Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Department of Integrated Neurophysiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Biol Psychiatry. 2022 Jun 15;91(12):1029-1038. doi: 10.1016/j.biopsych.2021.08.008. Epub 2021 Aug 19.
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.
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.
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.
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.
可卡因相关环境（即背景）会唤起对可卡因奖赏的持久记忆，从而促进可卡因使用者的成瘾行为的维持。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背景引发的可卡因记忆的神经回路，例如通过消退学习。腹内侧前额叶皮层（vmPFC）和背内侧前额叶皮层（dmPFC）被认为通过其投射到其他脑区的作用来双向调节对可卡因线索的反应。然而，这些 mPFC 亚区是否相互作用以实现对可卡因相关的上下文刺激的适应性反应仍不清楚。
我们使用顺行和逆行示踪结合化学遗传干预来研究 vmPFC 到 dmPFC 投射在小鼠可卡因诱导的位置偏好消退中的作用。此外，还使用电生理记录和光遗传学来确定 dmPFC 中的表达 parvalbumin 的抑制性中间神经元和锥体神经元是否由 vmPFC 投射支配。
我们发现，vmPFC 到 dmPFC 投射神经元在未强化的可卡因相关环境再暴露时被激活，选择性抑制这些细胞会损害消退学习。dmPFC 中的表达 parvalbumin 的抑制性中间神经元从 vmPFC 投射中接收更强的单突触兴奋性输入，而不是本地 dmPFC 锥体神经元，从而导致锥体神经元的双突触抑制。与此一致，我们表明化学遗传抑制 dmPFC 中的表达 parvalbumin 的抑制性中间神经元会损害消退学习。
我们的数据表明，vmPFC 投射通过在 dmPFC 中募集前馈抑制来介导可卡因相关的上下文记忆的消退，从而提供了促进消退诱导的抑制控制的新的神经元基质。
