Hebbian and neuromodulatory mechanisms interact to trigger associative memory formation

A long-standing hypothesis termed “Hebbian plasticity” suggests that memories are formed through strengthening of synaptic connections between neurons with correlated activity. In contrast, other theories propose that coactivation of Hebbian and neuromodulatory processes produce the synaptic strengthening that underlies memory formation. Using optogenetics we directly tested whether Hebbian plasticity alone is both necessary and sufficient to produce physiological changes mediating actual memory formation in behaving animals. Our previous work with this method suggested that Hebbian mechanisms are sufficient to produce aversive associative learning under artificial conditions involving strong, iterative training. Here we systematically tested whether Hebbian mechanisms are necessary and sufficient to produce associative learning under more moderate training conditions that are similar to those that occur in daily life. We measured neural plasticity in the lateral amygdala, a brain region important for associative memory storage about danger. Our findings provide evidence that Hebbian mechanisms are necessary to produce neural plasticity in the lateral amygdala and behavioral memory formation. However, under these conditions Hebbian mechanisms alone were not sufficient to produce these physiological and behavioral effects unless neuromodulatory systems were coactivated. These results provide insight into how aversive experiences trigger memories and suggest that combined Hebbian and neuromodulatory processes interact to engage associative aversive learning. Significance The influential Hebbian plasticity hypothesis suggests that an increase in the strength of connections between neurons whose activity is correlated produces memories. Other theories, however, propose that neuromodulatory systems need to be activated together with Hebbian plasticity mechanisms to engage memory formation. The present work provides direct in vivo evidence supporting the idea that a parallel mechanism involving neuromodulation and Hebbian processes is both necessary and sufficient to trigger synaptic strengthening and behavioral associative memory formation. This parallel process may represent a general mechanism used by many learning systems in the brain.