Excitatory cholecystokinin neurons in the CA3 area regulate the navigation learning and neuroplasticity

Hippocampus, a key hub of neural circuits for spatial learning and memory, has attracted tremendous studies. Neuronal information processing in the hippocampus can be regulated by many types of neuropeptides. Cholecystokinin (Cck), the most abundant neuropeptide in the central nervous system that is involved in modulating neuronal functions, such as cognition, memory, and neuroplasticity, is widely expressed in the hippocampus. However, whether local excitatory Cck neurons modulate hippocampal function is still unclear. In this study, we showed that CA1 pyramidal neurons receive projections from excitatory Cck neurons in area CA3 (CA3^Cck neurons) in adult mice. Subsequently, activation of the CA1-projecting CA3^Cck neurons triggers the release of Cck. Then, we found that the activity of CA3^Cck-CA1 neurons supports the hippocampal-dependent tasks. Furthermore, inhibition of CA3^Cck-CA1 projections or knockdown of CA3^Cck gene expression markedly impaired the behavioral tasks and neuroplasticity. Taken together, these results may add to a better understanding of how neuromodulators regulate the neural functions in the central nervous system.