CIRCUIT AND NEUROMODULATORY MECHANISMS ENABLING GENERALIZATION OF CUED FEAR EXTINCTION

Multiple-context fear extinction (MCFE) training represents a promising strategy for reducing the context-specificity that characterizes extinction memories in standard fear extinction paradigms. This limitation parallels failures of generalization commonly observed in human exposure therapy, highlighting the need for mechanistic insight into how MCFE alters extinction training. Using a mouse model, we have shown that MCFE produces a greater reduction in fear expression compared to single-context fear extinction (SCFE) training, independent of contextual novelty, and improves extinction recall at recent and remote timepoints. Using a dual activity-mapping approach (TRAP2xFos-IF), we found that MCFE produces a greater shift towards extinction-related ensemble recruitment in hippocampus, infralimbic cortex, and basolateral amygdala. MCFE was also associated with coordinated prefrontal-hippocampal activation, while SCFE preferentially engaged prefrontal-amygdala pathways. Chemogenetic inhibition further revealed a requirement of dorsal—but not ventral—hippocampus during MCFE to promote extinction generalization. Our working model is that MCFE engages a prediction-error associated neuromodulatory state that gates plasticity in prefrontal-hippocampal circuits. Indeed, preliminary in vivo calcium imaging of prelimbic and infralimbic cortices suggests that MCFE engages a fear-like neural state during extinction, creating the conditions for prediction-error signaling. Ongoing in vivo imaging focuses on assessment of population-level reorganization during MCFE in a within-subject design, in which every animal experiences SCFE and MCFE. We are also investigating candidate neuromodulatory gates underlying the enhanced memory updating in MCFE. Although dopamine was initially targeted based on its known role in prediction-error learning, preliminary D1-antagonist experiments in infralimbic cortex and dorsal hippocampus suggest limited involvement in extinction generalization.