Activation of a novel p70 S6 kinase 1-dependent intracellular cascade in the basolateral nucleus of the amygdala is required for the acquisition of extinction memory

T. N. Huynh, E. Santini, E. Mojica, A. E. Fink, B. S. Hall, R. N. Fetcho, L. Grosenick, K. Deisseroth, Joseph Ledoux, C. Liston, Eric Klann

Research output: Contribution to journalArticle

Abstract

Repeated presentations of a previously conditioned stimulus lead to a new form of learning known as extinction, which temporarily alters the response to the original stimulus. Previous studies have shown that the consolidation of extinction memory requires de novo protein synthesis. However, the role of specific nodes of translational control in extinction is unknown. Using auditory threat conditioning in mice, we investigated the role of mechanistic target of rapamycin complex 1 (mTORC1) and its effector p70 S6 kinase 1 (S6K1) in the extinction of auditory threat conditioning. We found that rapamycin attenuated the consolidation of extinction memory. In contrast, genetic deletion and pharmacological inhibition of S6K1, a downstream effector of mTORC1, blocked within-session extinction, indicating a role for S6K1 independent of protein synthesis. Indeed, the activation of S6K1 during extinction required extracellular signal-regulated kinase (ERK) activation in the basolateral nucleus of the amygdala (BLA) and was necessary for increased phosphorylation of the GluA1 (Thr840) subunit of the AMPA receptor following extinction training. Mice exposed to brief uncontrollable stress showed impaired within-session extinction as well as a downregulation of ERK and S6K1 signaling in the amygdala. Finally, using fiber photometry we were able to record calcium signals in vivo, and we found that inhibition of S6K1 reduces extinction-induced changes in neuronal activity of the BLA. These results implicate a novel ERK-S6K1-GluA1 signaling cascade critically involved in extinction.

Original languageEnglish (US)
Pages (from-to)1394-1401
Number of pages8
JournalMolecular Psychiatry
Volume23
Issue number6
DOIs
StatePublished - Jun 1 2018

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70-kDa Ribosomal Protein S6 Kinases
Amygdala
Ribosomal Protein S6 Kinases
Extracellular Signal-Regulated MAP Kinases
Basolateral Nuclear Complex
Psychological Extinction
Photometry
AMPA Receptors
Sirolimus
Proteins
Down-Regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Activation of a novel p70 S6 kinase 1-dependent intracellular cascade in the basolateral nucleus of the amygdala is required for the acquisition of extinction memory. / Huynh, T. N.; Santini, E.; Mojica, E.; Fink, A. E.; Hall, B. S.; Fetcho, R. N.; Grosenick, L.; Deisseroth, K.; Ledoux, Joseph; Liston, C.; Klann, Eric.

In: Molecular Psychiatry, Vol. 23, No. 6, 01.06.2018, p. 1394-1401.

Research output: Contribution to journalArticle

Huynh, T. N. ; Santini, E. ; Mojica, E. ; Fink, A. E. ; Hall, B. S. ; Fetcho, R. N. ; Grosenick, L. ; Deisseroth, K. ; Ledoux, Joseph ; Liston, C. ; Klann, Eric. / Activation of a novel p70 S6 kinase 1-dependent intracellular cascade in the basolateral nucleus of the amygdala is required for the acquisition of extinction memory. In: Molecular Psychiatry. 2018 ; Vol. 23, No. 6. pp. 1394-1401.
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