Subthreshold Fear Conditioning Produces a Rapidly Developing Neural Mechanism that Primes Subsequent Learning

Abstract

Learning results in various forms of neuronal plasticity that provide a lasting representation of past events, and understanding the mechanisms supporting lasting memories has been a primary pursuit of the neurobiological study of memory. However, learning also alters the capacity for future learning, an observation that likely reflects its adaptive significance. In the laboratory, we can study this essential property of memory by assessing how prior experience alters the capacity for subsequent learning. Previous studies have indicated that while a single weak fear conditioning trial is insufficient to support long-term memory (LTM), it can facilitate future learning such that another trial delivered within a protracted time window results in a robust memory. Here, we sought to determine whether or not manipulating neural activity in the basolateral amygdala (BLA) using designer receptors exclusively activated by designer drugs (DREADDs) during or after the initial learning trial would affect the ability of the initial trial to facilitate subsequent learning. Our results show that inhibiting the BLA in rats prior to the first trial prevented the ability of that trial to facilitate learning when a second trial was presented the next day. Inhibition of the BLA immediately after the first trial using DREADDs was not effective, nor was pharmacological inhibition of protein kinase A (PKA) or the mitogen-activated protein kinase (MAPK). These findings indicate that the neural mechanisms that permit an initial subthreshold fear conditioning trial to alter later learning develop rapidly and do not appear to require a typical post-learning consolidation period.

Sex difference in the facilitation of fear learning by prior fear conditioning

“…This difference was dependent on the interval between training sessions such that females displayed significantly less facilitation of visual fear conditioning when the interval was 24 hours, while both males and females showed equivalent and robust levels of facilitation when two training sessions were separated by 1 hour. Our findings also show that contextual fear conditioning did not have the same facilitatory effect, as the level of fear in both sexes trained with unsignaled shocks did not differ from rats that did not receive visual fear conditioning, which is consistent with prior work (Parsons and Davis, 2012;Cole and Parsons, 2019). However, the trend towards a difference in the rats trained with contextual fear conditioning in the current study leaves open the possibility that the right amount or intensity of contextual fear conditioning might facilitate later learning.…”

“…At least in males, there is good evidence that the facilitation of subsequent learning is dependent on some of the same molecular mechanisms as memory consolidation for the initial training. For example, our prior work has identified both the protein kinase A and mitogen-activated protein kinase signaling in the basolateral amygdala as being necessary for initial learning to facilitate subsequent fear conditioning (Parsons and Davis, 2012;Parsons, Walker, and Davis, 2016;Cole et al, 2019). The cyclic-AMP response element binding protein has also been implicated by our prior work (Parsons and Davis, 2012) and others studying the neural basis of fear memory linking (Rashid et al, 2016).…”

“…This approach has been valuable, but learning does not typically occur in isolation from other experiences, and in fact, many recent studies have described several conditions in which prior experience can alter the strength and underlying mechanisms of learning. For example, our previous work using Pavlovian fear conditioning showed that a single pairing of light and mild shock, insufficient to support memory formation when presented alone, was able to prime learning when a second trial was later presented (Parsons and Davis, 2012;Parsons, Walker and Davis, 2016;Cole et al, 2019). This priming effect was time dependent such that optimal facilitation was observed when the second trial occurred within an hour to several days later.…”