PARP-1 activity is required for the reconsolidation and extinction of contextual fear memory

Abstract

BackgroundMemory consolidation, reconsolidation, and extinction have been shown to require new gene expression. Poly ADP-ribosylation mediated by poly (ADP-ribose) polymerase-1 (PARP-1) is known to regulate transcription through histone modification. Recent studies have suggested that PARP-1 positively regulates the formation of long-term memory (LTM); however, the roles of PARP-1 in memory processes, especially processes after retrieval, remain unknown.ResultsHere, we show critical roles for PARP-1 in the consolidation, reconsolidation, and extinction of contextual fear memory in mice. We examined the effects of pharmacological inhibition of PARP-1 activity in the hippocampus or medial prefrontal cortex (mPFC) on these memory processes. Similarly with previous findings, a micro-infusion of the PARP-1 inhibitor 3-aminobenzamide or PJ34 into the dorsal hippocampus, but not mPFC, impaired LTM formation without affecting short-term memory (STM). Importantly, this pharmacological blockade of PARP-1 in the dorsal hippocampus, but not mPFC, also disrupted post-reactivation LTM without affecting post-reactivation STM. Conversely, micro-infusion of the PARP-1 inhibitors into the mPFC, but not dorsal hippocampus, blocked long-term extinction. Additionally, systemic administration of the PARP-1 inhibitor Tiq-A blocked c-fos induction in the hippocampus, which is observed when memory is consolidated or reconsolidated, and also blocked c-fos induction in the mPFC, which is observed when memory is extinguished.ConclusionsOur observations showed that PARP-1 activation is required for the consolidation, reconsolidation, and extinction of contextual fear memory and suggested that PARP-1 contributes to the new gene expression necessary for these memory processes.

N-glycosylation in the hippocampus is required for the consolidation and reconsolidation of contextual fear memory

“…The hippocampus is known to play an essential role in the consolidation and reconsolidation of contextual fear memory (Alberini, 2005;Anagnostaras et al, 2001;Debiec et al, 2002;Inaba et al, 2015;Kim et al, 1993;Lee et al, 2004;Mamiya et al, 2009;Phillips & LeDoux, 1992;Suzuki et al, 2008;Tronson & Taylor, 2007). We found that inhibiting hippocampal N-glycosylation blocked the consolidation and reconsolidation of contextual fear memory, suggesting that the induction of de novo N-glycosylation in the hippocampus in response to learning or retrieval plays a critical role in hippocampus-dependent memory consolidation and reconsolidation.…”

“…To assess this possibility, we examined the effects of inhibiting N-glycosylation on the expression of c-fos, whose expression is dependent upon neuronal activity (Frankland, Bontempi, Talton, Kaczmarek, & Silva, 2004;Inaba et al, 2015;Sheng, McFadden, & Greenberg, 1990;Strekalova et al, 2003). We measured the number of c-fos-positive cells in the hippocampal CA1 region at 90 min after training for contextual fear using immunohistochemistry.…”

“…The mice were trained and tested in conditioning chambers (17.5 × 17.5 × 15 cm) that had a stainless steel grid floor through which a footshock could be delivered (Inaba et al, 2015;Mamiya et al, 2009;Suzuki et al, 2004). Training consisted of placing the mice in the chamber and delivering an unsignaled footshock (2 s duration, 0.4 mA) 148 s later, and then the mice were returned to their home cage at 30 s after the footshock (training).…”

“…Surgery was performed as described previously (Frankland et al, 2006;Fukushima et al, 2014;Inaba, Tsukagoshi, & Kida, 2015). Under Nembutal anesthesia and using standard stereotaxic procedures, a stainless steel guide cannula (22 gauge) was implanted into the dorsal hippocampus (-1.9 mm, ± 1.8 mm, -1.9 mm; Paxinos & Franklin, 1997).…”

“…Immunohistochemistry was performed as described previously (Fukushima et al, 2014;Inaba et al, 2015;Zhang, Fukushima, & Kida, 2011). After anesthetization, all mice were perfused with 4% paraformaldehyde.…”