Foreground contextual fear memory consolidation requires two independent phases of hippocampal ERK/CREB activation

Abstract

Fear conditioning is a popular model for investigating physiological and cellular mechanisms of memory formation. In this paradigm, a footshock is either systematically associated to a tone (paired conditioning) or is pseudorandomly distributed (unpaired conditioning). In the former procedure, the tone/shock association is acquired, whereas in the latter procedure, the context/shock association will prevail. Animals with chronically implanted recording electrodes show enhanced amplitude of the extracellularly recorded field EPSP in CA1 pyramidal cells for up to 24 h after unpaired, but not paired, fear conditioning. This is paralleled by a differential activation of the ERK/CREB pathway in CA1, which is monophasic in paired conditioning (0-15 min post-conditioning), but biphasic (0-1 h and 9-12 h post-conditioning) in unpaired conditioning as revealed by immunocytochemistry and Western blotting. Intrahippocampal injection of the MEK inhibitor U0126 prior to each phase prevents the activation of both ERK1/2 and CREB after unpaired conditioning. Block of any activation phase leads to memory impairment. We finally reveal that the biphasic activation of ERK/CREB activity is independently regulated, yet both phases are critically required for the consolidation of long-term memories following unpaired fear conditioning. These data provide compelling evidence that CA1 serves different forms of memory by expressing differential cellular mechanisms that are dependent on the training regime.

Nicotine withdrawal disrupts both foreground and background contextual fear conditioning but not pre-pulse inhibition of the acoustic startle response in C57BL/6 mice

“…However, the effects of nicotine withdrawal on ERK and CREB signaling in the hippocampus remain unknown. Studies have demonstrated that both ERK and CREB are involved in foreground and background contextual fear conditioning [70,73,81], and that the acute effects of nicotine on background contextual fear conditioning critically depend on ERK [68]. Thus, withdrawal-associated changes in these signaling molecules could disrupt contextual fear conditioning.…”

“…A 3 × 3 repeated-measures ANOVA with dB (69,73,81) as the within subjects factor and drug condition (0.0, 6.3, 12.6 mg/kg/day) as the between subjects factor revealed that there was a significant within-subjects effect of pre-pulse intensity level on PPI [F(2, 35) = 35.06, p < 0.01]; higher dBs produced greater PPI. However, there was no significant overall effect of drug condition on PPI, nor was there a drug condition by pre-pulse intensity interaction (p > 0.05; Figure 2).…”

“…Thus, it is unknown if nicotine withdrawal will disrupt foreground as well as background fear conditioning Interestingly, acquisition and consolidation of background contextual fear conditioning may involve different cellular substrates than acquisition and consolidation of foreground contextual fear conditioning [62,77]. Trifilieff and colleagues [81] demonstrated that consolidation of foreground contextual fear conditioning recruits distinct early and late phases of protein synthesis in the hippocampus and amygdala, while background contextual fear conditioning recruits only the early phase. However, Trifilieff and colleagues used a conditioning paradigm in which the tone and shock were presented in an unpaired manner.…”

Regulatory Mechanisms of Fear Extinction and Depression-Like Behavior

“…Neuronal plasticity underlying memory formation (Atkins et al, 1998;Sananbenesi et al, 2002;Trifilieff et al, 2006) and stress-induced facilitation (Sananbenesi et al, 2003;Yang et al, 2004a;Revest et al, 2005) of contextual fear involves hippocampal ERK mechanisms regulated by several upstream kinases. ERK is also required for extinction of contextual fear (Szapiro et al, 2003;Fischer et al, 2007) and shows accelerated and more robust induction as well as increased nuclear accumulation (Chen et al, 2005;Fischer et al, 2007) when compared to fear conditioning.…”

Modulation of αCaMKII signaling by rapid ERα action

“…Like αCaMKII, all three proteins are involved in neuronal differentiation, and ERK1/2 and CREB have also been shown to play a role in LTP and memory processes (Trifilieff, 2006). E2 action has previously been linked to ERK1/2 and CREB phosphorylation in various populations of neurons and in vivo (Lee, 2004;Bryant DN, 2005;Szego, 2006), and we have provided evidence that αCaMKII action mediates their phosphorylation by E2 in NLT and primary hippocampal neurons.…”