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NATURE REVIEWS | NEUROSCIENCE VOLUME 4 | JANUARY 2003 | 5

Animals — including humans —can be conditioned to fear a neutralstimulus, such as a tone, if it isrepeatedly paired with somethingunpleasant, such as a mild shock.Presenting the tone without theshock can diminish thisconditioned fear; this process iscalled extinction. Since Pavlov’soriginal conditioning studies, a keyquestion has been whether thisextinction process erases thememory for the original fearconditioning, or instead lays downa new memory that inhibits thefear. New research by Milad andQuirk provides evidence for thelatter hypothesis and suggests thatextinction memory might becontrolled by the prefrontal cortex(PFC), a brain region long thoughtto be involved in executive control.

In this study, rats were firstconditioned to show a fear response(‘freezing’) to a tone. Next, the ratswere given extinction trials, duringwhich the freezing responsesdiminished. Finally, they weretested for recall of extinction. Theactivity of neurons in the medialPFC was recorded during each ofthese stages. Neuronal firing in thePFC increased in response to thetone, but only during the recall ofextinction. Furthermore, the ratsthat showed the lowest levels of freezing (the bestextinction) also exhibited the highest levels of PFCfiring in response to the tones.

Electrical stimulation of the PFC during tonepresentations reduced freezing in animals that didnot experience extinction trials. In other words,artificially activating the PFC imitated extinction.PFC stimulation could also hasten the appearanceof the extinction response in animals that receivedextinction training. Together with previous resultsshowing that destruction of the PFC blocksextinction memory, but not the originalconditioning or the learning of extinction, thedata provide evidence for a role of the PFC in thestorage of a new extinction memory that inhibitsor replaces the original fear memory.

The authors propose that, during extinctiontraining, neural inputs to the PFC from subcorticalareas are enhanced, aiding in the formation andconsolidation of extinction memory. Subsequent

exposure to the previously feared stimulustriggers increased neural activity in the PFC andsuppresses the original fear response. So, newextinction memories stored in the PFC inhibitfearful memories that probably reside insubcortical structures such as the amygdala,and dampen the expression of fear-relatedbehaviours. Clinically, the formation of extinctionmemory might provide a mechanism foralleviating fears that are associated with trauma or phobias. These results provide support for thedevelopment of strategies to treat phobias thatfocus on the PFC.

Anne Marie Brady,Albany Medical College

References and linksORIGINAL RESEARCH PAPER Milad, M. R. & Quirk, G. J. Neurons inmedial prefrontal cortex signal memory for fear extinction. Nature 420,70–74 (2002)FURTHER READING Myers, K. M. & Davis, M. Behavioral and neuralanalysis of extinction. Neuron 36, 567–584 (2002)

Overcoming our fears

L E A R N I N G A N D M E M O R Ycase, the reduced size of the hip-pocampus is probably conducive to anexaggerated hormonal and behav-ioural response to stress. This scenariowould also explain why only a fewpeople develop the disorder, despitethe fact that many are exposed to thesame trauma.

In the end, the relationshipbetween stress and hippocampal sizeis probably a two-way street. In otherwords, the egg (stress) often comesfirst, but sometimes the chicken (areduced hippocampus) has prece-dence. This should be taken as a signthat it is time to drop rhetoricalconundrums about chickens andeggs in the face of evidence thatnature and environment, brain andsociety, can often not be dissociated.After all, chicken and egg are one andthe same animal.

Suzana Herculano-Houzel,Universidade Federal do Rio de Janeiro

References and linksORIGINAL RESEARCH PAPER Gilbertson, M.W. et al. Smaller hippocampal volume predictspathologic vulnerability to psychological trauma.Nature Neurosci. 5, 1242–1247 (2002)FURTHER READING Sapolsky, R. M. Chickens,eggs and hippocampal atrophy. Nature Neurosci.5, 1111–1113 (2002)WEB SITESCiência hoje:http://www.uol.com.br/cienciahoje/cerebro.htm

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