Coregulation of Glutamate Uptake and Long-Term Sensitization in<i>Aplysia</i>

Khabour, Omar F.; Levenson, Jonathan M.; Lyons, Lisa C.; Kategaya, Lorna; Chin, Jeannie; Byrne, John H.; Eskin, Arnold

doi:10.1523/jneurosci.2167-04.2004

Cited by 21 publications

(28 citation statements)

References 78 publications

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“…2A). To confirm these findings, similar experiments were performed with a second MEK inhibitor PD98059 that also has been used to block MAPK in vivo in Aplysia ) and in sensory neurons and ganglia (Bailey et al 1997;Martin et al 1997;Khabour et al 2004). Animals injected with PD98059 prior to training exhibited no LTM ( Fig.…”

Section: Resultsmentioning

confidence: 68%

“…To determine if MAPK signaling was necessary for long-term LFI memory, animals were injected with a MAPK kinase inhibitor U0126 previously used to inhibit MAPK in vivo (Lyons et al 2006a), in ganglia and in semi-intact preparations in Aplysia (Chin et al 2002;Sharma et al 2003;Khabour et al 2004). Control animals were injected with matched amounts of U0124, an inactive analog of U0126, or the vehicle DMSO.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

PKG-mediated MAPK signaling is necessary for long-term operant memory in Aplysia

Michel¹,

Green²,

Eskin³

et al. 2011

Learn. Mem.

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Signaling pathways necessary for memory formation, such as the mitogen-activated protein kinase (MAPK) pathway, appear highly conserved across species and paradigms. Learning that food is inedible (LFI) represents a robust form of associative, operant learning that induces short-(STM) and long-term memory (LTM) in Aplysia. We investigated the role of MAPK signaling in LFI memory in vivo. Inhibition of MAPK activation in animals prior to training blocked STM and LTM. Discontinuing MAPK signaling immediately after training inhibited LTM with no impact on STM. Therefore, MAPK signaling appears necessary early in memory formation for STM and LTM, with prolonged MAPK activity required for LTM. We found that LFI training significantly increased phospho-MAPK levels in the buccal ganglia. Increased MAPK activation was apparent immediately after training with greater than basal levels persisting for 2 h. We examined the mechanisms underlying training-induced MAPK activation and found that PKG activity was necessary for the prolonged phase of MAPK activation, but not for the early MAPK phase required for STM. Furthermore, we found that neither the immediate nor the prolonged phase of MAPK activation was dependent upon nitric oxide (NO) signaling, although expression of memory was dependent on NO as previously reported. These studies emphasize the role of MAPK and PKG in negatively reinforced operant memory and demonstrate a role for PKG-dependent MAPK signaling in invertebrate associative memory. [Supplemental material is available for this article.]Invertebrate model systems with relatively simple nervous systems have proven invaluable in furthering our understanding of adaptive behavior and the mechanisms underlying memory, as core components appear highly conserved across phylogenies (reviewed in Bailey et al. 2008;Sweatt 2010). One conserved element, the mitogen-activated protein kinase cascade (MAPK) is necessary for intermediate and long-term sensitization in Aplysia Purcell et al. 2003;Sharma et al. 2003), olfactory conditioning in Drosophila (Moressis et al. 2009;Pagani et al. 2009), and associative memory in mammals (reviewed in Sweatt 2004). Recently, the nitric oxide-cGMP-Protein kinase G (NO-cGMP-PKG) pathway was identified upstream of MAPK activation during fear conditioning in mammals (Ota et al. 2008(Ota et al. , 2010b. In Aplysia, long-term hyperexcitability of nociceptive neurons following injury requires NO-cGMP-PKG signaling (Lewin and Walters 1999) for MAPK activation and nuclear translocation (Sung et al. 2004). Thus, the possibility exists that the PKG-MAPK pathway also may be conserved in invertebrate learning. However, no studies have addressed a PKG-MAPK link during associative memory formation in invertebrates.Feeding behavior in Aplysia and its underlying circuitry represent a highly plastic system (reviewed in Elliott and Susswein 2002;Cropper et al. 2004) amenable for comparative studies of complex learning through classical conditioning, operant reward learning, and negatively reinforced para...

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Section: Resultsmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

PKG-mediated MAPK signaling is necessary for long-term operant memory in Aplysia

Michel¹,

Green²,

Eskin³

et al. 2011

Learn. Mem.

View full text Add to dashboard Cite

show abstract

“…Animals were injected with the MAP kinase kinase (MEK) inhibitor U0126 (130 l/100 g body weight of 7.5 mM stock in DMSO) 30 min before LTS training at CT 9. U0126 has been used previously to inhibit MAPK activity in Aplysia ganglia and in semi-intact preparations (Chin et al, 2002;Sharma et al, 2003;Khabour et al, 2004). Inhibiting the MAPK signaling pathway prevented significant increases in C/EBP protein levels.…”

Section: Circadian Clock Modulated Changes Inmentioning

confidence: 99%

The Circadian Clock Modulates Core Steps in Long-Term Memory Formation inAplysia

Lyons

Collado²,

Khabour³

et al. 2006

J. Neurosci.

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The circadian clock modulates the induction of long-term sensitization (LTS) in Aplysia such that long-term memory formation is significantly suppressed when animals are trained at night. We investigated whether the circadian clock modulated core molecular processes necessary for memory formation in vivo by analyzing circadian regulation of basal and LTS-induced levels of phosphorylated mitogen-activated protein kinase (P-MAPK) and Aplysia CCAAT/enhancer binding protein (ApC/EBP). No basal circadian regulation occurred for P-MAPK or total MAPK in pleural ganglia. In contrast, the circadian clock regulated basal levels of ApC/EBP protein with peak levels at night, antiphase to the rhythm in LTS. Importantly, LTS training during the (subjective) day produced greater increases in P-MAPK and ApC/EBP than training at night. Thus, circadian modulation of LTS occurs, at least in part, by suppressing changes in key proteins at night. Rescue of long-term memory formation at night required both facilitation of MAPK and transcription in conjunction with LTS training, confirming that the circadian clock at night actively suppresses MAPK activation and transcription involved in memory formation.The circadian clock appears to modulate LTS at multiple levels. 5-HT levels are increased more when animals receive LTS training during the (subjective) day compared with the night, suggesting circadian modulation of 5-HT release. Circadian modulation also occurred downstream of 5-HT release because animals treated with 5-HT to induce LTS exhibited significantly greater LTS when treated during the (subjective) day compared with the night. Together, our studies suggest that the circadian clock modulates LTS at multiple steps and locations during the formation of long-term memory.

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“…The training protocol used in this study is known to induce LTS that persists for at least 48 h, but not 72 h, after treatment (Khabour et al 2004). Therefore, in the next experiment, feeding and B51 excitability were analyzed 72 h after treatment.…”

mentioning

confidence: 99%

Effects of aversive stimuli beyond defensive neural circuits: Reduced excitability in an identified neuron critical for feeding in Aplysia

et al. 2012

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In Aplysia, repeated trials of aversive stimuli produce long-term sensitization (LTS) of defensive reflexes and suppression of feeding. Whereas the cellular underpinnings of LTS have been characterized, the mechanisms of feeding suppression remained unknown. Here, we report that LTS training induced a long-term decrease in the excitability of B51 (a decisionmaking neuron in the feeding circuit) that recovered at a time point in which LTS is no longer observed (72 h post-treatment). These findings indicate B51 as a locus of plasticity underlying feeding suppression. Finally, treatment with serotonin to induce LTS failed to alter feeding and B51 excitability, suggesting that serotonin does not mediate the effects of LTS training on the feeding circuit.

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Coregulation of Glutamate Uptake and Long-Term Sensitization inAplysia

Cited by 21 publications

References 78 publications

PKG-mediated MAPK signaling is necessary for long-term operant memory in Aplysia

PKG-mediated MAPK signaling is necessary for long-term operant memory in Aplysia

The Circadian Clock Modulates Core Steps in Long-Term Memory Formation inAplysia

Effects of aversive stimuli beyond defensive neural circuits: Reduced excitability in an identified neuron critical for feeding in Aplysia

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