Synaptic plasticity in the lateral amygdala: A cellular hypothesis of fearconditioning

Fear conditioning is a form of associative learning in which subjects come to express defense responses to a neutral conditioned stimulus (CS) that is paired with an aversive unconditioned stimulus (US). Considerable evidence suggests that critical neural changes mediating the CS-US association occu r in the lateral nucleus of the amygdala (LA). Further, recent studies show that associative long-term potentiation (LTP) occurs in pathways that tran smit the CS to LA, and that drugs that interfere with this LTP also disrupt behavioral fear conditioning when infused into the LA, suggesting that ass ociative LTP in LA might be a mechanism for storing memories of the CS-US a ssociation. Here, we develop a detailed cellular hypothesis to explain how neural responses to the CS and US in LA could induce LTP-like changes that store memories during fear conditioning. Specifically, we propose that the CS evokes EPSPs at sensory input synapses onto LA pyramidal neurons, and th at the US strongly depolarizes these same LA neurons. This depolarization, in turn, causes calcium influx through NMDA receptors (NMDARs) and also cau ses the LA neuron to fire action potentials. The action potentials then bac k-propagate into the dendrites, where they collide with CS-evoked EPSPs, re sulting in calcium entry through voltage-gated calcium channels (VGCCs). Al though calcium entry through NMDARs is sufficient to induce synaptic change s that support short-term fear memory, calcium entry through both NMDARs an d VGCCs is required to initiate the molecular processes that consolidate sy naptic changes into a long-term memory.