Processing of unpredictability in fear learning and memory
Lim, Seh Hong Hong
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Unpredictability is one of the major drivers of associative learning. While unpredictability in the timing of events can enhance fear memory strength, the neural substrates that are involved in generating and processing these errors remain largely unknown. We first showed that unpredictability, generated by the varied timing of the aversive event following the predictive cue, greatly enhanced fear memory strength (Chapter 3). The unpredictability-processing neural network in basal and lateral amygdala (BLA) was then studied using time-lapse microendoscopy to monitor neuronal calcium response across fear conditioning and recall (Chapter 4). We identified four distinct functional classes of neurons based on the neuronal activity patterns during fear conditioning and long-term recall. “Memory Winner” neurons outcompeted the “Memory Loser” neurons to encode the fear memories; nonetheless, both classes of neurons exhibited learning-related plasticity during the fear conditioning. In contrast, Fear Expression neurons did not display learning-related plasticity during fear conditioning but did respond to the tone presentation during auditory fear recall. The introduction of temporal unpredictability during the fear conditioning increased the percentage of both the Memory Winner neurons and Fear Expression neurons, and decreased the percentage of Memory Loser neurons. Furthermore (Chapter 5), pharmacological inhibition of dorsal hippocampus and optogenetic silencing of CA1 revealed the essential involvement of dorsal hippocampus in the processing of negative prediction errors, which is generated by unpredictability in their timing. Collectively, our data suggest that the processing of temporal unpredictability of aversive events requires the dorsal hippocampal activation to process the negative prediction errors; and the rearrangement of the BLA neural representation of fear learning and memory. Taken together, these processes underlie the mechanism of the unpredictability-enhanced fear memory strength.