Bidirectional behavioral plasticity of memory reconsolidation depends on amygdalar protein kinase A

Tronson, Natalie C.; Wiseman, Shari; Olausson, Peter; Taylor, Jane R.

doi:10.1038/nn1628

Cited by 232 publications

(207 citation statements)

References 10 publications

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“…Low hippocampal levels of the PKA substrate pCREB observed after nonreinforced tests suggested that endogenous PKA was not activated to a comparable extent during extinction as during fear conditioning. Our findings are consistent with studies on extinction of tone-dependent fear demonstrating low amygdalar pCREB levels (Lin et al, 2003) and lack of Rp-cAMPS effects (Tronson et al, 2006). It should be noted, however, that unlike short-term PKA inhibition, long-term upregulation (Wang et al, 2004) or downregulation (Isiegas et al, 2006) of PKA signaling by genetic manipulations affecting both baseline and inducible PKA activity in several brain areas and over a long period of time might prevent or enhance fear extinction, respectively.…”

Section: Discussionsupporting

confidence: 91%

Regulatory Mechanisms of Fear Extinction and Depression-Like Behavior

Tronson

Schrick

Fischer

et al. 2007

Neuropsychopharmacol

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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.

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Section: Discussionsupporting

confidence: 91%

Regulatory Mechanisms of Fear Extinction and Depression-Like Behavior

Tronson

Schrick

Fischer

et al. 2007

Neuropsychopharmacol

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“…A longstanding hypothesis posits that a β-AR/Gs/protein kinase A (PKA) signaling pathway mediates memory reconsolidation (11)(12)(13), a process that strengthens, updates, or erases a previously acquired memory after recall (memory reactivation).…”

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confidence: 99%

β-Arrestin–biased signaling mediates memory reconsolidation

Liu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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A long-standing hypothesis posits that a G protein-coupled signaling pathway mediates β-adrenergic nervous system functions, including learning and memory. Here we report that memory retrieval (reactivation) induces the activation of β1-adrenergic β-arrestin signaling in the brain, which stimulates ERK signaling and protein synthesis, leading to postreactivation memory restabilization. β-Arrestin2-deficient mice exhibit impaired memory reconsolidation in object recognition, Morris water maze, and cocaine-conditioned place preference paradigms. Postreactivation blockade of both brain β-adrenergic Gs protein- and β-arrestin–dependent pathways disrupts memory reconsolidation. Unexpectedly, selective blockade of the Gs/cAMP/PKA signaling but not the β-arrestin/ERK signaling by the biased β-adrenergic ligands does not inhibit reconsolidation. Moreover, the expression of β-arrestin2 in the entorhinal cortex of β-arrestin 2–deficient mice rescues β1-adrenergic ERK signaling and reconsolidation in a G protein pathway-independent manner. We demonstrate that β-arrestin–biased signaling regulates memory reconsolidation and reveal the potential for β-arrestin–biased ligands in the treatment of memory-related disorders.

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“…Szapiro et al 169 reported that infusion of the PKA inhibitor Rp-cAMPs into the CA1 region of hippocampus either before or immediately after the first of several extinction exposures in a step-down avoidance paradigm produced a persistent impairment of extinction. On the other hand, Tronson et al 286 found that intra-BLA infusions of the PKA activator 6-BNZ-cAMP immediately following each of four daily tone extinction training sessions had no effect on extinction of freezing.…”

Section: Neurotransmitter Systemsmentioning

confidence: 99%

Mechanisms of fear extinction

2006

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Excessive fear and anxiety are hallmarks of a variety of disabling anxiety disorders that affect millions of people throughout the world. Hence, a greater understanding of the brain mechanisms involved in the inhibition of fear and anxiety is attracting increasing interest in the research community. In the laboratory, fear inhibition most often is studied through a procedure in which a previously fear conditioned organism is exposed to a fear-eliciting cue in the absence of any aversive event. This procedure results in a decline in conditioned fear responses that is attributed to a process called fear extinction. Extensive empirical work by behavioral psychologists has revealed basic behavioral characteristics of extinction, and theoretical accounts have emphasized extinction as a form of inhibitory learning as opposed to an erasure of acquired fear. Guided by this work, neuroscientists have begun to dissect the neural mechanisms involved, including the regions in which extinction-related plasticity occurs and the cellular and molecular processes that are engaged. The present paper will cover behavioral, theoretical and neurobiological work, and will conclude with a discussion of clinical implications. Molecular Psychiatry (2007) 12, 120-150.

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Bidirectional behavioral plasticity of memory reconsolidation depends on amygdalar protein kinase A

Cited by 232 publications

References 10 publications

Regulatory Mechanisms of Fear Extinction and Depression-Like Behavior

Regulatory Mechanisms of Fear Extinction and Depression-Like Behavior

β-Arrestin–biased signaling mediates memory reconsolidation

Mechanisms of fear extinction

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