Sensory cortices in extinction and second-order conditioning: the construction of internal models of threat and safety

Abstract

Threat conditioning, extinction, and second-order threat conditioning (SOC), as studied in animal models, provide insight into the brain-based mechanisms underlying fear- and anxiety-related disorders and their treatment. However, the precise locations and molecular mechanisms of threat and extinction memories remain to be elucidated. Recent evidence suggests that the basolateral amygdala (BLA) functions as the core of a broader network of structures involved in affective learning, including associative and sensory cortices capable of acquiring the valence associated with stimuli and events. Accordingly, this dissertation investigates the potential role of the sensory cortices in the storage of extinction and second-order conditioning memories. In Chapter 2 we explore the potential for the olfactory posterior piriform cortex (pPC) to store olfactory threat extinction memories via a depotentiation mechanism, as well as age-dependent changes in this process. Olfactory threat extinction depends upon NMDA receptor (NMDAR)-dependent long-term depression (LTD) in the pPC, a process which is impaired with aging, and which can be rescued with NMDAR agonism, findings which may have important implications for our understanding of age-related cognitive decline. In Chapter 3 we explore the circuit- and molecular mechanisms of an auditory-olfactory SOC model. We demonstrate the role of the BLA and pPC in the encoding and retrieval of SOC associations, as well as the molecular mechanisms therein. We shed light on unique epigenetic and neuromodulatory requirements in the pPC at different time-points during SOC and provide evidence for a BLA-based SOC by consolidation mechanism. These findings expand our understanding of the sensory cortices as functioning beyond mere sensory processors to include the construction of extinction and higher-order threat memories, internal models of threat and safety.