Social Isolation Stress-Induced Fear Memory Deficit is Mediated by Down-Regulated Neuro-Signaling System and Egr-1 Expression in the Brain
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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.
KeywordsSocial 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).
- 10.Yamada K, Gerber DJ, Iwayama Y, Ohnishi T, Ohba H, Toyota T, Aruga J, Minabe Y, Tonegawa S, Yoshikawa T (2007) Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia. Proc Natl Acad Sci USA 104:2815–2820PubMedCentralPubMedCrossRefGoogle Scholar
- 19.Zhao Q, Matsumoto K, Tsuneyama K, Tanaka K, Li F, Shibahara N, Miyata T, Yokozawa T (2011) Diabetes-induced central cholinergic neuronal loss and cognitive deficit are attenuated by tacrine and a Chinese herbal prescription, kangen-karyu: elucidation in type 2 diabetes db/db mice. J Pharmacol Sci 117:230–242PubMedCrossRefGoogle Scholar
- 20.Guzowski JF, Lyford GL, Stevenson GD, Houston FP, McGaugh JL, Worley PF, Barnes CA (2000) Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J Neurosci 20:3993–4001PubMedGoogle Scholar