RT Journal Article SR Electronic T1 CCK+ interneurons contribute to thalamus-evoked feed-forward inhibition in prelimbic prefrontal cortex JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP e0957232024 DO 10.1523/JNEUROSCI.0957-23.2024 A1 Kamalova, Aichurok A1 Manoocheri, Kasra A1 Liu, Xingchen A1 Casello, Sanne M. A1 Huang, Matthew A1 Baimel, Corey A1 Jang, Emily V. A1 Anastasiades, Paul G. A1 Collins, David P. A1 Carter, Adam G. YR 2024 UL http://www.jneurosci.org/content/early/2024/04/25/JNEUROSCI.0957-23.2024.abstract AB 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 feedforward inhibition across mouse cortex, including anterior cingulate cortex, where they are engaged by inputs from mediodorsal (MD) thalamus. In contrast, in the adjacent prelimbic cortex (PL), we find that PV+ interneurons are scarce in the principal thalamo-recipient 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, peri-somatic connections onto L3 pyramidal cells, where they exhibit cannabinoid 1 receptor (CB1R) mediated modulation. Moreover, MD-evoked feedforward 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.Significance Statement Here we use anatomy, slice physiology, and optogenetics to examine how mediodorsal (MD) thalamus evokes feed-forward inhibition in layer 3 of the prelimbic subregion of mouse prefrontal cortex (PFC). We first show that PV+ interneurons are relatively sparse in layer 3 of prelimbic PFC, whereas CCK+ interneurons are prevalent, and we describe the properties of these cells. We then show how MD thalamus preferentially drives a sub-population of fast-spiking CCK+ interneurons to fire more readily than nearby pyramidal cells and other interneurons. Lastly, we show that CCK+ interneurons make peri-somatic inhibitory connections onto pyramidal cells, and both CCK+ and thalamus-evoked inhibition are modulated by CB1 receptors. Our findings identify a novel and unexpected role for CCK+ interneurons in thalamus-evoked inhibition in the PFC.