Consolidation of CS and US representations in associative fear conditioning

Hippocampus. 2004;14(5):557-69. doi: 10.1002/hipo.10208.


Much attention has been paid to the associative processes that are necessary to fuse together representations of the various components of an episodic memory. In the present study, we focus on the processes involved in the formation of lasting representations of the individual components that make up a fear-conditioning episode. In one-trial contextual fear conditioning experiments, weak conditioning to context occurs if the shock is delivered immediately following placement of the animal in a novel conditioning apparatus, a phenomenon known as the immediate shock deficit. We show that the immediate shock deficit in mice may be alleviated by pre-exposure to either the context or shock. In using this approach to temporally dissect a contextual fear-conditioning task into its constituent representational and associative processes, we are able to examine directly the processes that are important for formation of lasting representations of the context conditioned stimulus (CS) or unconditioned stimulus (US). Our data indicate that the formation of a lasting representation of the context or shock engages protein synthesis-dependent processes. Furthermore, genetic disruption of cAMP-responsive element binding protein (CREB), a transcription factor that regulates the synthesis of new proteins required for long-term memory, disrupts the formation of lasting context memories. We go on to show that the stress hormone epinephrine modulates the consolidation of a context memory, and reverses consolidation deficits in the CREB-deficient mice. Finally we show that disrupting either NMDA or calcium/calmodulin-dependent kinase II (CaMKII) function impairs consolidation of context memories. Together, these data suggest that this approach is particularly suited for the characterization of molecular and cellular processes underlying the formation of stimulus representations.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Association Learning / physiology*
  • Avoidance Learning / physiology
  • Brain / cytology
  • Brain / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Conditioning, Classical / physiology*
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Electric Stimulation
  • Epinephrine / metabolism
  • Excitatory Amino Acid Antagonists / pharmacology
  • Fear / physiology*
  • Female
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Male
  • Memory / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Nerve Tissue Proteins / biosynthesis
  • Neural Pathways / cytology
  • Neural Pathways / metabolism
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Stress, Psychological / genetics
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology


  • Cyclic AMP Response Element-Binding Protein
  • Excitatory Amino Acid Antagonists
  • Nerve Tissue Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Epinephrine