Cue-Dependent Fear Learning Drives Nucleus Accumbens Spine Plasticity

Nucleus accumbens (NAc) dopamine 2 receptor expressing medium spiny neurons (D2-MSNs) are involved in stress and aversive learning, where repeated stress increases excitatory spine density. Whether this plasticity reflects cue-specific learning or generalized stress response remains unknown. Using Pavlovian fear conditioning in Tac1-Cre/Tdtomato mice, we dissociated associative plasticity from the effects of foot shock stress. Acute fear conditioning produced distinct physiological outcomes between stress in the presence or absence of a cue. Conditioning for 7 days consolidated cue learning and increased excitatory transmission frequency via an increase in the total spine density. However, repeated exposure to foot shock did not lead to this synaptic remodeling. Our results suggest that morphological changes supporting synaptic plasticity on NAc D2-MSNs are due to cue-dependent learning, but not foot shock stress alone. We propose that NAc D2-MSNs encode learning and response to threat cues, which may heighten later stress responsivity.