Differential classical conditioning of the gill-withdrawal reflex in Aplysia recruits both NMDA receptor-dependent enhancement and NMDA receptor-dependent depression of the reflex

J Neurosci. 2007 Mar 21;27(12):3064-8. doi: 10.1523/JNEUROSCI.2581-06.2007.


Differential classical conditioning of the gill-withdrawal response (GWR) in Aplysia can be elicited by training in which a conditioned stimulus (CS) delivered to one side of the siphon (the CS+) is paired with a noxious unconditioned stimulus (US; tail shock), while a second conditioned stimulus (the CS-), delivered to a different siphon site, is unpaired with the US. NMDA receptor (NMDAR) activation has been shown previously to be critical for nondifferential classical conditioning in Aplysia. Here, we used a semi-intact preparation to test whether differential classical conditioning of the GWR also depends on activation of NMDARs. Differential training produced conditioned enhancement of the reflexive response to the CS+ and a reduction in the response to the CS-. Comparison of the results after differential training with those after training in which only the two CSs were presented (CS-alone experiments) indicated that the decrement in the response to CS- after differential training was not caused by habituation. Surprisingly, differential training in the NMDAR antagonist APV (DL-2-amino-5-phosphonovalerate) blocked not only the conditioned enhancement of the GWR, but also the conditioning-induced depression of the GWR. We suggest that differential conditioning involves an NMDAR-dependent, competitive interaction between the separate neural pathways activated by the CS+ and CS-.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Aplysia
  • Conditioning, Classical / drug effects
  • Conditioning, Classical / physiology*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Gills / drug effects
  • Gills / physiology
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / physiology*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Reflex / drug effects
  • Reflex / physiology*


  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate