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

Abstract

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.Linked ArticlesThis article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc

Intranasal administration of a stapled relaxin‐3 mimetic has anxiolytic‐ and antidepressant‐like activity in rats

“…Because rats have been widely used in previous investigations of relaxin-3 and relaxin-3 B-chain peptides (see Kumar et al, 2017;Ma, Smith, Blasiak, & Gundlach, 2017), rats were used to allow comparison of the current results with the previous literature. Rats were also appropriate because they have been widely used in translational pharmacological research on anxiety, depression, and other neuropsychiatric disorders (Lezak, Missig, & Carlezon, 2017;Pollak, Rey, & Monje, 2010).…”

Distribution, physiology and pharmacology of relaxin‐3/RXFP3 systems in brain

“…For example, there is growing evidence for the impact of stress and CRF in the aetiology of neurodegenerative disorders such as Alzheimer's disease (Campbell et al, ; Park et al, ; Zhang et al, ), and the involvement of 5‐HT, orexin and other arousal networks in normal and abnormal cognitive processing and in the expression of comorbid symptoms of sleep dysregulation, anxiety and depression in multiple disorders (Chen et al, ; Kohler et al, ). These findings suggest there are exciting opportunities to examine the importance/involvement and/or therapeutic potential of relaxin‐3/RXFP3 signalling for the treatment of cognitive, affective and mood deficits and/or neurological disease progression in a range of clinical conditions or their validated experimental models (Smith et al, ; see Kumar et al, ).…”

Phylogenetic, sequence and structural analysis of Insulin superfamily proteins reveals an indelible link between evolution and structure-function relationship

“…Insulin family proteins are known to evolve from a single ancestral gene and these Lilliputians of the protein world are the regulators of many physiological processes in higher organisms, including sugar metabolism, growth and reproduction. A recent discovery (53) reveals that the fairly new member of this family, relaxin-3, is a neuropeptide and a potential target for the treatment of various neuropsychiatric disorders (54). It is intriguing to note that nature has optimized these sequences to perform optimal and intended function over millions of years, encompassing species of diverse nature and habitat.…”