Synaptic Plasticity in the Lateral Amygdala: A Cellular Hypothesis of Fear Conditioning

Abstract

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 occur in the lateral nucleus of the amygdala (LA). Further, recent studies show that associative long-term potentiation (LTP) occurs in pathways that transmit the CS to LA, and that drugs that interfere with this LTP also disrupt behavioral fear conditioning when infused into the LA, suggesting that associative LTP in LA might be a mechanism for storing memories of the CS-US association. 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 that the US strongly depolarizes these same LA neurons. This depolarization, in turn, causes calcium influx through NMDA receptors (NMDARs) and also causes the LA neuron to fire action potentials. The action potentials then back-propagate into the dendrites, where they collide with CS-evoked EPSPs, resulting in calcium entry through voltage-gated calcium channels (VGCCs). Although calcium entry through NMDARs is sufficient to induce synaptic changes that support short-term fear memory, calcium entry through both NMDARs and VGCCs is required to initiate the molecular processes that consolidate synaptic changes into a long-term memory.

Selective Modification of Short-Term Hippocampal Synaptic Plasticity and Impaired Memory Extinction in Mice with a Congenitally Reduced Hippocampal Commissure

“…Sample fEPSP traces were recorded at times a and b indicated on the graphs. may contribute (in ways still unclear) to consolidation of memory for fear conditioning (Clugnet and LeDoux, 1990;Rogan and LeDoux, 1995;McKernan and Shinnick-Gallagher, 1997;Rogan et al, 1997;Blair et al, 2001;Schafe et al, 2001). Several types of hippocampal LTP were intact in slices from 9XCA/Wah mice, and it is interesting that contextual fear conditioning, which is hippocampus dependent, was also preserved in these mice.…”

Cognitive and emotional consequences of binge drinking: role of amygdala and prefrontal cortex

“…The stimulation coincidence parameters that are necessary for induction of LTP in the lateral amygdala closely resemble those required for the formation of associations between CS and US in fear conditioning experiments . Taken together, these experiments suggest that LTP-like mechanisms underlie amygdala-mediated fear conditioning (Blair et al 2001). Why then should alcohol withdrawal affect such a mechanism?…”

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

“…Fear conditioning was previously shown to be a molecular process increasing synaptic efficacy on LA neuron dendrites as a result of input from cortical and/or thalamic fibres conveying the unconditioned (US) and conditioned stimulus (CS), commonly called long-term potentiation (LTP; reviewed in [67]). LTP in the LA appears to be a critical mechanism for storing memories of the association between the CS and US [68,69]. LTP formation may be enhanced when at least one of the involved pathways, thalamic or cortical, is more sensitive, as demonstrated in Tph2 2/2 mice.…”