Abstract
Conditioned fear responses to a tone previously paired with a shock diminish if the tone is repeatedly presented without the shock, a process known as extinction. Since Pavlov1 it has been hypothesized that extinction does not erase conditioning, but forms a new memory. Destruction of the ventral medial prefrontal cortex, which consists of infralimbic and prelimbic cortices, blocks recall of fear extinction2,3, indicating that medial prefrontal cortex might store long-term extinction memory. Here we show that infralimbic neurons recorded during fear conditioning and extinction fire to the tone only when rats are recalling extinction on the following day. Rats that froze the least showed the greatest increase in infralimbic tone responses. We also show that conditioned tones paired with brief electrical stimulation of infralimbic cortex elicit low freezing in rats that had not been extinguished. Thus, stimulation resembling extinction-induced infralimbic tone responses is able to simulate extinction memory. We suggest that consolidation of extinction learning potentiates infralimbic activity, which inhibits fear during subsequent encounters with fear stimuli.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Pavlov, I. P. Conditioned Reflexes (Oxford Univ. Press, London, 1927)
Quirk, G. J., Russo, G. K., Barron, J. L. & Lebron, K. The role of ventral medial prefrontal cortex in the recovery of extinguished fear. J. Neurosci. 20, 6225–6231 (2000)
Morgan, M. A., Romanski, L. M. & LeDoux, J. E. Extinction of emotional learning: contribution of medial prefrontal cortex. Neurosci. Lett. 163, 109–113 (1993)
Santini, E., Muller, R. U. & Quirk, G. J. Consolidation of extinction learning involves transfer from NMDA-independent to NMDA-dependent memory. J. Neurosci. 21, 9009–9017 (2001)
Morrow, B. A., Elsworth, J. D., Rasmusson, A. M. & Roth, R. H. The role of mesoprefrontal dopamine neurons in the acquisition and expression of conditioned fear in the rat. Neuroscience 92, 553–564 (1999)
Garcia, R., Vouimba, R. M., Baudry, M. & Thompson, R. F. The amygdala modulates prefrontal cortex activity relative to conditioned fear. Nature 402, 294–296 (1999)
Gewirtz, J. C., Falls, W. A. & Davis, M. Normal conditioned inhibition and extinction of freezing and fear-potentiated startle following electrolytic lesions of medial prefrontal cortex in rats. Behav. Neurosci. 111, 712–726 (1997)
Herry, C., Vouimba, R. M. & Garcia, R. Plasticity in the mediodorsal thalamo-prefrontal cortical transmission in behaving mice. J. Neurophysiol. 82, 2827–2832 (1999)
Robertson, A., Laferriere, A. & Milner, P. M. Development of brain stimulation reward in the medial prefrontal cortex: facilitation by prior electrical stimulation of the sulcal prefrontal cortex. Physiol. Behav. 28, 869–872 (1982)
Marsicano, G. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002)
Falls, W. A., Miserendino, M. J. D. & Davis, M. Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala. J. Neurosci. 12, 854–863 (1992)
Quirk, G. J., Repa, C. & LeDoux, J. E. Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat. Neuron 15, 1029–1039 (1995)
Repa, J. C. et al. Two different lateral amygdala cell populations contribute to the initiation and storage of memory. Nature Neurosci. 4, 724–731 (2001)
Fendt, M. & Fanselow, M. S. The neuroanatomical and neurochemical basis of conditioned fear. Neurosci. Biobehav. Rev. 23, 743–760 (1999)
Conde, F., Maire-Lepoivre, E., Audinat, E. & Crepel, F. Afferent connections of the medial frontal cortex of the rat. II. Cortical and subcortical afferents. J. Comp. Neurol. 352, 567–593 (1995)
McDonald, A. J. Organization of amygdala projections to the prefrontal cortex and associated striatum in the rat. Neuroscience 44, 1–14 (1991)
Perez-Jaranay, J. M. & Vives, F. Electrophysiological study of the response of medial prefrontal cortex neurons to stimulation of the basolateral nucleus of the amygdala in the rat. Brain Res. 564, 97–101 (1991)
Lu, K. T., Walker, D. L. & Davis, M. Mitogen-activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear-potentiated startle. J. Neurosci. [online] 21, RC162 (2001)
LeDoux, J. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000)
McDonald, A. J., Mascagni, F. & Guo, L. Projections of the medial and lateral prefrontal cortices to the amygdala: a Phaseolus vulgaris leucoagglutinin study in the rat. Neuroscience 71, 55–75 (1996)
Royer, S., Martina, M. & Pare, D. An inhibitory interface gates impulse traffic between the input and the output of the amygdala. J. Neurosci. 19, 10575–10583 (1999)
Royer, S., Martina, M. & Pare, D. Bistable behaviour of inhibitory neurons controlling impulse traffic through the amygdala: role of a slowly deinactivating K+ current. J. Neurosci. 20, 9034–9039 (2000)
Al Maskati, H. A. & Zbrozyna, A. W. Stimulation in prefrontal cortex area inhibits cardiovascular and motor components of the defence reaction in rats. J. Auton. Nerv. Syst. 28, 117–125 (1989)
Konorski, J. Integrative Activity of the Brain (Univ. Chicago Press, Chicago, 1967)
Herry, C. & Garcia, R. 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 (2002)
Bremner, J. D. et al. Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study. Biol. Psychiatry 45, 806–816 (1999)
Shin, L. M. et al. An fMRI study of anterior cingulate function in posttraumatic stress disorder. Biol. Psychiat. 50, 932–942 (2001)
Semple, W. E. et al. Higher brain blood flow at amygdala and lower frontal cortex blood flow in PTSD patients with comorbid cocaine and alcohol abuse compared with normals. Psychiatry 63, 65–74 (2000)
Eschweiler, G. W. et al. Left prefrontal activation predicts therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) in major depression. Psychiat. Res. 99, 161–172 (2000)
Morgan, M. A. & LeDoux, J. E. Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats. Behav. Neurosci. 109, 681–688 (1995)
Acknowledgements
We thank I. Vidal-Gonzalez for assistance with data collection, and K. Nader, D. Pare, and A. J. Silva for comments on the manuscript. This work was supported by a National Research Service Award from National Institute of Mental Health (NIMH) to M.R.M. and by grants from the NIMH and the National Institute of General Medical Science (MBRS) to G.J.Q.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests.
Rights and permissions
About this article
Cite this article
Milad, M., Quirk, G. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70–74 (2002). https://doi.org/10.1038/nature01138
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nature01138
This article is cited by
-
Fear extinction rescuing effects of dopamine and L-DOPA in the ventromedial prefrontal cortex
Translational Psychiatry (2024)
-
Systematic reduction of gray matter volume in anorexia nervosa, but relative enlargement with clinical symptoms in the prefrontal and posterior insular cortices: a multicenter neuroimaging study
Molecular Psychiatry (2024)
-
Prefrontal circuits encode both general danger and specific threat representations
Nature Neuroscience (2023)
-
Regulation of social interaction in mice by a frontostriatal circuit modulated by established hierarchical relationships
Nature Communications (2023)
-
Transcranial magnetic stimulation of the left middle frontal gyrus modulates the information people communicate in different social contexts
Scientific Reports (2023)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.