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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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).
Rumpel, S., LeDoux, J., Zador, A. & Malinow, R. Postsynaptic receptor trafficking underlying a form of associative learning. Science 308, 83–88 (2005).
Reijmers, L.G., Perkins, B.L., Matsuo, N. & Mayford, M. Localization of a stable neural correlate of associative memory. Science 317, 1230–1233 (2007).
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).
Han, J.H. et al. Neuronal competition and selection during memory formation. Science 316, 457–460 (2007).
Han, J.H. et al. Selective erasure of a fear memory. Science 323, 1492–1496 (2009).
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).
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).
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).
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).
Tan, W. et al. Silencing preBotzinger complex somatostatin-expressing neurons induces persistent apnea in awake rat. Nat. Neurosci. 11, 538–540 (2008).
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).
Kida, S. et al. CREB required for the stability of new and reactivated fear memories. Nat. Neurosci. 5, 348–355 (2002).
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).
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).
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).
Josselyn, S.A., Kida, S. & Silva, A.J. Inducible repression of CREB function disrupts amygdala-dependent memory. Neurobiol. Learn. Mem. 82, 159–163 (2004).
McKernan, M.G. & Shinnick-Gallagher, P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 390, 607–611 (1997).
Huang, Y.Y. & Kandel, E.R. Postsynaptic induction and PKA-dependent expression of LTP in the lateral amygdala. Neuron 21, 169–178 (1998).
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).
Dong, Y. et al. CREB modulates excitability of nucleus accumbens neurons. Nat. Neurosci. 9, 475–477 (2006).
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).
Murphy, G.G. et al. Increased neuronal excitability, synaptic plasticity, and learning in aged Kvbeta1.1 knockout mice. Curr. Biol. 14, 1907–1915 (2004).
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).
Storm, J.F. Potassium currents in hippocampal pyramidal cells. Prog. Brain Res. 83, 161–187 (1990).
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).
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).
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).
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).
Losonczy, A., Makara, J.K. & Magee, J.C. Compartmentalized dendritic plasticity and input feature storage in neurons. Nature 452, 436–441 (2008).
Silva, A.J., Kogan, J.H., Frankland, P.W. & Kida, S. CREB and memory. Annu. Rev. Neurosci. 21, 127–148 (1998).
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).
Mayr, B. & Montminy, M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat. Rev. Mol. Cell Biol. 2, 599–609 (2001).
Lonze, B.E. & Ginty, D.D. Function and regulation of CREB family transcription factors in the nervous system. Neuron 35, 605–623 (2002).
Carlezon, W.A. Jr., Duman, R.S. & Nestler, E.J. The many faces of CREB. Trends Neurosci. 28, 436–445 (2005).
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).
Won, J. & Silva, A.J. Molecular and cellular mechanisms of memory allocation in neuronetworks. Neurobiol. Learn. Mem. 89, 285–292 (2008).
Sassone-Corsi, P. Transcription factors responsive to cAMP. Annu. Rev. Cell Dev. Biol. 11, 355–377 (1995).
Lim, F. & Neve, R.L. Current Protocols in Neuroscience (Greene Publishing Assoc. and Wiley-Interscience, New York, 1999).
Paxinos, G. & Franklin, K.B.J. The Mouse Brain in Stereotaxic Coordinates (Academic Press, San Diego, 2003).
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).
Faber, E.S. & Sah, P. Opioids inhibit lateral amygdala pyramidal neurons by enhancing a dendritic potassium current. J. Neurosci. 24, 3031–3039 (2004).
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).
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).
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.
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). https://doi.org/10.1038/nn.2405
Cerebral Cortex (2020)
Memory and the circadian system: Identifying candidate mechanisms by which local clocks in the brain may regulate synaptic plasticity
Neuroscience & Biobehavioral Reviews (2020)
Neurobiology of Learning and Memory (2020)
Exposure to Novelty Promotes Long-Term Contextual Fear Memory Formation in Juvenile Mice: Evidence for a Behavioral Tagging
Molecular Neurobiology (2020)