Dynorphin / kappa-opioid receptor regulation of excitation-inhibition balance toggles afferent control of prefrontal cortical circuits in a pathway-specific manner.

The medial prefrontal cortex (mPFC) controls emotional behaviors and cognition via connections with limbic excitatory afferents that engage various intra-mPFC inhibitory motifs The mPFC dynorphin (Dyn) / kappa-opioid receptor (KOR) system regulates affect and cognition and is implicated in neuropsychiatric disorders. However, its unclear how neuropeptides in the mPFC, including the Dyn / KOR system, control excitatory and inhibitory circuit motifs integral in information processing. Here, we provide a circuit-based framework wherein selective KOR expression in mPFC afferents or within mPFC feedforward and feedback inhibitory circuits gates how distinct limbic afferent inputs control mPFC neurons. Dyn/KOR signaling directly decreases the ability of KOR-expressing afferent inputs to drive mPFC cell activity. Dyn/KOR signaling also suppresses afferent-driven recruitment of inhibitory sub-networks via several mechanisms, disinhibiting KOR-negative excitatory afferent control of mPFC ensembles. Thus, the Dyn/KOR system toggles which afferent input controls mPFC circuits, providing mechanistic insights into the role of neuropeptides in shaping mPFC function. HighlightO_LIPathway-specific KOR expression confers selective filtering of mPFC afferents by dynorphin C_LIO_LIEndogenous dynorphin release gates KOR-expressing inputs to both dynorphin-expressing and lacking mPFC neurons C_LIO_LIDynorphin / KOR modulation reveals parallel channels within amygdalo-cortical and cortical-cortical circuits C_LIO_LIDynorphin disinhibits mPFC pyramidal neurons via KOR-mediated suppression of distinct inhibitory circuit motifs that preferentially impact SST-mediated feedforward inhibition C_LIO_LIDynorphin / KOR signaling biases afferent control of mPFC principal cells away from KOR-positive and towards KOR-negative afferent inputs C_LI