Abstract
BackgroundCocaine-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 medial prefrontal cortex (vmPFC) and dorsal medial prefrontal cortex (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. MethodsWe 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 and pyramidal neurons in the dmPFC are innervated by vmPFC projections. ResultsWe 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. Parvalbumin-expressing inhibitory interneurons in the dmPFC receive stronger monosynaptic excitatory input from vmPFC projections than local dmPFC pyramidal neurons, consequently resulting in disynaptic inhibition of pyramidal neurons. In line with this, we show that chemogenetic suppression of dmPFC parvalbumin-expressing inhibitory interneurons impairs extinction learning. ConclusionsOur 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.
Highlights
Cocaine-associated environments evoke persistent memories of cocaine reward and thereby contribute to the maintenance of addictive behavior in cocaine users
We aimed to identify the neuronal target of ventral medial prefrontal cortex (vmPFC) pyramidal neurons (PNs) projections that promote extinction learning
Whereas dense mCherry1 axonal fibers were observed in the dorsal medial prefrontal cortex (dmPFC) after retrograde labeling, very sparse mCherry1 fibers were observed in the nucleus accumbens (NAc) shell (Figure 1D), suggesting that vmPFC neurons that project to the dmPFC and NAc shell overlap to a small extent only
Summary
Cocaine-associated environments (i.e., contexts) evoke persistent memories of cocaine reward and thereby contribute to the maintenance of addictive behavior in cocaine users. The ventral medial prefrontal cortex (vmPFC) and dorsal medial prefrontal cortex (dmPFC) are thought to bidirectionally regulate responding to cocaine cues through their projections to other brain regions. Whether these mPFC subregions interact to enable adaptive responding to cocaine-associated contextual stimuli has remained elusive. 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. 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
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.