Synaptic and associative mechanisms mediating Pavlovian conditioning to unpredictable threats
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Date
2021-04-08
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Abstract
Mental illness is one of society’s most important and pressing challenges. In particular, trauma-related disorders represent some of the most common and debilitating forms of psychopathology that contribute to substantial societal and economic burden. In the laboratory, Pavlovian fear conditioning has been a powerful experimental model for understanding the associative and molecular underpinnings of fear-related behavior. Despite significant advances, our understanding of the circuits underlying conditioned fear is restricted largely to paradigms that have employed highly predictable experimental conditions, largely due to the fact that early theories of associative learning emphasized the importance of predictive relationships in the formation of associative relationships. However, intolerance to uncertainty is argued to be a common feature across fear and anxiety-related disorders and a better understanding of fundamental mechanisms underlying behavioral responses to unpredictable threats may help inform behavioral and brain techniques for intervention. In the current work, we employed an unpredictable backward (BW) conditioning procedure in rodents to examine both the synaptic and associative mechanisms underlying the acquisition and expression of fear to an unpredictable conditioned stimulus (CS). Specifically, we show that NMDA receptors within the BNST play a privileged role in the acquisition of fear to an unpredictable BW CS, whereas those in the CeA are required for the acquisition of fear to both a predictable and unpredictable CS. Next, we examined the associative structure underlying the expression of BW conditioning; we show that the expression of fear to an unpredictable BW CS is mediated by a contextual fear memory and recruits hippocampal (HPC) neurons to a greater degree than a predictable CS. Importantly, chemogenetic reactivation of a BW-tagged HPC ensemble was sufficient to support freezing behavior in neutral context. Lastly, from a translational perspective an important finding was that presentation of the BW CS resulted in the reactivation of a HPC contextual fear memory that was sensitive to disruption by protein synthesis inhibition. Overall, these data provide important insight into the brain mechanisms underlying fear to unpredictable threats.
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Pavlovian conditioning, unpredictable threats, reconsolidation