Post-traumatic stress disorder, panic disorder and phobia manifest in ways that are consistent with an uncontrollable state of fear. Their development involves heredity, previous sensitizing experiences, association of aversive events with previous neutral stimuli, and inability to inhibit or extinguish fear after it is chronic and disabling. We highlight recent progress in fear learning and memory, differential susceptibility to disorders of fear, and how these findings are being applied to the understanding, treatment and possible prevention of fear disorders. Promising advances are being translated from basic science to the clinic, including approaches to distinguish risk versus resilience before trauma exposure, methods to interfere with fear development during memory consolidation after a trauma, and techniques to inhibit fear reconsolidation and to enhance extinction of chronic fear. It is hoped that this new knowledge will translate to more successful, neuroscientifically informed and rationally designed approaches to disorders of fear regulation.
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Breslau, N. et al. Trauma and posttraumatic stress disorder in the community: the 1996 Detroit Area Survey of Trauma. Arch. Gen. Psychiatry 55, 626–632 (1998).
Kessler, R.C., Sonnega, A., Bromet, E., Hughes, M. & Nelson, C.B. Posttraumatic stress disorder in the National Comorbidity Survey. Arch. Gen. Psychiatry 52, 1048–1060 (1995).
Binder, E.B. et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. J. Am. Med. Assoc. 299, 1291–1305 (2008).
McTeague, L.M. et al. Aversive imagery in posttraumatic stress disorder: trauma recurrence, comorbidity, and physiological reactivity. Biol. Psychiatry 67, 346–356 (2010).
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn., Text Revision (DSMIV-TR) Ch. 7 (American Psychiatric Association, Washington, DC, 2000).
Moriceau, S., Wilson, D.A., Levine, S. & Sullivan, R.M. Dual circuitry for odor-shock conditioning during infancy: corticosterone switches between fear and attraction via amygdala. J. Neurosci. 26, 6737–6748 (2006).
Steckler, T. & Risbrough, V. Pharmacological treatment of PTSD – established and new approaches. Neuropharmacology 62, 617–627 (2012).
Cain, C.K., Maynard, G.D. & Kehne, J.H. Targeting memory processes with drugs to prevent or cure PTSD. Expert Opin. Investig. Drugs 21, 1323–1350 (2012).
LeDoux, J.E., Cicchetti, P., Xagoraris, A. & Romanski, L.M. The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning. J. Neurosci. 10, 1062–1069 (1990).
Campeau, S. & Davis, M. Involvement of subcortical and cortical afferents to the lateral nucleus of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli. J. Neurosci. 15, 2312–2327 (1995).
Shi, C. & Davis, M. Pain pathways involved in fear conditioning measured with fear-potentiated startle: lesion studies. J. Neurosci. 19, 420–430 (1999).
Lanuza, E., Nader, K. & LeDoux, J.E. Unconditioned stimulus pathways to the amygdala: effects of posterior thalamic and cortical lesions on fear conditioning. Neuroscience 125, 305–315 (2004).
Johansen, J.P., Tarpley, J.W., LeDoux, J.E. & Blair, H.T. Neural substrates for expectation-modulated fear learning in the amygdala and periaqueductal gray. Nat. Neurosci. 13, 979–986 (2010).
Pape, H.C. & Pare, D. Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear. Physiol. Rev. 90, 419–463 (2010).
LeDoux, J.E., Iwata, J., Cicchetti, P. & Reis, D.J. Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J. Neurosci. 8, 2517–2529 (1988).
Goosens, K.A. & Maren, S. Pretraining NMDA receptor blockade in the basolateral complex, but not the central nucleus, of the amygdala prevents savings of conditional fear. Behav. Neurosci. 117, 738–750 (2003).
Wilensky, A.E., Schafe, G.E., Kristensen, M.P. & LeDoux, J.E. Rethinking the fear circuit: the central nucleus of the amygdala is required for the acquisition, consolidation, and expression of Pavlovian fear conditioning. J. Neurosci. 26, 12387–12396 (2006).
Ciocchi, S. et al. Encoding of conditioned fear in central amygdala inhibitory circuits. Nature 468, 277–282 (2010).
Haubensak, W. et al. Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature 468, 270–276 (2010).
Muller, J., Corodimas, K.P., Fridel, Z. & LeDoux, J.E. Functional inactivation of the lateral and basal nuclei of the amygdala by muscimol infusion prevents fear conditioning to an explicit conditioned stimulus and to contextual stimuli. Behav. Neurosci. 111, 683–691 (1997).
Kim, J.J. & Fanselow, M.S. Modality-specific retrograde amnesia of fear. Science 256, 675–677 (1992).
Sanders, M.J. & Fanselow, M.S. Pre-training prevents context fear conditioning deficits produced by hippocampal NMDA receptor blockade. Neurobiol. Learn. Mem. 80, 123–129 (2003).
Bechara, A. et al. Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science 269, 1115–1118 (1995).
LaBar, K.S., Gatenby, J.C., Gore, J.C., LeDoux, J.E. & Phelps, E.A. Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study. Neuron 20, 937–945 (1998).
Cheng, D.T., Knight, D.C., Smith, C.N. & Helmstetter, F.J. Human amygdala activity during the expression of fear responses. Behav. Neurosci. 120, 1187–1195 (2006).
Alvarez, R.P., Biggs, A., Chen, G., Pine, D.S. & Grillon, C. Contextual fear conditioning in humans: cortical-hippocampal and amygdala contributions. J. Neurosci. 28, 6211–6219 (2008).
Drabant, E.M., McRae, K., Manuck, S.B., Hariri, A.R. & Gross, J.J. Individual differences in typical reappraisal use predict amygdala and prefrontal responses. Biol. Psychiatry 65, 367–373 (2009).
Etkin, A. & Wager, T.D. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am. J. Psychiatry 164, 1476–1488 (2007).
Corcoran, K.A., Desmond, T.J., Frey, K.A. & Maren, S. Hippocampal inactivation disrupts the acquisition and contextual encoding of fear extinction. J. Neurosci. 25, 8978–8987 (2005).
Heldt, S.A., Stanek, L., Chhatwal, J.P. & Ressler, K.J. Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol. Psychiatry 12, 656–670 (2007).
Knight, D.C., Smith, C.N., Cheng, D.T., Stein, E.A. & Helmstetter, F.J. Amygdala and hippocampal activity during acquisition and extinction of human fear conditioning. Cogn. Affect. Behav. Neurosci. 4, 317–325 (2004).
Quirk, G.J., Russo, G.K., Barron, J.L. & Lebron, K. The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J. Neurosci. 20, 6225–6231 (2000).
Milad, M.R. & Quirk, G.J. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70–74 (2002).
Choi, D.C. et al. Prelimbic cortical BDNF is required for memory of learned fear but not extinction or innate fear. Proc. Natl. Acad. Sci. USA 107, 2675–2680 (2010).
Peters, J., Dieppa-Perea, L.M., Melendez, L.M. & Quirk, G.J. Induction of fear extinction with hippocampal-infralimbic BDNF. Science 328, 1288–1290 (2010).
Phelps, E.A., Delgado, M.R., Nearing, K.I. & LeDoux, J.E. Extinction learning in humans: role of the amygdala and vmPFC. Neuron 43, 897–905 (2004).
Milad, M.R. et al. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol. Psychiatry 62, 446–454 (2007).
Carrión, V.G., Haas, B.W., Garrett, A., Song, S. & Reiss, A.L. Reduced hippocampal activity in youth with posttraumatic stress symptoms: an FMRI study. J. Pediatr. Psychol. 35, 559–569 (2010).
Bremner, J.D. Neuroimaging in posttraumatic stress disorder and other stress-related disorders. Neuroimaging Clin. N. Am. 17, 523–538 (2007).
Britton, J.C., Phan, K.L., Taylor, S.F., Fig, L.M. & Liberzon, I. Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery. Biol. Psychiatry 57, 832–840 (2005).
Jovanovic, T. et al. Reduced neural activation during an inhibition task is associated with impaired fear inhibition in a traumatized civilian sample. Cortex doi:10.1016/j.cortex.2012.08.011 (1 October 2012).
Maren, S., Aharonov, G., Stote, D.L. & Fanselow, M.S. N-methyl-D-aspartate receptors in the basolateral amygdala are required for both acquisition and expression of conditional fear in rats. Behav. Neurosci. 110, 1365–1374 (1996).
Schafe, G.E. & LeDoux, J.E. Memory consolidation of auditory pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala. J. Neurosci. 20, RC96 (2000).
Johansen, J.P., Cain, C.K., Ostroff, L.E. & LeDoux, J.E. Molecular mechanisms of fear learning and memory. Cell 147, 509–524 (2011).
Orsini, C.A. & Maren, S. Neural and cellular mechanisms of fear and extinction memory formation. Neurosci. Biobehav. Rev. 36, 1773–1802 (2012).
Good, A.J. & Westbrook, R.F. Effects of a microinjection of morphine into the amygdala on the acquisition and expression of conditioned fear and hypoalgesia in rats. Behav. Neurosci. 109, 631–641 (1995).
McNally, G.P. & Westbrook, R.F. Opioid receptors regulate the extinction of Pavlovian fear conditioning. Behav. Neurosci. 117, 1292–1301 (2003).
Knoll, A.T. et al. Kappa opioid receptor signaling in the basolateral amygdala regulates conditioned fear and anxiety in rats. Biol. Psychiatry 70, 425–433 (2011).
Van't Veer, A., Yano, J.M., Carroll, F.I., Cohen, B.M. & Carlezon, W.A. Jr. Corticotropin-releasing factor (CRF)-induced disruption of attention in rats is blocked by the κ-opioid receptor antagonist JDTic. Neuropsychopharmacology 37, 2809–2816 (2012).
Saxe, G. et al. Relationship between acute morphine and the course of PTSD in children with burns. J. Am. Acad. Child Adolesc. Psychiatry 40, 915–921 (2001).
Holbrook, T.L., Galarneau, M.R., Dye, J.L., Quinn, K. & Dougherty, A.L. Morphine use after combat injury in Iraq and post-traumatic stress disorder. N. Engl. J. Med. 362, 110–117 (2010).
LaLumiere, R.T., Buen, T.V. & McGaugh, J.L. Post-training intra-basolateral amygdala infusions of norepinephrine enhance consolidation of memory for contextual fear conditioning. J. Neurosci. 23, 6754–6758 (2003).
Pitman, R.K. et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol. Psychiatry 51, 189–192 (2002).
Hurlemann, R. et al. Human amygdala reactivity is diminished by the beta-noradrenergic antagonist propranolol. Psychol. Med. 40, 1839–1848 (2010).
Stein, M.B., Kerridge, C., Dimsdale, J.E. & Hoyt, D.B. Pharmacotherapy to prevent PTSD: results from a randomized controlled proof-of-concept trial in physically injured patients. J. Trauma. Stress 20, 923–932 (2007).
Sharp, S., Thomas, C., Rosenberg, L., Rosenberg, M. & Meyer, W. III. Propranolol does not reduce risk for acute stress disorder in pediatric burn trauma. J. Trauma 68, 193–197 (2010).
McGhee, L.L. et al. The effect of propranolol on posttraumatic stress disorder in burned service members. J. Burn Care Res. 30, 92–97 (2009).
Myers, K.M., Ressler, K.J. & Davis, M. Different mechanisms of fear extinction dependent on length of time since fear acquisition. Learn. Mem. 13, 216–223 (2006).
Maren, S. & Chang, C.H. Recent fear is resistant to extinction. Proc. Natl. Acad. Sci. USA 103, 18020–18025 (2006).
Rothbaum, B.O. et al. Early intervention may prevent the development of posttraumatic stress disorder: a randomized pilot civilian study with modified prolonged exposure. Biol. Psychiatry 72, 957–963 (2012).
Quirk, G.J. Memory for extinction of conditioned fear is long-lasting and persists following spontaneous recovery. Learn. Mem. 9, 402–407 (2002).
Bouton, M.E. & King, D.A. Contextual control of the extinction of conditioned fear: tests for the associative value of the context. J. Exp. Psychol. Anim. Behav. Process. 9, 248–265 (1983).
Rescorla, R.A. & Heth, C.D. Reinstatement of fear to an extinguished conditioned stimulus. J. Exp. Psychol. Anim. Behav. Process. 1, 88–96 (1975).
Falls, W.A., Miserendino, M.J. & Davis, M. Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala. J. Neurosci. 12, 854–863 (1992).
Walker, D.L., Ressler, K.J., Lu, K.T. & Davis, M. Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J. Neurosci. 22, 2343–2351 (2002).
Richardson, R., Ledgerwood, L. & Cranney, J. Facilitation of fear extinction by D-cycloserine: theoretical and clinical implications. Learn. Mem. 11, 510–516 (2004).
Ressler, K.J. et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch. Gen. Psychiatry 61, 1136–1144 (2004).
Otto, M.W. et al. Efficacy of D-cycloserine for enhancing response to cognitive-behavior therapy for panic disorder. Biol. Psychiatry 67, 365–370 (2010).
Hofmann, S.G. et al. Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Arch. Gen. Psychiatry 63, 298–304 (2006).
Kushner, M.G. et al. -Cycloserine augmented exposure therapy for obsessive-compulsive disorder. Biol. Psychiatry 62, 835–838 (2007).
de Kleine, R.A., Hendriks, G.J., Kusters, W.J., Broekman, T.G. & van Minnen, A. A randomized placebo-controlled trial of D-cycloserine to enhance exposure therapy for posttraumatic stress disorder. Biol. Psychiatry 71, 962–968 (2012).
Norberg, M.M., Krystal, J.H. & Tolin, D.F. A meta-analysis of D-cycloserine and the facilitation of fear extinction and exposure therapy. Biol. Psychiatry 63, 1118–1126 (2008).
Bontempo, A., Panza, K.E. & Bloch, M.H. -Cycloserine augmentation of behavioral therapy for the treatment of anxiety disorders: a meta-analysis. J. Clin. Psychiatry 73, 533–537 (2012).
Andero, R. & Ressler, K.J. Fear extinction and BDNF: translating animal models of PTSD to the clinic. Genes Brain Behav. 11, 503–512 (2012).
Chhatwal, J.P., Stanek-Rattiner, L., Davis, M. & Ressler, K.J. Amygdala BDNF signaling is required for consolidation but not encoding of extinction. Nat. Neurosci. 9, 870–872 (2006).
Andero, R. et al. Effect of 7,8-dihydroxyflavone, a small-molecule TrkB agonist, on emotional learning. Am. J. Psychiatry 168, 163–172 (2011).
Egan, M.F. et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257–269 (2003).
Soliman, F. et al. A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science 327, 863–866 (2010).
Rakofsky, J.J., Ressler, K.J. & Dunlop, B.W. BDNF function as a potential mediator of bipolar disorder and post-traumatic stress disorder comorbidity. Mol. Psychiatry 17, 22–35 (2012).
Frustaci, A., Pozzi, G., Gianfagna, F., Manzoli, L. & Boccia, S. Meta-analysis of the brain-derived neurotrophic factor gene (BDNF) Val66Met polymorphism in anxiety disorders and anxiety-related personality traits. Neuropsychobiology 58, 163–170 (2008).
Nader, K., Schafe, G.E. & Le Doux, J.E. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406, 722–726 (2000).
Nader, K. & Hardt, O. A single standard for memory: the case for reconsolidation. Nat. Rev. Neurosci. 10, 224–234 (2009).
Tronson, N.C. & Taylor, J.R. Molecular mechanisms of memory reconsolidation. Nat. Rev. Neurosci. 8, 262–275 (2007).
Kindt, M., Soeter, M. & Vervliet, B. Beyond extinction: erasing human fear responses and preventing the return of fear. Nat. Neurosci. 12, 256–258 (2009).
Brunet, A. et al. Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. J. Psychiatr. Res. 42, 503–506 (2008).
Fiorenza, N.G., Sartor, D., Myskiw, J.C. & Izquierdo, I. Treatment of fear memories: interactions between extinction and reconsolidation. An. Acad. Bras. Cienc. 83, 1363–1372 (2011).
Lin, C.H., Lee, C.C. & Gean, P.W. Involvement of a calcineurin cascade in amygdala depotentiation and quenching of fear memory. Mol. Pharmacol. 63, 44–52 (2003).
Mao, S.C., Hsiao, Y.H. & Gean, P.W. Extinction training in conjunction with a partial agonist of the glycine site on the NMDA receptor erases memory trace. J. Neurosci. 26, 8892–8899 (2006).
Milekic, M.H. & Alberini, C.M. Temporally graded requirement for protein synthesis following memory reactivation. Neuron 36, 521–525 (2002).
Suzuki, A. et al. Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J. Neurosci. 24, 4787–4795 (2004).
Inda, M.C., Muravieva, E.V. & Alberini, C.M. Memory retrieval and the passage of time: from reconsolidation and strengthening to extinction. J. Neurosci. 31, 1635–1643 (2011).
Duvarci, S., Bauer, E.P. & Pare, D. The bed nucleus of the stria terminalis mediates inter-individual variations in anxiety and fear. J. Neurosci. 29, 10357–10361 (2009).
Jovanovic, T. & Ressler, K.J. How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD. Am. J. Psychiatry 167, 648–662 (2010).
Yehuda, R. & LeDoux, J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 56, 19–32 (2007).
Monfils, M.H., Cowansage, K.K., Klann, E. & LeDoux, J.E. Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science 324, 951–955 (2009).
Clem, R.L. & Huganir, R.L. Calcium-permeable AMPA receptor dynamics mediate fear memory erasure. Science 330, 1108–1112 (2010).
Schiller, D. et al. Preventing the return of fear in humans using reconsolidation update mechanisms. Nature 463, 49–53 (2010).
Chan, W.Y., Leung, H.T., Westbrook, R.F. & McNally, G.P. Effects of recent exposure to a conditioned stimulus on extinction of Pavlovian fear conditioning. Learn. Mem. 17, 512–521 (2010).
Davis, M. The role of the amygdala in fear and anxiety. Annu. Rev. Neurosci. 15, 353–375 (1992).
Support was provided by the US National Institutes of Health (F32MH090700, R01MH071537, R01MH094757 and R01MH096764), the Burroughs Wellcome Fund and a US National Institutes of Health National Center for Research Resources base grant (P51RR000165) to Yerkes National Primate Research Center.
K.J.R. is a cofounder of Therapade/Extinction LLC for the licensing of d-cycloserine for the enhancement of psychotherapy. K.J.R. has received no income or royalties from this relationship in the past 3 years.
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Parsons, R., Ressler, K. Implications of memory modulation for post-traumatic stress and fear disorders. Nat Neurosci 16, 146–153 (2013). https://doi.org/10.1038/nn.3296
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