CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala


The mechanisms that determine how information is allocated to specific regions and cells in the brain are important for memory capacity, storage and retrieval, but are poorly understood. We manipulated CREB in a subset of lateral amygdala neurons in mice with a modified herpes simplex virus (HSV) and reversibly inactivated transfected neurons with the Drosophila allatostatin G protein–coupled receptor (AlstR)/ligand system. We found that inactivation of the neurons transfected with HSV-CREB during training disrupted memory for tone conditioning, whereas inactivation of a similar proportion of transfected control neurons did not. Whole-cell recordings of fluorescently tagged transfected neurons revealed that neurons with higher CREB levels are more excitable than neighboring neurons and showed larger synaptic efficacy changes following conditioning. Our findings demonstrate that CREB modulates the allocation of fear memory to specific cells in lateral amygdala and suggest that neuronal excitability is important in this process.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Selective and reversible modulation of a set of genetically targeted lateral amygdala neurons.
Figure 2: Local infusion of allatostatin selectively impairs auditory fear memory in HSV-CREB mice.
Figure 3: Allatostatin does not disrupt conditioning in HSV-CREB mice established before viral transfection.
Figure 4: HSV-CREB neurons in conditioned mice show increased synaptic efficacy.
Figure 5: CREB increases neuronal excitability in transfected lateral amygdala neurons.
Figure 6: HSV-CREB changes the input-output function of transfected lateral amygdala neurons.


  1. 1

    Repa, J.C. et al. Two different lateral amygdala cell populations contribute to the initiation and storage of memory. Nat. Neurosci. 4, 724–731 (2001).

    CAS  Article  Google Scholar 

  2. 2

    Rumpel, S., LeDoux, J., Zador, A. & Malinow, R. Postsynaptic receptor trafficking underlying a form of associative learning. Science 308, 83–88 (2005).

    CAS  Article  Google Scholar 

  3. 3

    Reijmers, L.G., Perkins, B.L., Matsuo, N. & Mayford, M. Localization of a stable neural correlate of associative memory. Science 317, 1230–1233 (2007).

    CAS  Article  Google Scholar 

  4. 4

    Schafe, G.E., Doyere, V. & LeDoux, J.E. Tracking the fear engram: the lateral amygdala is an essential locus of fear memory storage. J. Neurosci. 25, 10010–10014 (2005).

    CAS  Article  Google Scholar 

  5. 5

    Han, J.H. et al. Neuronal competition and selection during memory formation. Science 316, 457–460 (2007).

    CAS  Article  Google Scholar 

  6. 6

    Han, J.H. et al. Selective erasure of a fear memory. Science 323, 1492–1496 (2009).

    CAS  Article  Google Scholar 

  7. 7

    Clark, M.S. et al. Overexpression of 5-HT1B receptor in dorsal raphe nucleus using herpes simplex virus gene transfer increases anxiety behavior after inescapable stress. J. Neurosci. 22, 4550–4562 (2002).

    CAS  Article  Google Scholar 

  8. 8

    Birgül, N., Weise, C., Kreienkamp, H.J. & Richter, D. Reverse physiology in Drosophila: identification of a novel allatostatin-like neuropeptide and its cognate receptor structurally related to the mammalian somatostatin/galanin/opioid receptor family. EMBO J. 18, 5892–5900 (1999).

    Article  Google Scholar 

  9. 9

    Karschin, C., Dissmann, E., Stuhmer, W. & Karschin, A. IRK(1–3) and GIRK(1–4) inwardly rectifying K+ channel mRNAs are differentially expressed in the adult rat brain. J. Neurosci. 16, 3559–3570 (1996).

    CAS  Article  Google Scholar 

  10. 10

    Tan, E.M. et al. Selective and quickly reversible inactivation of mammalian neurons in vivo using the Drosophila allatostatin receptor. Neuron 51, 157–170 (2006).

    CAS  Article  Google Scholar 

  11. 11

    Tan, W. et al. Silencing preBotzinger complex somatostatin-expressing neurons induces persistent apnea in awake rat. Nat. Neurosci. 11, 538–540 (2008).

    CAS  Article  Google Scholar 

  12. 12

    Lechner, H.A., Lein, E.S. & Callaway, E.M. A genetic method for selective and quickly reversible silencing of mammalian neurons. J. Neurosci. 22, 5287–5290 (2002).

    CAS  Article  Google Scholar 

  13. 13

    Kida, S. et al. CREB required for the stability of new and reactivated fear memories. Nat. Neurosci. 5, 348–355 (2002).

    CAS  Article  Google Scholar 

  14. 14

    Bourtchuladze, R. et al. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element binding protein. Cell 79, 59–68 (1994).

    CAS  Article  Google Scholar 

  15. 15

    Yamamoto, T., Shimura, T., Sako, N., Yasoshima, Y. & Sakai, N. Neural substrates for conditioned taste aversion in the rat. Behav. Brain Res. 65, 123–137 (1994).

    CAS  Article  Google Scholar 

  16. 16

    Lamprecht, R., Hazvi, S. & Dudai, Y. cAMP response element binding protein in the amygdala is required for long- but not short-term conditioned taste aversion memory. J. Neurosci. 17, 8443–8450 (1997).

    CAS  Article  Google Scholar 

  17. 17

    Josselyn, S.A., Kida, S. & Silva, A.J. Inducible repression of CREB function disrupts amygdala-dependent memory. Neurobiol. Learn. Mem. 82, 159–163 (2004).

    CAS  Article  Google Scholar 

  18. 18

    McKernan, M.G. & Shinnick-Gallagher, P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 390, 607–611 (1997).

    CAS  Article  Google Scholar 

  19. 19

    Huang, Y.Y. & Kandel, E.R. Postsynaptic induction and PKA-dependent expression of LTP in the lateral amygdala. Neuron 21, 169–178 (1998).

    CAS  Article  Google Scholar 

  20. 20

    Han, M.H. et al. Role of cAMP response element-binding protein in the rat locus ceruleus: regulation of neuronal activity and opiate withdrawal behaviors. J. Neurosci. 26, 4624–4629 (2006).

    CAS  Article  Google Scholar 

  21. 21

    Dong, Y. et al. CREB modulates excitability of nucleus accumbens neurons. Nat. Neurosci. 9, 475–477 (2006).

    CAS  Article  Google Scholar 

  22. 22

    Viosca, J., Lopez de Armentia, M., Jancic, D. & Barco, A. Enhanced CREB-dependent gene expression increases the excitability of neurons in the basal amygdala and primes the consolidation of contextual and cued fear memory. Learn. Mem. 16, 193–197 (2009).

    Article  Google Scholar 

  23. 23

    Murphy, G.G. et al. Increased neuronal excitability, synaptic plasticity, and learning in aged Kvbeta1.1 knockout mice. Curr. Biol. 14, 1907–1915 (2004).

    CAS  Article  Google Scholar 

  24. 24

    Faber, E.S., Callister, R.J. & Sah, P. Morphological and electrophysiological properties of principal neurons in the rat lateral amygdala in vitro. J. Neurophysiol. 85, 714–723 (2001).

    CAS  Article  Google Scholar 

  25. 25

    Storm, J.F. Potassium currents in hippocampal pyramidal cells. Prog. Brain Res. 83, 161–187 (1990).

    CAS  Article  Google Scholar 

  26. 26

    Oh, M.M., McKay, B.M., Power, J.M. & Disterhoft, J.F. Learning-related postburst afterhyperpolarization reduction in CA1 pyramidal neurons is mediated by protein kinase A. Proc. Natl. Acad. Sci. USA 106, 1620–1625 (2009).

    CAS  Article  Google Scholar 

  27. 27

    Santini, E., Quirk, G.J. & Porter, J.T. Fear conditioning and extinction differentially modify the intrinsic excitability of infralimbic neurons. J. Neurosci. 28, 4028–4036 (2008).

    CAS  Article  Google Scholar 

  28. 28

    Staff, N.P. & Spruston, N. Intracellular correlate of EPSP-spike potentiation in CA1 pyramidal neurons is controlled by GABAergic modulation. Hippocampus 13, 801–805 (2003).

    CAS  Article  Google Scholar 

  29. 29

    Carvalho, T.P. & Buonomano, D.V. Differential effects of excitatory and inhibitory plasticity on synaptically driven neuronal input-output functions. Neuron 61, 774–785 (2009).

    CAS  Article  Google Scholar 

  30. 30

    Losonczy, A., Makara, J.K. & Magee, J.C. Compartmentalized dendritic plasticity and input feature storage in neurons. Nature 452, 436–441 (2008).

    CAS  Article  Google Scholar 

  31. 31

    Silva, A.J., Kogan, J.H., Frankland, P.W. & Kida, S. CREB and memory. Annu. Rev. Neurosci. 21, 127–148 (1998).

    CAS  Article  Google Scholar 

  32. 32

    Shaywitz, A.J. & Greenberg, M.E. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu. Rev. Biochem. 68, 821–861 (1999).

    CAS  Article  Google Scholar 

  33. 33

    Mayr, B. & Montminy, M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat. Rev. Mol. Cell Biol. 2, 599–609 (2001).

    CAS  Article  Google Scholar 

  34. 34

    Lonze, B.E. & Ginty, D.D. Function and regulation of CREB family transcription factors in the nervous system. Neuron 35, 605–623 (2002).

    CAS  Article  Google Scholar 

  35. 35

    Carlezon, W.A. Jr., Duman, R.S. & Nestler, E.J. The many faces of CREB. Trends Neurosci. 28, 436–445 (2005).

    CAS  Article  Google Scholar 

  36. 36

    Jancic, D., Lopez de Armentia, M., Valor, L.M., Olivares, R. & Barco, A. Inhibition of cAMP response element binding protein reduces neuronal excitability and plasticity, and triggers neurodegeneration. Cereb. Cortex published online, doi:10.1093/cercor/bhp004 (12 February 2009).

  37. 37

    Won, J. & Silva, A.J. Molecular and cellular mechanisms of memory allocation in neuronetworks. Neurobiol. Learn. Mem. 89, 285–292 (2008).

    CAS  Article  Google Scholar 

  38. 38

    Sassone-Corsi, P. Transcription factors responsive to cAMP. Annu. Rev. Cell Dev. Biol. 11, 355–377 (1995).

    CAS  Article  Google Scholar 

  39. 39

    Lim, F. & Neve, R.L. Current Protocols in Neuroscience (Greene Publishing Assoc. and Wiley-Interscience, New York, 1999).

    Google Scholar 

  40. 40

    Paxinos, G. & Franklin, K.B.J. The Mouse Brain in Stereotaxic Coordinates (Academic Press, San Diego, 2003).

  41. 41

    Barrot, M. et al. CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli. Proc. Natl. Acad. Sci. USA 99, 11435–11440 (2002).

    CAS  Article  Google Scholar 

  42. 42

    Faber, E.S. & Sah, P. Opioids inhibit lateral amygdala pyramidal neurons by enhancing a dendritic potassium current. J. Neurosci. 24, 3031–3039 (2004).

    CAS  Article  Google Scholar 

  43. 43

    Liebmann, L. et al. Differential effects of corticosterone on the slow afterhyperpolarization in the basolateral amygdala and CA1 region: possible role of calcium channel subunits. J. Neurophysiol. 99, 958–968 (2008).

    CAS  Article  Google Scholar 

  44. 44

    Humeau, Y. et al. A pathway-specific function for different AMPA receptor subunits in amygdala long-term potentiation and fear conditioning. J. Neurosci. 27, 10947–10956 (2007).

    CAS  Article  Google Scholar 

Download references


We thank T. Carvalho, Y.-S. Lee, P. Golshani, D. Buonomano, B. Wiltgen, W. Tan, J. Shobe, J. Feldman and J. Guzowski for helpful advice, E. Callaway for AlstR cDNA and K. Cai for technical support. This work was supported by grants from the US National Institutes of Health (P50-MH0779720 and R37-AG13622) to A.J.S. and a Marie Curie Outgoing fellowship of the European Commission (PIOF-GA-2008-219622) to P.P.

Author information




Y.Z., J.W. and A.J.S. designed the experiments. Y.Z., J.W., M.G.K. and T.R. carried out the behavioral experiments. Y.Z. performed the patch-clamp and whole-cell recording experiments. J.W. generated the viral vectors and R.N. provided the viral preparations. M.Z. carried out the western blot analysis. Y.Z. and J.W. analyzed the data. B.J. and P.P. helped with the discussion. Y.Z and A.J.S. wrote the paper.

Corresponding author

Correspondence to Alcino J Silva.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Table 1 (PDF 295 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zhou, Y., Won, J., Karlsson, M. et al. CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala. Nat Neurosci 12, 1438–1443 (2009).

Download citation

Further reading


Quick links

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing