Abstract
The neural circuit linking the medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) has crucial roles in both the acquisition and the extinction of fear. However, the mechanism by which this circuit encodes fear and extinction remains unknown. In this study, we monitored changes in the magnitude of evoked field potentials (EFPs) in the mPFC–BLA and BLA–mPFC pathways following auditory fear conditioning and extinction, in freely moving rats. We report that extinction of fear is mediated by depression of the EFPs in the mPFC–BLA and by potentiation in the reciprocal pathway of BLA–mPFC. Interestingly, reinstatement of fear was associated with recovery of freezing and with reversal of the changes in EFPs that were observed following extinction in both pathways. The findings indicate that the mPFC–BLA circuit expresses differential changes following fear and extinction and point to dynamic and plastic changes underlying fear, extinction, and reinstatement. Manipulations targeting these different types of plasticity could constitute a therapeutic tool for the treatment of anxiety disorders.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Akirav I, Maroun M (2007). The role of the medial prefrontal cortex-amygdala circuit in stress effects on the extinction of fear. Neural Plast 2007: 30873.
Akirav I, Raizel H, Maroun M (2006). Enhancement of conditioned fear extinction by infusion of the GABA(A) agonist muscimol into the rat prefrontal cortex and amygdala. Eur J Neurosci 23: 758–764.
Akirav I, Segev A, Motanis H, Maroun M (2009). D-cycloserine into the BLA reverses the impairing effects of exposure to stress on the extinction of contextual fear, but not conditioned taste aversion. Learn Mem 16: 682–686.
Berger TW, Thompson RF (1982). Hippocampal cellular plasticity during extinction of classically conditioned nictitating membrane behavior. Behav Brain Res 4: 63–76.
Brambilla R, Gnesutta N, Minichiello L, White G, Roylance AJ, Herron CE et al (1997). Role for the Ras signaling pathway in synaptic transmission and long-term memory. Nature 390: 281–286.
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.
Fanselow MS, LeDoux JE (1999). Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala. Neuron 23: 229–232.
Farinelli M, Deschaux O, Hugues S, Thevenet A, Garcia R (2006). Hippocampal train stimulation modulates recall of fear extinction independently of prefrontal cortex synaptic plasticity and lesions. Learn Mem 13: 329–334.
Garcia R, Paquereau J, Vouimba RM, Jaffard R (1998). Foot-shock stress but not contextual fear conditioning induces long-term enhancement of auditory-evoked potentials in the basolateral amygdala of the freely behaving rat. Eur J Neurosci 10: 457–463.
Garcia R, Spennato G, Nilsson-Todd L, Moreau JL, Deschaux O (2008). Hippocampal low-frequency stimulation and chronic mild stress similarly disrupt fear extinction memory in rats. Neurobiol Learn Mem 89: 560–566.
Garcia R, Vouimba RM, Baudry M, Thompson RF (1999). The amygdala modulates prefrontal cortex activity relative to conditioned fear. Nature 402: 294–296.
Herry C, Ciocchi S, Senn V, Demmou L, Müller C, Lüthi A (2008). Switching on and off fear by distinct neuronal circuits. Nature 454: 600–606.
Herry C, Garcia R (2002). Prefrontal cortex long-term potentiation, but not long-term depression, is associated with the maintenance of extinction of learned fear in mice. J Neurosci 22: 577–583.
Herry C, Vouimba RM, Garcia R (1999). Plasticity in the mediodorsal thalamo-prefrontal cortical transmission in behaving mice. J Neurophysiol 82: 2827–2832.
Hikind N, Maroun M (2008). Microinfusion of the D1 receptor antagonist, SCH23390 into the IL but not the BLA impairs consolidation of extinction of auditory fear conditioning. Neurobiol Learn Mem 90: 217–222.
Hugues S, Chessel A, Lena I, Marsault R, Garcia R (2006). Prefrontal infusion of PD098059 immediately after fear extinction training blocks extinction-associated prefrontal synaptic plasticity and decreases prefrontal ERK2 phosphorylation. Synapse 60: 280–287.
Hugues S, Garcia R, Léna I (2007). Time course of extracellular catecholamine and glutamate levels in the rat medial prefrontal cortex during and after extinction of conditioned fear. Synapse 61: 933–937.
Izquierdo A, Wellman CL, Holmes A (2006). Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice. J Neurosci 26: 5733–5738.
Judo C, Matsumoto M, Yamazaki D, Hiraide S, Yanagawa Y, Kimura S et al (2010). Early stress exposure impairs synaptic potentiation in the rat medial prefrontal cortex underlying contextual fear extinction. Neuroscience 169: 1705–1714.
Kavushansky A, Vouimba RM, Cohen H, Richter-Levin G (2006). Activity and plasticity in the CA1, the dentate gyrus, and the amygdala following controllable vs uncontrollable water stress. Hippocampus 16: 35–42.
Kim SC, Jo YS, Kim IH, Kim H, Choi JS (2010). Lack of medial prefrontal cortex activation underlies the immediate extinction deficit. J Neurosci 30: 832–837.
Koseki H, Matsumoto M, Togashi H, Miura Y, Fukushima K, Yoshioka M (2009). Alteration of synaptic transmission in the hippocampal-mPFC pathway during extinction trials of context-dependent fear memory in juvenile rat stress models. Synapse 63: 805–813.
LeDoux JE (2000). Emotion circuits in the brain. Annu Rev Neurosci 23: 155–184.
Likhtik E, Pelletier JG, Paz R, Paré D (2005). Prefrontal control of the amygdala. J Neurosci 25: 7429–7437.
Lin CH, Lee CC, Gean PW (2003). Involvement of a calcineurin cascade in amygdala depotentiation and quenching of fear memory. Mol Pharmacol 63: 44–52.
Maren S (1999). Long-term potentiation in the amygdala: a mechanism for emotional learning and memory. Trends Neurosci 22: 561–567.
Maroun M (2006). Stress reverses plasticity in the pathway projecting from the ventromedial prefrontal cortex to the basolateral amygdala. Eur J Neurosci 24: 2917–2922.
Maroun M, Richter-Levin G (2003). Exposure to acute stress blocks the induction of long-term potentiation of the amygdala-prefrontal cortex pathway in vivo. J Neurosci 23: 4406–4409.
McKernan MG, Shinnick-Gallagher P (1997). Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 390: 607–611.
Milad MR, Quirk GJ (2002). Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 7: 70–74.
Morgan MA, Romanski LM, LeDoux JE (1993). Extinction of emotional learning: contribution of medial prefrontal cortex. Neurosci Lett 26: 109–113.
Motanis H, Maroun M (2010). Exposure to a novel context following contextual fear conditioning enhances the induction of hippocampal long-term potentiation. Eur J Neurosci 32: 840–846.
Paxinos G, Watson C (1998). The Rat Brain in Stereotaxic Coordinates. Academic Press: San Diego, CA.
Quirk GJ, Likhtik E, Pelletier JG, Pare D (2003). Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. J Neurosci 23: 8800–8807.
Repa JC, Muller J, Apergis J, Desrochers TM, Zhou Y, LeDoux JE (2001). Two different lateral amygdala cell populations contribute to the initiation and storage of memory. Nat Neurosci 4: 724–731.
Richter-Levin G, Maroun M (2010). Stress and amygdala suppression of metaplasticity in the medial prefrontal cortex. Cereb Cortex 20: 2433–2441.
Rocher C, Spedding M, Munoz C, Jay TM (2004). Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants. Cereb Cortex 14: 224–229.
Rodríguez Manzanares PA, Isoardi NA, Carrer HF, Molina VA (2005). Previous stress facilitates fear memory, attenuates GABAergic inhibition, and increases synaptic plasticity in the rat basolateral amygdala. J Neurosci 25: 8725–8734.
Rogan MT, Leon KS, Perez DL, Kandel ER (2005). Distinct neural signatures for safety and danger in the amygdala and striatum of the mouse. Neuron 46: 309–320.
Rogan MT, Stäubli UV, LeDoux JE (1997). Fear conditioning induces associative long-term potentiation in the amygdala. Nature 390: 604–607.
Royer S, Paré D (2002). Bidirectional synaptic plasticity in intercalated amygdala neurons and the extinction of conditioned fear responses. Neuroscience 115: 455–462.
Rosenkranz JA, Moore H, Grace AA (2003). The prefrontal cortex regulates lateral amygdala neuronal plasticity and responses to previously conditioned stimuli. J Neurosci 23: 11054–11064.
Santini E, Quirk GJ, Porter JT (2008). Fear conditioning and extinction differentially modify the intrinsic excitability of infralimbic neurons. J Neurosci 28: 4028–4036.
Sotres-Bayon F, Quirk GJ (2010). Prefrontal control of fear: more than just extinction. Curr Opin Neurobiol 20: 231–235.
Storsve AB, McNally GP, Richardson R (2010). US habituation, like CS extinction, produces a decrement in conditioned fear responding that is NMDA dependent and subject to renewal and reinstatement. Neurobiol Learn Mem 93: 463–471.
Tang J, Wotjak CT, Wagner S, Williams G, Schachner M, Dityatev A (2001). Potentiated amygdaloid auditory-evoked potentials and freezing behavior after fear conditioning in mice. Brain Res 919: 232–241.
Vidal-Gonzalez I, Vidal-Gonzalez B, Rauch SL, Quirk GJ (2006). Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear. Learn Mem 13: 728–733.
Vouimba RM, Yaniv D, Diamond D, Richter-Levin G (2004). Effects of inescapable stress on LTP in the amygdala vs the dentate gyrus of freely behaving rats. Eur J Neurosci 19: 1887–1894.
Acknowledgements
We thank Professor Rene Garcia for his critical and valuable comments on the MS. This work was supported by the Israel Science Foundation (ISF, grant # 469/07) to MM.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Vouimba, RM., Maroun, M. Learning-Induced Changes in mPFC–BLA Connections After Fear Conditioning, Extinction, and Reinstatement of Fear. Neuropsychopharmacol 36, 2276–2285 (2011). https://doi.org/10.1038/npp.2011.115
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2011.115
Keywords
This article is cited by
-
Selective Disruption of Perineuronal Nets in Mice Lacking Crtl1 is Sufficient to Make Fear Memories Susceptible to Erasure
Molecular Neurobiology (2023)
-
Increased mGlu5 mRNA expression in BLA glutamate neurons facilitates resilience to the long-term effects of a single predator scent stress exposure
Brain Structure and Function (2021)
-
Extinction Learning as a Potential Mechanism Linking High Vagal Tone with Lower PTSD Symptoms among Abused Youth
Journal of Abnormal Child Psychology (2019)
-
Common neurocircuitry mediating drug and fear relapse in preclinical models
Psychopharmacology (2019)
-
Post-retrieval oxytocin facilitates next day extinction of threat memory in humans
Psychopharmacology (2019)