Although many theories of learning have proposed that plasticity at specific synapses in the central nervous system is critical to memory storage, there have been very few experimental preparations in which it has been possible to test this hypothesis rigorously. For this reason, the past program of research supported by this grant has been devoted to studies of the cellular mechanisms of simple forms of learning of the gill-and siphon-withdrawal reflex in Aplysia. Previous has suggested that a mechanism to dishabituation and sensitization of the reflex is presynaptic facilitation of the siphon sensory neurons, and that a mechanism contribution to classical conditioning of the reflex is an amplification of this mechanism by sensitization by the occurrence of spike activity in the sensory neurons just before the sensitizing stimulus. Recent results have suggested that in addition to this presynaptic mechanism, Hebbian long-term potentiation (LTP) may also contribute to conditioning of the reflex. However, the studies performed at the behavioral and cellular levels have generally used different preparations and procedures, so that the relationship between the two was inferred rather than tested directly. To test the relationship between cellular events and behavior more rigorously, we developed two simplified preparations with which it is relatively easy to record the activity of single identified neurons during behavior. Our initial studies with these preparations provided the first direct evidence that habituation, dishabituation, and sensitization of the reflex involve plasticity at the sensory-motor neuron synapses. In addition, our results have indicated that other sites and mechanisms of plasticity also contribute. Thus, these preparations provide an opportunity to analyze parallel processing and examine mechanisms contribution to learning at the system level as well as the cellular level. We now propose to utilize these simplified preparations to examine in more detail the mechanisms contribution to dishabituation and sensitization, and to perform a similar analysis of classical conditioning. Specifically, we will test the contributions of activity-dependent presynaptic facilitation and Hebbian long-term potentiation to conditioning, differential conditioning, and second-order conditioning, and also examine the contribution of their cellular mechanisms and explore how they are integrated at the behavioral level. In addition to these studies attempting to relate cellular events to behavior, we also plan to perform experiments on single sensory and motor neurons in cell culture to analyze mechanisms of activity-dependent plasticity (post-tetanic potentiation, activity-dependent facilitation by serotonin, and LTP) that may contribute to the learning.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH026212-28
Application #
6625331
Study Section
Special Emphasis Panel (ZRG1-IFCN-7 (01))
Program Officer
Asanuma, Chiiko
Project Start
1977-09-01
Project End
2005-11-30
Budget Start
2002-12-01
Budget End
2005-11-30
Support Year
28
Fiscal Year
2003
Total Cost
$250,902
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurosciences
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Jin, Iksung; Udo, Hiroshi; Hawkins, Robert D (2011) Rapid increase in clusters of synaptophysin at onset of homosynaptic potentiation in Aplysia. Proc Natl Acad Sci U S A 108:11656-61
Jin, Iksung; Kandel, Eric R; Hawkins, Robert D (2011) Whereas short-term facilitation is presynaptic, intermediate-term facilitation involves both presynaptic and postsynaptic protein kinases and protein synthesis. Learn Mem 18:96-102
Antonov, Igor; Ha, Thomas; Antonova, Irina et al. (2007) Role of nitric oxide in classical conditioning of siphon withdrawal in Aplysia. J Neurosci 27:10993-1002
Hawkins, Robert D; Cohen, Tracey E; Kandel, Eric R (2006) Dishabituation in Aplysia can involve either reversal of habituation or superimposed sensitization. Learn Mem 13:397-403
Hawkins, Robert D; Clark, Gregory A; Kandel, Eric R (2006) Operant conditioning of gill withdrawal in Aplysia. J Neurosci 26:2443-8
Hawkins, Robert D; Kandel, Eric R; Bailey, Craig H (2006) Molecular mechanisms of memory storage in Aplysia. Biol Bull 210:174-91
Udo, Hiroshi; Jin, Iksung; Kim, Joung-Hun et al. (2005) Serotonin-induced regulation of the actin network for learning-related synaptic growth requires Cdc42, N-WASP, and PAK in Aplysia sensory neurons. Neuron 45:887-901
Jin, Iksung; Hawkins, Robert D (2003) Presynaptic and postsynaptic mechanisms of a novel form of homosynaptic potentiation at aplysia sensory-motor neuron synapses. J Neurosci 23:7288-97
Antonov, Igor; Antonova, Irina; Kandel, Eric R et al. (2003) Activity-dependent presynaptic facilitation and hebbian LTP are both required and interact during classical conditioning in Aplysia. Neuron 37:135-47
Antonova, I; Arancio, O; Trillat, A C et al. (2001) Rapid increase in clusters of presynaptic proteins at onset of long-lasting potentiation. Science 294:1547-50

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