Extinction of cocaine memory depends on a feed-forward inhibition circuit within the medial prefrontal cortex
2021
Abstract BACKGROUND Cocaine-associated environments (i.e. contexts) evoke persistent memories of cocaine reward and thereby contribute to the maintenance of addictive behavior in cocaine users. From a therapeutic perspective, enhancing inhibitory control over cocaine-conditioned responses is of pivotal importance, but requires a more detailed understanding of the neural circuitry that can suppress context-evoked cocaine memories, e.g. through extinction learning. The ventral and dorsal medial prefrontal cortex (vmPFC and dmPFC) are thought to bidirectionally regulate responding to cocaine cues through their projections to other brain regions. However, whether these mPFC subregions interact to enable adaptive responding to cocaine-associated contextual stimuli has remained elusive. METHODS We used antero- and retrograde tracing combined with chemogenetic intervention to examine the role of vmPFC-to-dmPFC projections in extinction of cocaine-induced place preference in mice. In addition, electrophysiological recordings and optogenetics were used to determine whether Parvalbumin-expressing inhibitory interneurons (PV-INs) and pyramidal neurons (PNs) in the dmPFC are innervated by vmPFC projections. RESULTS We found that vmPFC-to-dmPFC projecting neurons are activated during unreinforced re-exposure to a cocaine-associated context and selective suppression of these cells impairs extinction learning. PV-INs in the dmPFC receive stronger monosynaptic excitatory input from vmPFC projections than local dmPFC PNs, consequently resulting in disynaptic inhibition of PNs. In line with this, we show that chemogenetic suppression of dmPFC PV-INs impairs extinction learning. CONCLUSIONS Our data reveal that vmPFC projections mediate extinction of a cocaine-associated contextual memory through recruitment of feed-forward inhibition in the dmPFC, thereby providing a novel neuronal substrate that promotes extinction-induced inhibitory control.
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