Perhaps the most basic form of associative learning, classical conditioning has been the subject of scientific investigation for a century. Nevertheless, the neurobiological mechanisms underlying classical conditioning remain poorly understood. The goal of the proposed research is to use a simple reflex that exhibits classical conditioning, and can be studied using reductionist neurobiological tools. Many of the neurons that underlie this reflex have been identified. In particular, the sensory and motor neurons for the reflex have been identified in the central nervous system (CNS). Moreover, the sensory and motor neurons can be individually dissociated from the CNS and placed into cell culture. This makes possible in vitro electrophysiological and molecular investigations of learning-related neuronal plasticity. In vitro studies of synaptic plasticity will be combined with studies of classical condititioning in semi-intact preparations that permit simultaneous electrophysiological and behavioral manipulation and measurement. A major focus of the proposed research will be on the roles of postsynaptic glutamate receptors, particularly NMDA and AMPA receptors, in classical conditioning. One potential mechanism for classical conditioning is modulation of the intracellular trafficking of AMPA receptors by the monoamine serotonin (5-HT). The cellular and molecular mechanisms of 5-HT-dependent modulation of AMPA receptor trafficking will be investigated in both neurons in culture and in the CNS. Pharmacological agents that block modulation of AMPA receptor trafficking will be used to identify the protein kinases involved in this modulation. Whether modulation of AMPAR receptor trafficking depends upon protein synthesis will also be studied. Immunohistochemical techniques will be used to label AMPA receptors, both in vitro and in the CNS. This will permit the direct visualization of changes in AMPA receptor distribution and number due to 5-HT and to learning. Furthermore, in situ hybridization will be used to determine whether long-term (>=24 hr) classical conditioning depends upon increased expression of genes for AMPA and NMDA receptors. Finally, the interactions between 5-HT-dependent processes and NMDA receptor-dependent processes during classical conditioning will be examined. The results of the project will clarify the basic neurobiology of learning, and will thereby facilitate the development of treatments for diseases of memory, such as Alzheimer's.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (07))
Program Officer
Babcock, Debra J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Bougie, Joanna K; Cai, Diancai; Hastings, Margaret et al. (2012) Serotonin-induced cleavage of the atypical protein kinase C Apl III in Aplysia. J Neurosci 32:14630-40
Glanzman, David L (2012) Behavioral neuroscience: no easy path from genes to cognition. Curr Biol 22:R302-4
Cai, Diancai; Pearce, Kaycey; Chen, Shanping et al. (2012) Reconsolidation of long-term memory in Aplysia. Curr Biol 22:1783-8
Cai, Diancai; Pearce, Kaycey; Chen, Shanping et al. (2011) Protein kinase M maintains long-term sensitization and long-term facilitation in aplysia. J Neurosci 31:6421-31
Glanzman, David L (2009) Habituation in Aplysia: the Cheshire cat of neurobiology. Neurobiol Learn Mem 92:147-54
Villareal, Greg; Li, Quan; Cai, Diancai et al. (2009) Role of protein kinase C in the induction and maintenance of serotonin-dependent enhancement of the glutamate response in isolated siphon motor neurons of Aplysia californica. J Neurosci 29:5100-7
Glanzman, David L (2008) New tricks for an old slug: the critical role of postsynaptic mechanisms in learning and memory in Aplysia. Prog Brain Res 169:277-92
Fulton, Daniel; Condro, Michael C; Pearce, Kaycey et al. (2008) The potential role of postsynaptic phospholipase C activity in synaptic facilitation and behavioral sensitization in Aplysia. J Neurophysiol 100:108-16
Cai, Diancai; Chen, Shanping; Glanzman, David L (2008) Postsynaptic regulation of long-term facilitation in Aplysia. Curr Biol 18:920-5
Villareal, Greg; Li, Quan; Cai, Diancai et al. (2007) The role of rapid, local, postsynaptic protein synthesis in learning-related synaptic facilitation in aplysia. Curr Biol 17:2073-80

Showing the most recent 10 out of 26 publications