If we train a mouse to fear a tone that is paired with an electric shock, the mouse will freeze the next time it hears the tone, expecting to receive another shock. But if we continue to present the tone in the absence of shock, the association between the two stimuli will gradually become weaker, and the mouse will stop freezing.

This phenomenon is called extinction — defined as the reduction of a learned behavioural response on repeated presentations of a conditioned stimulus in the absence of a reinforcer. As the extinction of aversive memories might be affected in states such as post-traumatic stress disorder and in certain phobias, it is important to find the mechanism(s) behind extinction.

So, what are the neural bases of extinction? Reporting in Nature, Marsicano et al. provide evidence that endocannabinoids are crucially involved. Marsicano et al. generated mice that lacked the cannabinoid receptor Cb1 and trained them in the aversive task described above. Cb1−/− mice learned to freeze in response to the tone; however, in contrast to wild-type mice, the Cb1-deficient animals failed to extinguish this behavioural response. Moreover, the Cb1 antagonist SR141716A had the same effect on extinction if it was administered immediately before the tone.

The area of the brain that is key to learning the tone–shock association is the amygdala. Marsicano et al. therefore predicted that the levels of endogenous cannabinoids should rise in the amygdala immediately after presentation of the tone. Indeed, they confirmed this prediction for two endocannabinoids — anandamide and 2-arachidonoylglycerol. But how might these molecules affect synaptic transmission in the amygdala during extinction? We don't yet know, but the authors made an intriguing finding. In wild-type animals, low-frequency stimulation of inhibitory synapses in the amygdala led to a persistent depression of their efficacy. By contrast, this effect was missing in the amygdala of Cb1−/− mice or in the presence of SR141716A. So, endocannabinoids seem to participate in this synaptic depression, and it will now be important to determine whether and how this effect is related to extinction.