Regulatory Mechanisms of Fear Extinction and Depression-Like Behavior

Abstract

Human anxiety is frequently accompanied by depression, and when they co-occur both conditions exhibit greater severity and resistance to treatment. Little is known, however, about the molecular processes linking these emotional and mood disorders. Based on previously reported phosphorylation patterns of extracellular signal-regulated kinase (ERK) in the brain, we hypothesized that ERK's upstream activators intertwine fear and mood regulation through their hippocampal actions. We tested this hypothesis by studying the upstream regulation of ERK signaling in behavioral models of fear and depression. Wild-type and ERK1-deficient mice were used to study the dorsohippocampal actions of the putative ERK activators: mitogen-activated and extracellular signal-regulated kinase (MEK), protein kinase C (PKC), and cAMP-dependent protein kinase (PKA). Mice lacking ERK1 exhibited enhanced fear extinction and reduced depression caused by overactivation of ERK2. Both behaviors were reversed by inhibition of MEK, however the extinction phenotype depended on hippocampal, whereas the depression phenotype predominantly involved extrahippocampal MEK. Unexpectedly, inhibition of PKC accelerated extinction and decreased depression by ERK-independent mechanisms, whereas inhibition of PKA did not produce detectable molecular or behavioral effects in the employed paradigm. These results indicate that, contrary to fear conditioning but similar to mood stabilization, extinction of fear required upregulation of MEK/ERK and downregulation of ERK-independent PKC signaling. The dissociation of these pathways may thus represent a common mechanism for fear and mood regulation, and a potential therapeutic option for comorbid anxiety and depression.

ERK2 Contributes to the Control of Social Behaviors in Mice

“…Thus, the deficiency in long-term memory in Erk2 CKO mice was caused by the loss of ERK2 per se, rather than by a secondary upregulation of ERK1 activity. It was also reported that in mice lacking ERK1, ERK2 did not only compensate for the lack of ERK1, but also exhibited stronger biological activity in some regions (Mazzucchelli et al, 2002;Tronson et al, 2008). Erk1 KO mice exhibited dramatic enhancement of striatum-dependent long-term memory likely due to enhanced activation of ERK2 (Mazzucchelli et al, 2002).…”

Role of phosphorylated ERK in amygdala neuronal apoptosis in single-prolonged stress rats

“…it is well-established that stress exposure activates the erK1/2 signaling pathway (11,12), and it has been speculated that the erK signaling pathway in the lateral amygdala is involved in anxiety (13,14). Generally, activation of erK1/2 promotes cell survival; however, under certain conditions, erK1/2 exhibits pro-apoptotic functions (15).…”

Hippocampal Erk mechanisms linking prediction error to fear extinction: Roles of shock expectancy and contextual aversive valence

“…At a molecular level, the extracellular signal-regulated kinase (Erk) has recently been identified as an important mediator of fear extinction (Szapiro et al 2003;Chen et al 2005;Tronson et al 2008). Erk shows rapid and sustained phosphorylation shortly preceding and during fear extinction, which subsides after fear has stably extinguished (Fischer et al 2007;Ryu et al 2008).…”