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.Hebbian plasticity | amygdala | neuromodulation | instructive signals | associative learning H ebbian plasticity refers to the strengthening of a presynaptic input onto a postsynaptic neuron when both pre-and postsynaptic neurons are coactive (1). This was originally proposed as a mechanism for memory formation. Findings from in vitro and in vivo physiological studies suggest that Hebbian processes control synaptic strengthening (2-10). However, other results and theories suggest that Hebbian mechanisms alone are not normally sufficient for producing synaptic plasticity and that synaptic strengthening mediating memory formation involves interactions between Hebbian and neuromodulatory mechanisms (3,4,7,(11)(12)(13)(14)(15)(16)(17)(18)(19). Although molecules that may mediate Hebbian processes in memory formation have been identified (3,11,16,17,(20)(21)(22), it has been difficult to directly test whether Hebbian plasticity alone or in combination with neuromodulation is necessary and sufficient to produce neural plasticity and memories in behaving animals (especially in mammals). This is because of technical limitations in controlling correlated activity between pre-and postsynaptic neurons involved in memory storage in a temporally/spatially precise manner while measuring behavioral memory formation and neural plasticity.To overcome these problems, we used optogenetic techniques to directly manipulate Hebbian mechanisms in pyramidal neurons in the lateral nucl...
Aversive experiences powerfully regulate memory formation, and memory strength is proportional to the intensity of these experiences. Inhibition of the neural circuits that convey aversive signals when they are predicted by other sensory stimuli is hypothesized to set associative memory strength. However, the neural circuit mechanisms that produce this predictive inhibition to regulate memory formation are unknown. Here we show that predictive sensory cues recruit a descending feedback circuit from the central amygdala that activates a specific population of midbrain periaqueductal gray pain-modulatory neurons to control aversive memory strength. Optogenetic inhibition of this pathway disinhibited predicted aversive responses in lateral amygdala neurons, which store fear memories, resulting in the resetting of fear learning levels. These results reveal a control mechanism for calibrating learning signals to adaptively regulate the strength of behavioral learning. Dysregulation of this circuit could contribute to psychiatric disorders associated with heightened fear responsiveness.
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