The temporal effect of hippocampal Arc in the working memory paradigm during novelty exploration.

Arc (activity-regulated cytoskeleton-associated protein) is one of the neuronal Immediate Early Genes (IEG), which is involved in the consolidation of memory and is an essential factor in the induction of Long-term Potentiation (LTP), Long-term Depression (LTD) and homeostatic synaptic plasticity. It has also been implicated in the increased familiarization of novel environments during reference memory paradigms. However, the Arc associated temporal effects in a working memory paradigm during novelty exploration are not well studied. Therefore, in the present study, we used spontaneous alternation behavior (SAB) test along with the expression analysis of Arc to study its temporal effects on the working memory paradigms. Using a modified SAB test, we found that the increase in the duration of exposure to a novel environment in the short time-scale (<min) increases the alternations showing that short-term habituation increases the alternation rate. Additionally, during repeated exposure to a novel environment, the alternation rates decrease after shorter inter-session interval. Parallelly, we observed the upregulation of Arc mRNA and protein level 30 min after the SAB test in the cortex and hippocampus of mice, which returns to near-basal level after two hours. The novel experience, associated with the enhanced expression of Arc, helps in the decrease of alternations in subsequent sessions. This change in alternations was absent if the environment was familiar. Further, the role of Arc during these SAB test was confirmed by the inhibition of hippocampal Arc protein through the stereotaxic infusion of Arc antisense oligodeoxynucleotides. We observed that the Arc is involved in the temporal decrease of spontaneous alternations during a series of exposures to a novel environment. Finally, the significance of these results has been discussed in the light of Wagner's Sometimes Opponent Processes model, where we suggest that Arc reduces the ability for short-term habituation during repeated exposures in the working memory paradigm, and the loss of this ability is more prominent when subjected to a novel environment.