Neuropeptide S modulation of learning and memory: a systematic review

BACKGROUND: In the last two decades, Neuropeptide S (NPS) has been identified as a key bioactive peptide in the mammalian brain, influencing fear, anxiety, wakefulness, reward, and learning. While some reviews have addressed its role in reward-seeking and anxiety, few have addressed its particular role in learning and memory. The neuropeptide S receptor 1 is highly expressed in key areas for learning processing, such as the hippocampus, cortex, thalamus, and amygdala. This review aims to examine evidence from human and animal studies that focused on the NPS system's role in modulating learning and memory. A special focus is given to experiments addressing the impact of NPS on associative learning leading to addiction and in fear conditioning, pointing to its potential therapeutic value in associated pathologies. MAIN BODY: An advanced search was conducted using the databases PubMed, Google Scholar, Web of Science, and Scopus, focusing on memory and Neuropeptide S. The reviewed data suggest that NPS modulation occurs at all memory phases, including acquisition, consolidation, and retrieval, and in extinction learning, whether motivated by appetitive or aversive stimuli. The summarized evidence shows that the NPS system interferes with working and short-term memory, mitigates learning impairments, enhances spatial and object memory consolidation, supports fear extinction learning and inhibitory avoidance consolidation, and reinstates drug-seeking behaviors. The NPS system closely interacts with key neuromodulators, including orexinergic, dopaminergic, and noradrenergic systems, in influencing memory. CONCLUSION: The Neuropeptide S system emerges as a critical modulator of memory processes. The NPS signaling may preferentially influence learning that involves emotionally or motivationally relevant stimuli. This highlights the NPS system's potential as a target for therapeutic interventions for particular memory impairments.