Cholecystokinin neurons in the central nervous system: Functional diversity, circuit mechanisms, and translational...

Cholecystokinin (CCK)-expressing neurons are widely distributed across the central nervous system, with high densities in the cortex, amygdala, and hippocampus. These neurons, which co-express fast-acting neurotransmitters such as GABA or glutamate, are critical for regulating appetite, pain perception, emotional processing, and cognitive function. Dysregulation of CCK signaling has been implicated in schizophrenia, anxiety, chronic pain, and obesity, highlighting its therapeutic potential. Recent advances in cell-type-specific genetic models, in vivo imaging, and single-cell transcriptomics have provided unprecedented insights into CCK neuron function, particularly within cortical and limbic circuits. This review critically examines CCK-expressing neurons in the cortex, amygdala, and hippocampus, where mechanistic evidence is most robust. We synthesize insights from neuroanatomy, physiology, and behavioral neuroscience to define a canonical CCK interneuron circuit motif characterized by the dynamic interplay of fast GABAergic transmission, endocannabinoid-mediated plasticity, and slower peptidergic modulation. Despite these advancements, fundamental questions persist: (1) How does CCK produce bidirectional behavioral effects across different circuits? (2) What mechanisms underlie its dose- and time-dependent actions? (3) How does CCK integrate with other neuromodulatory systems? By proposing testable hypotheses and outlining experimental strategies, this review provides a mechanism-driven roadmap to accelerate translation of circuit knowledge into targeted therapeutic interventions for neuropsychiatric and metabolic disorders.