A significant percentage of people in the US suffer from behavioral disorders, including posttraumatic stress disorder (PTSD), anxiety disorders, and drug addiction, that are effectively diseases of memory dysfunction. Therefore, an understanding of the cell biology of learning and memory should facilitate the development of treatments for these disorders. One of the fundamental forms of associative learning is classical conditioning. During classical conditioning an animal learns to associate a neutral stimulus (the conditioned stimulus) with the delivery of a reinforcing stimulus (unconditioned stimulus). This project will exploit the significant experimental advantages of the marine mollusk Aplysia californica to develop a mechanistic understanding of classical conditioning. This animal has a simple nervous system that is highly suited to electrophysiological, pharmacological, and molecular experimental techniques. The project will focus on a classical conditioning of the defensive withdrawal reflex in Aplysia. This form of learning is mediated by a combination of homosynaptic, NMDA receptor-dependent plasticity and heterosynaptic, serotonergic neuromodulation. The PI hypothesizes that the postsynaptic motor neuron is a major cite of associative interaction between these two processes. The project will investigate the potential postsynaptic interactions between Hebbian and neuromodulatory processes. Toward this end, the PI will perform imaging of calcium in the motor neuron to determine whether intracellular calcium resulting from postsynaptic NMDA receptor activity and calcium released from postsynaptic intracellular stores by serotonin stimulation interact. In addition, the potential rol of postsynaptic calcium- calmodulin kinase II and postsynaptic metabotropic glutamate receptors will be examined. The PI will also investigate the role of modulation of postsynaptic AMPA receptor trafficking in classical conditioning by expressing constructs in Aplysia motor neurons that block AMPA receptor trafficking. The proposed studies will use both sensorimotor cocultures and reduced preparations of Aplysia.

Public Health Relevance

Brain disorders related to learning and memory, including Alzheimer's disease, posttraumatic stress disorder (PTSD) and drug addiction, afflict a substantial percentage of the population of the United States. The proposed project will use a simple model system to better understand the cellular and molecular bases of classical conditioning, one of the most important forms of learning. The proposed research is expected to facilitate the development of effective treatments for memory-related disorders.

National Institute of Health (NIH)
Research Project (R01)
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Study Section
Neurobiology of Learning and Memory Study Section (LAM)
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Babcock, Debra J
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Glanzman, David L (2009) Habituation in Aplysia: the Cheshire cat of neurobiology. Neurobiol Learn Mem 92:147-54
Bedi, Supinder S; Cai, Diancai; Glanzman, David L (2008) Effects of axotomy on cultured sensory neurons of Aplysia: long-term injury-induced changes in excitability and morphology are mediated by different signaling pathways. J Neurophysiol 100:3209-24
Jami, Shekib A; Wright, William G; Glanzman, David L (2007) 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 27:3064-8
Glanzman, David L (2006) The cellular mechanisms of learning in Aplysia: of blind men and elephants. Biol Bull 210:271-9
Li, Quan; Roberts, Adam C; Glanzman, David L (2005) Synaptic facilitation and behavioral dishabituation in Aplysia: dependence on release of Ca2+ from postsynaptic intracellular stores, postsynaptic exocytosis, and modulation of postsynaptic AMPA receptor efficacy. J Neurosci 25:5623-37
Roberts, Adam C; Glanzman, David L (2003) Learning in Aplysia: looking at synaptic plasticity from both sides. Trends Neurosci 26:662-70
Ezzeddine, Youssef; Glanzman, David L (2003) Prolonged habituation of the gill-withdrawal reflex in Aplysia depends on protein synthesis, protein phosphatase activity, and postsynaptic glutamate receptors. J Neurosci 23:9585-94
Bedi, S S; Glanzman, D L (2001) Axonal rejoining inhibits injury-induced long-term changes in Aplysia sensory neurons in vitro. J Neurosci 21:9667-77
Chitwood, R A; Li, Q; Glanzman, D L (2001) Serotonin facilitates AMPA-type responses in isolated siphon motor neurons of Aplysia in culture. J Physiol 534:501-10
Murphy, G G; Glanzman, D L (1999) Cellular analog of differential classical conditioning in Aplysia: disruption by the NMDA receptor antagonist DL-2-amino-5-phosphonovalerate. J Neurosci 19:10595-602

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