Neurochemical Research

, Volume 39, Issue 5, pp 875–882 | Cite as

Social Isolation Stress-Induced Fear Memory Deficit is Mediated by Down-Regulated Neuro-Signaling System and Egr-1 Expression in the Brain

  • Ryo Okada
  • Kinzo Matsumoto
  • Ryohei Tsushima
  • Hironori Fujiwara
  • Koichi Tsuneyama
Original Paper


We previously reported that social isolation (SI) rearing of rodents not only elicits a variety of behavioral abnormalities including attention deficit hyperactivity disorder-like behaviors, but also impairs fear memory in mice. This study aimed to clarify a putative mechanism underlying SI-induced conditioned fear memory deficit. Mice were group-housed (GH) or socially isolated for 2 weeks or more before the experiments. SI animals acquired contextual and auditory fear memory elucidated at 90 min and 4 h after training, respectively; however, they showed significantly impaired contextual and auditory memory performance at 24 h and 4 days after the training, respectively, indicating SI-induced deficit of the consolidation process of fear memory. Neurochemical studies conducted after behavioral tests revealed that SI mice had a significantly down-regulated level of Egr-1 but not Egr-2 in the hippocampal and cortical cytosolic fractions compared with those levels in the GH control animals. Moreover, in the SI group, phosphorylated levels of synaptic plasticity-related signaling proteins in the hippocampus, NR1 subunit of N-methyl-d-aspartate receptor, glutamate receptor 1, and calmodulin-dependent kinase II but not cyclic AMP-responsive element binding protein were significantly down-regulated compared with those levels in GH animals, whereas non-phosphorylated levels of these proteins were not affected by SI. These findings suggest that dysfunctions of Egr-1 and neuro-signaling systems are involved in SI-induced deficits of fear memory consolidation in mice.


Social isolation stress ADHD model Long-term fear memory Egr-1 Neuro-signaling system 



This study was in part supported by a Grant-in-Aid for Challenging Exploratory Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) to KM (#24659347).


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Ryo Okada
    • 1
  • Kinzo Matsumoto
    • 1
  • Ryohei Tsushima
    • 1
  • Hironori Fujiwara
    • 1
  • Koichi Tsuneyama
    • 2
  1. 1.Division of Medicinal Pharmacology, Institute of Natural MedicineUniversity of ToyamaToyamaJapan
  2. 2.Department of Diagnostic Pathology, Graduate School of Medical and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan

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