Differential expression of the immediate early genes c-Fos, Arc, Egr-1, and Npas4 during long-term memory formation in the context preexposure facilitation effect (CPFE)

Neurobiol Learn Mem. 2018 Jan;147:128-138. doi: 10.1016/j.nlm.2017.11.016. Epub 2017 Dec 6.


The context preexposure facilitation effect (CPFE) is a contextual fear conditioning paradigm in which learning about the context, acquiring the context-shock association, and retrieving/expressing contextual fear are temporally dissociated into three distinct phases (context preexposure, immediate-shock training, and retention). The current study examined changes in the expression of plasticity-associated immediate early genes (IEGs) during context and contextual fear memory formation on the preexposure and training days of the CPFE, respectively. Using adolescent Long-Evans rats, preexposure and training day expression of the IEGs c-Fos, Arc, Egr-1, and Npas4 in the medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC), and basolateral amygdala (BLA) was analyzed using qPCR as an extension of previous studies from our lab examining Egr-1 via in situ hybridization (Asok, Schreiber, Jablonski, Rosen, & Stanton, 2013; Schreiber, Asok, Jablonski, Rosen, & Stanton, 2014). In Expt. 1, context preexposure induced expression of c-Fos, Arc, Egr-1 and Npas4 significantly above that of home-cage (HC) controls in all three regions. In Expt. 2, immediate-shock was followed by a post-shock freezing test, resulting in increased mPFC c-Fos expression in a group preexposed to the training context but not a control group preexposed to an alternate context, indicating expression related to associative learning. This was not seen with other IEGs in mPFC or with any IEG in dHPC or BLA. Finally, when the post-shock freezing test was omitted in Expt. 3, training-related increases were observed in prefrontal c-Fos, Arc, Egr-1, and Npas4, hippocampal c-Fos, and amygdalar Egr-1 expression. These results indicate that context exposure in a post-shock freezing test re-engages IEG expression that may obscure associatively-induced expression during contextual fear conditioning. Additionally, these studies suggest a key role for long-term synaptic plasticity in the mPFC in supporting the CPFE.

Keywords: CPFE; Context learning; Contextual fear conditioning; Immediate early genes; Medial prefrontal cortex.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Basolateral Nuclear Complex / physiology
  • Behavior, Animal / physiology*
  • Conditioning, Classical / physiology*
  • Cytoskeletal Proteins / metabolism
  • Early Growth Response Protein 1 / metabolism
  • Fear / physiology*
  • Female
  • Gene Expression / physiology*
  • Genes, Immediate-Early / physiology*
  • Hippocampus / physiology
  • Male
  • Memory, Long-Term / physiology*
  • Nerve Tissue Proteins / metabolism
  • Neuronal Plasticity / physiology*
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / physiology*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Rats, Long-Evans


  • Basic Helix-Loop-Helix Transcription Factors
  • Cytoskeletal Proteins
  • Early Growth Response Protein 1
  • Egr1 protein, rat
  • Nerve Tissue Proteins
  • Npas4 protein, rat
  • Proto-Oncogene Proteins c-fos
  • activity regulated cytoskeletal-associated protein