Neuropeptide S modulation of learning and memory: a systematic review
Clinical Snapshot
PICO Framework
| P — Population | Human and animal subjects (mammalian models) with focus on learning and memory processes |
| I — Intervention | Neuropeptide S (NPS) system modulation or measurement |
| C — Comparator | Control conditions or baseline NPS activity |
| O — Outcomes | Learning and memory performance across acquisition, consolidation, retrieval, and extinction phases; specific focus on associative learning, fear conditioning, spatial memory, and addiction-related behaviors |
Bottom Line
This systematic review identifies Neuropeptide S as a critical modulator of learning and memory processes across acquisition, consolidation, and retrieval phases. The NPS system particularly influences emotionally and motivationally relevant learning, including fear conditioning and addiction-related behaviors. While the review synthesizes evidence from multiple databases and both human and animal studies, it lacks methodological rigor expected of high-quality systematic reviews, including detailed search strategies, quality assessment, and quantitative synthesis. The findings suggest therapeutic potential for NPS receptor targeting in memory disorders, addiction, and anxiety-related conditions. However, the evidence base remains largely preclinical, limiting immediate clinical translation. Australian clinicians should view this as promising foundational research requiring further clinical validation before therapeutic application.
Key Findings
P Value: Not applicable - qualitative review
Effect Size: Not quantified - narrative synthesis only
Primary Outcome: NPS modulation occurs across all memory phases (acquisition, consolidation, retrieval, extinction) in both appetitive and aversive learning paradigms
Nnt Or Sensitivity: NPS system shows consistent modulatory effects on working memory, spatial memory consolidation, fear extinction, and drug-seeking reinstatement
Confidence Interval: Not applicable - no meta-analysis performed
Clinical Application
Currently limited to research settings; NPS receptor targeting requires further clinical development Relevant to Australian neuroscience research priorities and potential future TGA submissions for NPS-targeted therapeutics; aligns with NHMRC mental health research frameworks Patients with memory impairments, anxiety disorders, addiction, and fear-related conditions
Abstract
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.
References
- 1.Caragea, V. M., Jüngling, K., & Méndez-Couz, M. (2026). Neuropeptide S modulation of learning and memory: a systematic review. Behavioral and Brain Functions, Article 42069596. https://doi.org/10.1016/j.neubiorev.2020.09.030
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