Noradrenergic Signaling in Infralimbic Cortex Increases Cell Excitability and Strengthens Memory for Fear Extinction

Abstract

Emotional arousal strengthens memory. This is most apparent in aversive conditioning, in which the stress-related neurotransmitter norepinephrine (NE) enhances associations between sensory stimuli and fear-inducing events. In contrast to conditioning, extinction decreases fear responses, and is thought to form a new memory. It is not known, however, whether NE is necessary for extinction learning. Previous work has shown that the infralimbic prefrontal cortex (IL) is a site of extinction consolidation. Here, we show that blocking noradrenergic ␤-receptors in IL before extinction training impaired retrieval of extinction the following day, consistent with a weakened extinction memory. We further found that the sequelae of ␤-receptor activation, including protein kinase A (PKA), gene transcription and translation in IL, are necessary for extinction. To determine whether activation of this cascade modulates IL excitability, we measured the response of IL pyramidal neurons to injected current. NE increased the excitability of IL neurons in a ␤-receptor-and PKA-dependent manner. We suggest that NE released in IL during fear extinction activates a PKA-mediated molecular cascade that strengthens extinction memory. Thus, emotional arousal evoked by conditioned fear paradoxically promotes the subsequent extinction of that fear, thereby ensuring behavioral flexibility.

Infralimbic cortex controls the activity of the hypothalamus–pituitary–adrenal axis and the formation of aversive memory: Effects of environmental enrichment

“…In support of this hypothesis, it has been shown that EE increases the resilience of animals to social defeat stress by enhancing infralimbic cortical outputs to downstream limbic areas [9]. Also, in line with this possibility, it has been shown that an increased excitability in the PFC is associated with enhanced control over stress [33] and extinction learning [31]. Confirming our previous work [20,23,30], we also show in this study that EE reduces motor activity in the open field suggesting a faster habituation of enriched animals to novel environments (mild stress).…”

“…This analysis also showed that foot shock stress (0.6 mA, 2 s) increased corticosterone concentrations in vehicle injected animals (Fig. 4B) although it did not reach statistical significance (F (1,31) =1.36; p= 0.25). Picrotoxin did not significantly change the stress-induced concentrations of corticosterone compared to vehicle (F (1,31) = 4.12; n.s.…”

“…An increase of cortical excitability could account for the enhanced activation of the infralimbic cortex found in enriched animals. In fact, previous studies have suggested that an increased cortical excitability facilitates whereas a decreased cortical excitability reduces, cortical activation involved in fear memory [31][32][33].…”

“…Moreover, EE enhances the control that the infralimbic cortex exerts on the HPA axis. A stronger interaction between the infralimbic cortex and the HPA axis as well as other limbic areas might facilitate the extinction of fear-related memories [12,31,39] and protect enriched animals to stress-related disorders [9].…”

Inhibition of Hippocampal β-Adrenergic Receptors Impairs Retrieval But Not Reconsolidation of Cocaine-Associated Memory and Prevents Subsequent Reinstatement

“…However, this interpretation is unlikely given that b-AR activation enhances, rather than impedes, memory formation (McGaugh, 2000). Accordingly, b-AR blockade impairs, rather than facilitates, extinction of several appetitive and aversive behaviors (Merlo and Izquierdo, 1967;Mueller et al, 2008;LaLumiere et al, 2010).…”