Abstract
The molecular processes that establish fear memory are complex and involve a combination of genetic and epigenetic influences. Dysregulation of these processes can manifest in humans as a range of fear-related anxiety disorders like post-traumatic stress disorders (PTSD). In the present study, immunohistochemistry for acetyl H3, H4, c-fos, CBP (CREB-binding protein) in the infralimbic prefrontal cortex (IL-PFC) and prelimbic prefrontal cortex (PL-PFC) of mPFC (medial prefrontal cortex) and basal amygdala (BA), lateral amygdala (LA), centrolateral amygdala (CeL), centromedial amygdala (CeM) of the amygdala was performed to link region-specific histone acetylation to fear and extinction learning. It was found that the PL-PFC and IL-PFC along with the sub-regions of the amygdala responded differentially to the fear learning and extinction. Following fear learning, c-fos and CBP expression and acetylation of H3 and H4 increased in the BA, LA, CeM, and CeL and the PL-PFC but not in the IL-PFC as compared to the naive control. Similarly, following extinction learning, c-fos and CBP expression increased in BA, LA, CeL, and IL-PFC but not in PL-PFC and CeM as compared to the naive control and conditioned group. However, the acetylation of H3 increased in both IL and PL as opposed to H4 which increased only in the IL-PFC following extinction learning. Overall, region-specific activation in amygdala and PFC following fear and extinction learning as evident by the c-fos activation paralleled the H3/H4 acetylation in these regions. These results suggest that the differential histone acetylation in the PFC and amygdala subnuclei following fear learning and extinction may be associated with the region-specific changes in the neuronal activation pattern resulting in more fear/less fear.
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References
Alarcón JM, Malleret G, Touzani K et al (2004) Chromatin acetylation, memory, and LTP are impaired in CBP ± mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 42:947–959. doi:10.1016/j.neuron.2004.05.021
Arruda-Carvalho M, Clem RL (2015) Prefrontal-amygdala fear networks come into focus. Front Syst Neurosci 9:145. doi:10.3389/fnsys.2015.00145
Bousiges O, Neidl R, Majchrzak M et al (2013) Detection of histone acetylation levels in the dorsal hippocampus reveals early tagging on specific residues of H2B and H4 histones in response to learning. PLoS ONE 8:e57816. doi:10.1371/journal.pone.0057816
Bouton ME, García-Gutiérrez A (2006) Intertrial interval as a contextual stimulus. Behav Processes 71:307–317. doi:10.1016/j.beproc.2005.12.003
Bowers ME, Xia B, Carreiro S et al (2015) The class I HDAC inhibitor RGFP963 enhances consolidation of cued fear extinction. Learn Mem 22:225–231. doi:10.1101/lm.036699.114
Bredy TW, Wu H, Crego C et al (2007) Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn Mem 14:268–276. doi:10.1101/lm.500907
Burgos-Robles A, Vidal-Gonzalez I, Santini E, Quirk GJ (2007) Consolidation of fear extinction requires NMDA receptor-dependent bursting in the ventromedial prefrontal cortex. Neuron 53:871–880. doi:10.1016/j.neuron.2007.02.021
Burgos-Robles A, Vidal-Gonzalez I, Quirk GJ (2009) Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure. J Neurosci 29:8474–8482. doi:10.1523/JNEUROSCI.0378-09.2009
Carrere M, Alexandre F (2015) A pavlovian model of the amygdala and its influence within the medial temporal lobe. Front Syst Neurosci 9:41. doi:10.3389/fnsys.2015.00041
Clayton AL, Rose S, Barratt MJ, Mahadevan LC (2000) Phosphoacetylation of histone H3 on c-fos- and c-jun-associated nucleosomes upon gene activation. EMBO J 19:3714–3726. doi:10.1093/emboj/19.14.3714
Corcoran KA, Maren S (2001) Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction. J Neurosci 21:1720–1726
Corcoran KA, Desmond TJ, Frey KA, Maren S (2005) Hippocampal inactivation disrupts the acquisition and contextual encoding of fear extinction. J Neurosci 25:8978–8987. doi:10.1523/JNEUROSCI.2246-05.2005
Dragunow M (1996) A role for immediate-early transcription factors in learning and memory. Behav Genet 26:293–299
Federman N, Fustiñana MS, Romano A (2009) Histone acetylation is recruited in consolidation as a molecular feature of stronger memories. Learn Mem 16:600–606. doi:10.1101/lm.1537009
Giustino TF, Maren S (2015) The role of the medial prefrontal cortex in the conditioning and extinction of fear. Front Behav Neurosci 9:298. doi:10.3389/fnbeh.2015.00298
Goldberg AD, Allis CD, Bernstein E (2007) Epigenetics: a landscape takes shape. Cell 128:635–638. doi:10.1016/j.cell.2007.02.006
Goswami S, Rodríguez-Sierra O, Cascardi M, Paré D (2013) Animal models of post-traumatic stress disorder: face validity. Front Neurosci 7:89. doi:10.3389/fnins.2013.00089
Guan Z, Giustetto M, Lomvardas S et al (2002) Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure. Cell 111:483–493. doi:10.1016/S0092-8674(02)01074-7
Hall J, Thomas KL, Everitt BJ (2001) Fear memory retrieval induces CREB phosphorylation and Fos expression within the amygdala. Eur J Neurosci 13:1453–1458. doi:10.1046/j.0953-816x.2001.01531.x
Handel AE, Ebers GC, Ramagopalan SV (2010) Epigenetics: molecular mechanisms and implications for disease. Trends Mol Med 16:7–16. doi:10.1016/j.molmed.2009.11.003
Hartley CA, Phelps EA (2010) Changing fear: the neurocircuitry of emotion regulation. Neuropsychopharmacology 35:136–146. doi:10.1038/npp.2009.121
Hawk JD, Abel T (2011) The role of NR4A transcription factors in memory formation. Brain Res Bull 85:21–29. doi:10.1016/j.brainresbull.2011.02.001
Herry C, Mons N (2004) Resistance to extinction is associated with impaired immediate early gene induction in medial prefrontal cortex and amygdala. Eur J Neurosci 20:781–790. doi:10.1111/j.1460-9568.2004.03542.x
Herry C, Ciocchi S, Senn V et al (2008) Switching on and off fear by distinct neuronal circuits. Nature 454:600–606. doi:10.1038/nature07166
Herry C, Ferraguti F, Singewald N et al (2010) Neuronal circuits of fear extinction. Eur J Neurosci 31:599–612. doi:10.1111/j.1460-9568.2010.07101.x
Impey S, Fong AL, Wang Y et al (2002) Phosphorylation of CBP mediates transcriptional activation by neural activity and CaM kinase IV. Neuron 34:235–244. doi:10.1016/S0896-6273(02)00654-2
Johansen JP, Cain CK, Ostroff LE, LeDoux JE (2011) Molecular mechanisms of fear learning and memory. Cell 147:509–524. doi:10.1016/j.cell.2011.10.009
Karmodiya K, Krebs AR, Oulad-Abdelghani M et al (2012) H3K9 and H3K14 acetylation co-occur at many gene regulatory elements, while H3K14ac marks a subset of inactive inducible promoters in mouse embryonic stem cells. BMC Genomics 13:424. doi:10.1186/1471-2164-13-424
Kawashima T, Okuno H, Bito H (2014) A new era for functional labeling of neurons: activity-dependent promoters have come of age. Front Neural Circuits 8:37. doi:10.3389/fncir.2014.00037
Keifer OP, Hurt RC, Ressler KJ, Marvar PJ (2015) The physiology of fear: reconceptualizing the role of the central amygdala in fear learning. Physiology 30(5):389–401. doi:10.1152/physiol.00058.2014
Knapska E, Maren S (2009) Reciprocal patterns of c-Fos expression in the medial prefrontal cortex and amygdala after extinction and renewal of conditioned fear. Learn Mem 16:486–493. doi:10.1101/lm.1463909
Korzus E, Rosenfeld MG, Mayford M (2004) CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42:961–972. doi:10.1016/j.neuron.2004.06.002
Krettek JE, Price JL (1978) Amygdaloid projections to subcortical structures within the basal forebrain and brainstem in the rat and cat. J Comp Neurol 178:225–254. doi:10.1002/cne.901780204
Lee Y-S, Silva AJ (2009) The molecular and cellular biology of enhanced cognition. Nat Rev Neurosci 10:126–140. doi:10.1038/nrn2572
Levenson JM, O’Riordan KJ, Brown KD et al (2004) Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem 279:40545–40559. doi:10.1074/jbc.M402229200
Likhtik E, Pelletier JG, Paz R, Paré D (2005) Prefrontal control of the amygdala. J Neuro sci 25:7429–7437. doi:10.1523/JNEUROSCI.2314-05.2005
Likhtik E, Popa D, Apergis-Schoute J et al (2008) Amygdala intercalated neurons are required for expression of fear extinction. Nature 454:642. doi:10.1038/nature07167
Liu L, Johnson HL, Cousens S et al (2012) Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet (London, England) 379:2151–2161. doi:10.1016/S0140-6736(12)60560-1
Lubin FD, Sweatt JD (2007) The IkappaB kinase regulates chromatin structure during reconsolidation of conditioned fear memories. Neuron 55:942–957. doi:10.1016/j.neuron.2007.07.039
Lubin FD, Roth TL, Sweatt JD (2008) Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J Neurosci 28:10576–10586. doi:10.1523/JNEUROSCI.1786-08.2008
Lunyak VV, Burgess R, Prefontaine GG et al (2002) Corepressor-dependent silencing of chromosomal regions encoding neuronal genes. Science 298:1747–1752. doi:10.1126/science.1076469
Maren S, Quirk GJ (2004) Neuronal signalling of fear memory. Nat Rev Neurosci 5:844–852. doi:10.1038/nrn1535
McDonald AJ (1998) Cortical pathways to the mammalian amygdala. Prog Neurobiol 55:257–332. doi:10.1016/S0301-0082(98),00003-3
Mcdonald AJ, Mascagni F, Guo L (1996) Projections of the medial and lateral prefrontal cortices to the amygdala: a phaseolus vulgaris leucoagglutinin study in the rat. Neuroscience 71:55–75. doi:10.1016/0306-4522(95)00417-3
Milad MR, Quirk GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420:70–74. doi:10.1038/nature01138
Milad MR, Quirk GJ, Pitman RK et al (2007) A role for the human dorsal anterior cingulate cortex in fear expression. Biol Psychiatry. doi:10.1016/j.biopsych.2007.04.032
Miller CA, Sweatt JD (2007) Covalent modification of DNA regulates memory formation. Neuron 53:857–869. doi:10.1016/j.neuron.2007.02.022
Miller CA, Campbell SL, Sweatt JD (2008) DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity. Neurobiol Learn Mem 89:599–603. doi:10.1016/j.nlm.2007.07.016
Monsey MS, Ota KT, Akingbade IF et al (2011) Epigenetic alterations are critical for fear memory consolidation and synaptic plasticity in the lateral amygdala. PLoS ONE. doi:10.1371/journal.pone.0019958
Nader K, Schafe GE, Le Doux JE (2000) Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406:722–726. doi:10.1038/35021052
Ons S, Rotllant D, Marín-Blasco IJ, Armario A (2010) Immediate-early gene response to repeated immobilization: fos protein and arc mRNA levels appear to be less sensitive than c-fos mRNA to adaptation. Eur J Neurosci 31:2043–2052. doi:10.1111/j.1460-9568.2010.07242.x
Orsini CA, Maren S (2012) Neural and cellular mechanisms of fear and extinction memory formation. Neurosci Biobehav Rev 36:1773–1802. doi:10.1016/j.neubiorev.2011.12.014
Pape H-C, Pare D (2010) Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear. Physiol Rev 90:419–463. doi:10.1152/physrev.00037.2009
Pare D, Duvarci S (2012) Amygdala microcircuits mediating fear expression and extinction. Curr Opin Neurobiol 22:717–723. doi:10.1016/j.conb.2012.02.014
Pare D, Pare D (2004) New Vistas on Amygdala Networks in Conditioned Fear. J Neurophysiol 92(1):1-9
Parsons RG, Ressler KJ (2013) Implications of memory modulation for post-traumatic stress and fear disorders. Nat Neurosci 16:146–153. doi:10.1038/nn.3296
Peixoto L, Abel T (2013) The role of histone acetylation in memory formation and cognitive impairments. Neuropsychopharmacology 38:62–76. doi:10.1038/npp.2012.86
Peleg S, Sananbenesi F, Zovoilis A et al (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328:753–756. doi:10.1126/science.1186088
Pérez-Cadahía B, Drobic B, Davie J (2011) Activation and function of immediate-early genes in the nervous system. Biochem Cell Biol 89(1):61–73. doi:10.1139/O10-138
Petrovich GD, Swanson LW (1997) Projections from the lateral part of the central amygdalar nucleus to the postulated fear conditioning circuit. Brain Res 763:247–254. doi:10.1016/S0006-8993(96)01361-3
Pokholok DK, Harbison CT, Levine S et al (2005) Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 122:517–527. doi:10.1016/j.cell.2005.06.026
Quirk GJ, Mueller D (2008) Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33:56–72. doi:10.1038/sj.npp.1301555
Rao VR, Finkbeiner S (2007) NMDA and AMPA receptors: old channels, new tricks. Trends Neurosci 30(6):284–291. doi:10.1016/j.tins.2007.03.012
Redondo RL, Kim J, Arons AL et al (2014) Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature 513:426–430. doi:10.1038/nature13725
Rosenkranz JA, Grace AA (2002) Dopamine-mediated modulation of odour-evoked amygdala potentials during pavlovian conditioning. Nature 417:282–287. doi:10.1038/417282a
Sah P, Faber ESL, Lopez De Armentia M, Power J (2003) The amygdaloid complex: anatomy and physiology. Physiol Rev 83:803–834. doi:10.1152/physrev.00002.2003
Santini E, Muller RU, Quirk GJ (2001) Consolidation of extinction learning involves transfer from NMDA-independent to NMDA-dependent memory. J Neurosci 21:9009–9017
Santini E, Ge H, Ren K (2004) Behavioral/systems/cognitive consolidation of fear extinction requires protein synthesis in the medial prefrontal cortex. J Neurosci. doi:10.1523/JNEUROSCI.0786-04.2004
Shima T, Inada K, Ito M (2013) Creating a false memory in the hippocampus. Science 341(July):387–392. doi:10.1126/science.1239073
Sintoni S, Kurtys E, Scandaglia M et al (2013) Chronic valproic acid administration impairs contextual memory and dysregulates hippocampal GSK-3β in rats. Pharmacol Biochem Behav 106:8–15. doi:10.1016/j.pbb.2013.02.013
Stefanko DP, Barrett RM, Ly AR et al (2009) Modulation of long-term memory for object recognition via HDAC inhibition. Proc Natl Acad Sci USA 106:9447–9452. doi:10.1073/pnas.0903964106
Thomas GM, Huganir RL (2004) MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5:173–183. doi:10.1038/nrn1346
Tovote P, Fadok JP, Lüthi A (2015) Neuronal circuits for fear and anxiety. Nat Rev Neurosci 16:317–331. doi:10.1038/nrn3945
Tronson NC, Corcoran KA, Jovasevic V, Radulovic J (2012) Fear conditioning and extinction: emotional states encoded by distinct signaling pathways. Trends Neurosci 35:145–155. doi:10.1016/j.tins.2011.10.003
Tsankova NM, Kumar A, Nestler EJ (2004) Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures. J Neurosci 24:5603–5610. doi:10.1523/JNEUROSCI.0589-04.2004
Turner BM (2002) Cellular memory and the histone code. Cell 111:285–291. doi:10.1016/S0092-8674(02)01080-2
Turner BH, Herkenham M (1991) Thalamoamygdaloid projections in the rat: a test of the amygdala’s role in sensory processing. J Comp Neurol 313:295–325. doi:10.1002/cne.903130208
Veening JG, Swanson LW, Sawchenko PE (1984) The organization of projections from the central nucleus of the amygdala to brainstem sites involved in central autonomic regulation: a combined retrograde transport-immunohistochemical study. Brain Res 303:337–357. doi:10.1016/0006-8993(84)91220-4
Wei W, Coelho CM, Li X (2012) p300/CBP-associated factor selectively regulates the extinction of conditioned fear. J Neurosci 32:11930–11941. doi:10.1523/JNEUROSCI.0178-12.2012
Whittle N, Singewald N (2014) HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand? Biochem Soc Trans 42:569–581. doi:10.1042/BST20130233
Whittle N, Schmuckermair C, GunduzCinar O et al (2013) Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model. Neuropharmacology 64:414–423. doi:10.1016/j.neuropharm.2012.06.001
Wood MA, Kaplan MP, Park A (2005) Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage. Learn Mem 12:111–119. doi:10.1101/lm.86605
Zovkic IB, Sweatt JD (2012) Epigenetic mechanisms in learned fear: implications for PTSD. Neuropsychopharmacology 38:77–93. doi:10.1038/npp.2012.79
Zovkic IB, Guzman-Karlsson MC, Sweatt JD (2013) Epigenetic regulation of memory formation and maintenance. Learn Mem 20:61–74. doi:10.1101/lm.026575.112
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The authors thank the Department of Biotechnology, New Delhi, India, for funding this research (BT/PR14365/MED/30/522/2012).
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Siddiqui, S.A., Singh, S., Ranjan, V. et al. Enhanced Histone Acetylation in the Infralimbic Prefrontal Cortex is Associated with Fear Extinction. Cell Mol Neurobiol 37, 1287–1301 (2017). https://doi.org/10.1007/s10571-017-0464-6
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DOI: https://doi.org/10.1007/s10571-017-0464-6