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 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.

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 and pyramidal neurons 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. 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.

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.

中文翻译：

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可卡因记忆的消失取决于内侧前额叶皮层内的前馈抑制电路

背景

与可卡因相关的环境（即上下文）唤起了对可卡因奖励的持久记忆，从而有助于维持可卡因使用者的成瘾行为。从治疗的角度来看，增强对可卡因条件反应的抑制控制至关重要，但需要更详细地了解可以抑制情境诱发的可卡因记忆的神经回路，例如通过消退学习。腹侧内侧前额叶皮层 (vmPFC) 和背侧内侧前额叶皮层 (dmPFC) 被认为通过投射到其他大脑区域来双向调节对可卡因线索的反应。然而，这些 mPFC 子区域是否相互作用以实现对可卡因相关背景刺激的适应性反应仍然难以捉摸。

方法

我们使用顺行和逆行追踪结合化学遗传学干预来检查 vmPFC 到 dmPFC 预测在小鼠可卡因诱导的位置偏好消退中的作用。此外，电生理记录和光遗传学用于确定 dmPFC 中表达小白蛋白的抑制性中间神经元和锥体神经元是否受到 vmPFC 投射的支配。

结果

我们发现 vmPFC-to-dmPFC 投射神经元在未强化的再暴露于可卡因相关环境中被激活，并且对这些细胞的选择性抑制会损害消退学习。dmPFC 中表达 Parvalbumin 的抑制性中间神经元比局部 dmPFC 锥体神经元接收来自 vmPFC 投射的更强的单突触兴奋性输入，从而导致锥体神经元的非突触抑制。与此一致，我们表明表达 dmPFC 小白蛋白的抑制性中间神经元的化学遗传学抑制会损害灭绝学习。

结论

我们的数据表明，vmPFC 预测通过在 dmPFC 中募集前馈抑制来介导可卡因相关上下文记忆的消退，从而提供一种促进消退诱导的抑制控制的新型神经元底物。