Interneurons in the medial prefrontal cortex (PFC) regulate local neural activity to influence cognitive, motivated, and emotional behaviors. Parvalbumin-expressing (PV+) interneurons are the primary mediators of thalamus-evoked feed-forward inhibition across the mouse cortex, including the anterior cingulate cortex, where they are engaged by inputs from the mediodorsal (MD) thalamus. In contrast, in the adjacent prelimbic (PL) cortex, we find that PV+ interneurons are scarce in the principal thalamorecipient layer 3 (L3), suggesting distinct mechanisms of inhibition. To identify the interneurons that mediate MD-evoked inhibition in PL, we combine slice physiology, optogenetics, and intersectional genetic tools in mice of both sexes. We find interneurons expressing cholecystokinin (CCK+) are abundant in L3 of PL, with cells exhibiting fast-spiking (fs) or non–fast-spiking (nfs) properties. MD inputs make stronger connections onto fs-CCK+ interneurons, driving them to fire more readily than nearby L3 pyramidal cells and other interneurons. CCK+ interneurons in turn make inhibitory, perisomatic connections onto L3 pyramidal cells, where they exhibit cannabinoid 1 receptor (CB1R) mediated modulation. Moreover, MD-evoked feed-forward inhibition, but not direct excitation, is also sensitive to CB1R modulation. Our findings indicate that CCK+ interneurons contribute to MD-evoked inhibition in PL, revealing a mechanism by which cannabinoids can modulate MD-PFC communication.

内侧前额叶皮层 (PFC) 中的中间神经元调节局部神经活动，从而影响认知、动机和情绪行为。表达小白蛋白（PV+）的中间神经元是丘脑诱发的整个小鼠皮质（包括前扣带皮层）前馈抑制的主要介质，它们在此处受到来自内侧（MD）丘脑的输入的参与。相比之下，在邻近的前边缘 (PL) 皮层中，我们发现主要丘脑接受层 3 (L3) 中的 PV+ 中间神经元很少，这表明了不同的抑制机制。为了确定介导 PL 中 MD 诱发抑制的中间神经元，我们结合了两性小鼠的切片生理学、光遗传学和交叉遗传工具。我们发现表达胆囊收缩素 (CCK+) 的中间神经元在 PL L3 中丰富，细胞表现出快速尖峰 (fs) 或非快速尖峰 (nfs) 特性。 MD 输入与 fs-CCK+ 中间神经元建立更强的连接，促使它们比附近的 L3 锥体细胞和其他中间神经元更容易放电。 CCK+ 中间神经元反过来在 L3 锥体细胞上形成抑制性的体周连接，在其中表现出大麻素 1 受体 (CB1R) 介导的调节。此外，MD 引起的前馈抑制（而非直接激发）也对 CB1R 调节敏感。我们的研究结果表明，CCK+ 中间神经元有助于 MD 诱发的 PL 抑制，揭示了大麻素调节 MD-PFC 通讯的机制。