Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

Molecular Psychiatry volume 23, pages 1394–1401 (2018)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Sotres-Bayon F, Quirk GJ . Prefrontal control of fear: more than just extinction. Curr Opin Neurobiol 2010; 20: 231–235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Quirk GJ, Mueller D . Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 2007; 33: 56–72.

    Article  PubMed  Google Scholar 

  3. Myers KM, Davis M . Mechanisms of fear extinction. Mol Psychiatry 2006; 12: 120–150.

    Article  PubMed  Google Scholar 

  4. Herry C, Trifilieff P, Micheau J, Lüthi A, Mons N . Extinction of auditory fear conditioning requires MAPK/ERK activation in the basolateral amygdala. Eur J Neurosci 2006; 24: 261–269.

    Article  PubMed  Google Scholar 

  5. Sotres-Bayon F, Bush DEA, LeDoux JE . Acquisition of fear extinction requires activation of NR2B-containing NMDA receptors in the lateral amygdala. Neuropsychopharmacology 2007; 32: 1929–1940.

    Article  CAS  PubMed  Google Scholar 

  6. Hugues S . Postextinction infusion of a mitogen-activated protein kinase inhibitor into the medial prefrontal cortex impairs memory of the extinction of conditioned fear. Learn Mem 2004; 11: 540–543.

    Article  PubMed  Google Scholar 

  7. Sotres-Bayon F, Diaz-Mataix L, Bush DEA, Ledoux JE . Dissociable roles for the ventromedial prefrontal cortex and amygdala in fear extinction: NR2B contribution. Cereb Cortex 2009; 19: 474–482.

    Article  PubMed  Google Scholar 

  8. Santini E . Consolidation of fear extinction requires protein synthesis in the medial prefrontal cortex. J Neurosci 2004; 24: 5704–5710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Santini E, Huynh TN, Klann E . Mechanisms of translation control underlying long-lasting synaptic plasticity and the consolidation of long-term memory. Prog Mol Biol Transl Sci 2014; 122: 131–167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Huynh TN, Santini E, Klann E . Requirement of mammalian target of rapamycin complex 1 downstream effectors in cued fear memory reconsolidation and its persistence. J Neurosci 2014; 34: 9034–9039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hoeffer CA, Cowansage KK, Arnold EC, Banko JL, Moerke NJ, Rodriguez R et al. Inhibition of the interactions between eukaryotic initiation factors 4E and 4G impairs long-term associative memory consolidation but not reconsolidation. Proc Natl Acad Sci 2011; 108: 3383–3388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Iijima Y . c-Raf/MEK/ERK pathway controls protein kinase C-mediated p70S6K activation in adult cardiac muscle cells. J Biol Chem 2002; 277: 23065–23075.

    Article  CAS  PubMed  Google Scholar 

  13. Izquierdo A . Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice. J Neurosci 2006; 26: 5733–5738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hoffman AN, Lorson NG, Sanabria F, Foster Olive M, Conrad CD . Chronic stress disrupts fear extinction and enhances amygdala and hippocampal Fos expression in an animal model of post-traumatic stress disorder. Neurobiol Learn Mem 2014; 112: 139–147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shima H, Pende M, Chen Y, Fumagalli S, Thomas G, Kozma SC . Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase. EMBO J 1998; 17: 6649–6659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Santini E, Huynh TN, MacAskill AF, Carter AG, Pierre P, Ruggero D et al. Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature 2013; 493: 411–415.

    Article  CAS  PubMed  Google Scholar 

  17. Gunaydin LA, Grosenick L, Finkelstein JC, Kauvar IV, Fenno LE, Adhikari A et al. Natural neural projection dynamics underlying social behavior. Cell 2014; 157: 1535–1551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Antion MD, Merhav M, Hoeffer CA, Reis G, Kozma SC, Thomas G et al. Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity. Learn Mem 2008; 15: 29–38.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Delgado JY, Coba M, Anderson CNG, Thompson KR, Gray EE, Heusner CL et al. NMDA receptor activation dephosphorylates AMPA receptor glutamate receptor 1 subunits at threonine 840. J Neurosci 2007; 27: 13210–13221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Aubry AV, Serrano PA, Burghardt NS . Molecular mechanisms of stress-induced increases in fear memory consolidation within the amygdala. Front Behav Neurosci 2016; 10: 191.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chen T-W, Wardill TJ, Sun Y, Pulver SR, Renninger SL, Baohan A et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 2013; 499: 295–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lee HK, Barbarosie M, Kameyama K, Bear MF, Huganir RL . Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 2000; 405: 955–959.

    Article  CAS  PubMed  Google Scholar 

  23. Jenkins MA, Wells G, Bachman J, Snyder JP, Jenkins A, Huganir RL et al. Regulation of GluA1 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor function by protein kinase C at serine-818 and threonine-840. Mol Pharmacol 2014; 85: 618–629.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Quirk GJ, Armony JL, LeDoux JE . Fear conditioning enhances different temporal components of tone-evoked spike trains in auditory cortex and lateral amygdala. Neuron 1997; 19: 613–624.

    Article  CAS  PubMed  Google Scholar 

  25. Herry C, Ciocchi S, Demmou L, Muller C, Luthi A . Switching on and off fear by distinct neuronal circuits. Nature 2008; 454: 600–606.

    Article  CAS  PubMed  Google Scholar 

  26. Campbell DG, Felker BL, Liu C-F, Yano EM, Kirchner JE, Chan D, Rubinstein LV, Chaney EF . Prevalence of depression-PTSD comorbidity: implications for clinical practice guidelines and primary care-based interventions. J Gen Intern Med 2007; 22: 711–718.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Jernigan CS, Goswami DB, Austin MC, Iyo AH, Chandran A, Stockmeier CA et al. The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 1774–1779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dwyer JM, Maldonado-Avilés JG, Lepack AE, DiLeone RJ, Duman RS . Ribosomal protein S6 kinase 1 signaling in prefrontal cortex controls depressive behavior. Proc Natl Acad Sci 2015; 112: 6188–6193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bhattacharya A, Kaphzan H, Alvarez-Dieppa AC, Murphy JP, Pierre P, Klann E . Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron 2012; 76: 325–337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Santini E, Klann E . Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders. Sci Signal 2014; 7: re10–re10.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Chris Cain and the LeDoux lab for their input throughout the development of this project, Francis S Lee for his advice regarding the manuscript text and Shawn Singh for his assistance with Nissl staining. This work was funded by grants from the National Institutes of Health grants to EK (NS034007, NS047384 and HD082013) and ES (NS087112).

Author contributions

TNH, CL, JEL and EK designed the research. TNH, ES, EM, AEF, BSH and RNF performed the experiments. LG, KD and CL contributed to the development of the fiber photometry experiments. TNH and EK analyzed the data and wrote the manuscript, which was edited by all authors.

Author information

Author notes

  1. E Santini

    Present address: 6Current address: Department of Neurology, Columbia University, New York, NY 10032, USA.,

Authors and Affiliations

  1. Center for Neural Science, New York University, New York, NY, USA

    T N Huynh, E Santini, E Mojica, A E Fink, J E LeDoux & E Klann

  2. Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA

    T N Huynh, B S Hall, R N Fetcho & C Liston

  3. Department of Psychiatry, Weill Cornell Medical College, New York, NY, USA

    T N Huynh, B S Hall, R N Fetcho & C Liston

  4. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

    L Grosenick & K Deisseroth

  5. Department of Bioengineering, Stanford University, Stanford, CA, USA

    L Grosenick & K Deisseroth

Authors
  1. T N Huynh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Santini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Mojica
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A E Fink
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B S Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R N Fetcho
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Grosenick
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Deisseroth
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J E LeDoux
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C Liston
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. E Klann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E Klann.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huynh, T., Santini, E., Mojica, E. et al. 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. Mol Psychiatry 23, 1394–1401 (2018). https://doi.org/10.1038/mp.2017.99

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2017.99

This article is cited by

Search

Advanced search

Quick links