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Relaxin-3 has been proposed to modulate emotional-behavioural functions such as arousal and behavioural activation, appetite regulation, stress responses, anxiety, memory, sleep and circadian rhythm. The nucleus incertus (NI), in the midline tegmentum close to the fourth ventricle, projects widely throughout the brain and is the primary site of relaxin-3 neurons. Over recent years, a number of preclinical studies have explored the function of the NI and relaxin-3 signalling, including reports of mRNA or peptide expression changes in the NI in response to behavioural or pharmacological manipulations, effects of lesions or electrical or pharmacological manipulations of the NI, effects of central microinfusions of relaxin-3 or related agonist or antagonist ligands on physiology and behaviour, and the impact of relaxin-3 gene deletion or knockdown. Although these individual studies reveal facets of the likely functional relevance of the NI and relaxin-3 systems for human physiology and behaviour, the differences observed in responses between species (e.g. rat vs. mouse), the clearly identified heterogeneity of NI neurons and procedural differences between laboratories are some of the factors that have prevented a precise understanding of their function. This review aims to draw attention to the current preclinical evidence available that suggests the relevance of the NI/relaxin-3 system to the pathology and/or symptoms of certain neuropsychiatric disorders and to provide cognizant directions for future research to effectively and efficiently uncover its therapeutic potential.

Relaxin’ the brain: a case for targeting the nucleus incertus network and relaxin‐3/RXFP3 system in neuropsychiatric disorders