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bioRxiv · 10.1101/2025.03.21.644656

A Prefrontal Cortex-Nucleus Accumbens Circuit Attenuates Cocaine-conditioned Place Preference Memories

Wu, X.·Kobeissi, A. M.·Phillips, H. L.·Dai, H.·Yao, W.-D.
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Abstract

The infralimbic (IL) subregion of the prefrontal cortex (PFC), via its descending projection to the nucleus accumbens (NAc), inhibits cue-induced drug seeking and reinstatement, but the underlying mechanisms are not fully understood. Here we show that the intrinsic membrane excitability of IL layer 5 pyramidal neurons projecting to the NAc shell (IL-NAcSh neurons) suppresses cocaine-associated memories. Following repeated cocaine exposures in a conditioned place preference paradigm, IL-NAcSh neurons anatomically traced by fluorescent retrobeads undergo prolonged decrease of membrane excitability, lasting for at least 15 days after cocaine withdrawal. This persistent IL-NAcSh neuron hypoexcitability was accompanied by an increase in the rheobase, an increase in the afterhyperpolarization potential, and a decrease in the membrane input resistance. This cocaine induced neuroadapation in intrinsic excitability was not observed in prelimibic cortex neurons projecting to the NAc core (PL-NAcCo neurons), a separate descending circuit thought to promote cue-triggered drug seeking. Chemogenetic restoration of IL-NAcSh neuron activity extinguishes both the acquisition and retention of cocaine conditioned place preference memories. Our results provide direct support for the notion that the IL-NAcSh circuit serves to extinct drug associated memories and restoring the drug impaired excitability of IL-NAcSh neurons has the potential to mitigate drug-cue association memories and drug seeking.

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Wu, X., Kobeissi, A. M., Phillips, H. L., Dai, H., Yao, W.-D.. 2025-03-24. A Prefrontal Cortex-Nucleus Accumbens Circuit Attenuates Cocaine-conditioned Place Preference Memories. https://doi.org/10.1101/2025.03.21.644656

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