temporal constraints.

“Rather, the optimal interval may be determined by kinetics for the recruitment of MAPK following a wide range of training stimuli which will have their own unique temporal constraints.”

Two appropriately spaced training trials can support LTM induction in Aplysia and rats.

“Together with recent findings that just two appropriately spaced training trials can support LTM induction in Aplysia (Philips et al., 2007) and rats (Parsons and Davis, 2012)”

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In Aplysia, the simplest training interval for LTM for sensitization is defined in part through the temporally restricted recruitment of MAPK by an initial experience.

“In Aplysia, the simplest training interval for LTM for sensitization is defined in part through the temporally restricted re-cruitment of MAPK by an initial experience.”

A single training shock releases 5HT onto tail SNs and sensorimotor synapses.

“A single training shock (TS) releases 5HT onto tail SNs and sensorimotor synapses(Marinesco and Carew, 2002;Philips et al., 2011).”

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Zhang et al. (2012) used a computer model incorporating basic knowledge of the kinetics of PKA and MAPK activation following a single training trial in the tail SNs of Aplysia to predict effective five-trial spaced training patterns that would result in maximal coincident recruitment of PKA and MAPK signaling.

“A recent seminal study by Zhang et al. (2012) used a computer model, which incorporated basic knowledge of the kinetics of PKA and MAPK activation following a single training trial in the tail SNs of Aplysia, to predict effective five-trial spaced training patterns that would result in the maximal coincident recruitment of PKA and MAPK signaling.”

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Parsons and Davis (2012) identified a two-trial training window for fear-potentiated startle in rats that ranged from 1 h to several days.

“As a striking example, Parsons and Davis (2012) recently re-examined multiple trial memory formation for fear-potentiated startle in rats and identified a remarkable two-trial training window that ranged from 1 h to several days.”

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Several factors influence the benefit of specific training intervals.

“Thus several factors influence the benefit of specific training intervals.”

Protein synthesis is increased within minutes following brief 5HT treatment to isolated SN neurites in culture.

“protein synthesis is increased within minutes following brief 5HT treatment to isolated SN neurites in culture (Casadio et al., 1999;Si et al., 2003)”

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Just two appropriately spaced training trials can support LTM induction in Aplysia.

“Together with recent findings that just two appropriately spaced training trials can support LTM induction in Aplysia (Philips”

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Protein synthesis may account, at least in part, for the delayed activation of Trial 1 MAPK.

“Trial 1 MAPK activation requires protein synthesis which may account, at least in part, for its delayed activation.”

During two-trial training, the initial experience (Trial 1) recruits signaling events that must interact with a subsequent experience (Trial 2) provided within a temporally bounded window to establish LTM.

“During two-trial training the contribution of each trial to the induction of memory can be easily understood: the initial experience (Trial 1) recruits signaling events that must interact with a subsequent experience (Trial 2) provided within a temporally bounded window to establish LTM.”

A MAPK-dependent ApC/EBP induction by Trial 1 may interact with 5HT release following Trial 2 to support two-trial LTM formation.

“Indeed, a MAPK-dependent ApC/EBP induction by Trial 1 may interact with 5HT release following Trial 2 to support two-trial LTM formation.”