SummaryThe 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, it’s 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.HighlightPathway-specific KOR expression confers selective filtering of mPFC afferents by dynorphinEndogenous dynorphin release gates KOR-expressing inputs to both dynorphin-expressing and lacking mPFC neuronsDynorphin / KOR modulation reveals parallel channels within amygdalo-cortical and cortical-cortical circuitsDynorphin disinhibits mPFC pyramidal neurons via KOR-mediated suppression of distinct inhibitory circuit motifs that preferentially impact SST-mediated feedforward inhibitionDynorphin / KOR signaling biases afferent control of mPFC principal cells away from KOR-positive and towards KOR-negative afferent inputs
Dopamine release in striatal circuits, including the nucleus accumbens (NAc), tracks separable features of reward such as motivation and reinforcement. However, the cellular and circuit mechanisms by which dopamine receptors transform dopamine release into distinct constructs of reward remain unclear. Here, we show that dopamine D3 receptor (D3R) signaling in the NAc drives motivated behavior by regulating local NAc microcircuits. Furthermore, D3Rs co-express with dopamine D1 receptors (D1Rs), which regulate reinforcement, but not motivation. Paralleling dissociable roles in reward function, we report non-overlapping physiological actions of D3R and D1R signaling in NAc neurons. Our results establish a novel cellular framework wherein dopamine signaling within the same NAc cell type is physiologically compartmentalized via actions on distinct dopamine receptors. This structural and functional organization provides neurons in a limbic circuit with the unique ability to orchestrate dissociable aspects of reward-related behaviors that are relevant to the etiology of neuropsychiatric disorders.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.