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Neurons in medial prefrontal cortex signal memory for fear extinction

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.

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Figure 1: Tone response of a representative neuron in medial prefrontal cortex (infralimbic area, IL) during acquisition and extinction of conditioned fear.
Figure 4: Brief IL stimulation (stim.) paired with tones simulates extinction memory.
Figure 2: IL tone responses are correlated with spontaneous recovery of freezing after extinction.
Figure 3: Average freezing (top) and IL tone response (bottom) in each phase of training.

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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.

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Correspondence to Gregory J. Quirk.

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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

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