Sleep and circadian instability in delayed sleep-wake phase disorder.

Study Objectives: In patients with delayed sleep-wake phase disorder (DSWPD), the circadian clock may be more easily affected by light at night. This creates a potential vulnerability, whereby individuals with irregular schedules may have less stable circadian rhythms. We investigated the stability of circadian timing and regularity of sleep in patients with DSWPD and healthy controls.

Increased sensitivity of the circadian system to light in delayed sleep-wake phase disorder.

Key Points: This is the first study to demonstrate an altered circadian phase shifting response in a circadian rhythm sleep disorder. Patients with delayed sleep-wake phase disorder (DSWPD) demonstrate greater sensitivity of the circadian system to the phase-delaying effects of light. Increased circadian sensitivity to light is associated with later circadian timing within both control and DSWPD groups.

Relaxin-3 receptor (Rxfp3) gene knockout mice display reduced running wheel activity: implications for role of relaxin-3/RXFP3 signalling in sustained arousal.

Anatomical and pharmacological evidence suggests the neuropeptide, relaxin-3, is the preferred endogenous ligand for the relaxin family peptide-3 receptor (RXFP3) and suggests a number of putative stress- and arousal-related roles for RXFP3 signalling. However, in vitro and in vivo evidence demonstrates exogenous relaxin-3 can activate other relaxin peptide family receptors, and the role of relaxin-3/RXFP3 signalling in specific brain circuits and associated behaviours in mice is not well described. In this study, we characterised the behaviour of cohorts of male and female Rxfp3 gene knockout (KO) mice (C57/B6J(RXFP3TM1/DGen)), relative to wild-type (WT) littermates to determine if this receptor KO strain has a similar phenotype to its ligand KO equivalent.

Relaxin-3/RXFP3 networks: an emerging target for the treatment of depression and other neuropsychiatric diseases?

Animal and clinical studies of gene-environment interactions have helped elucidate the mechanisms involved in the pathophysiology of several mental illnesses including anxiety, depression, and schizophrenia; and have led to the discovery of improved treatments. The study of neuropeptides and their receptors is a parallel frontier of neuropsychopharmacology research and has revealed the involvement of several peptide systems in mental illnesses and identified novel targets for their treatment. Relaxin-3 is a newly discovered neuropeptide that binds, and activates the G-protein coupled receptor, RXFP3.

Pharmacological activation of RXFP3 is not orexigenic in C57BL/6J mice.

The neuropeptide relaxin-3 and its cognate G-protein-coupled receptor, RXFP3, have been implicated in the control of feeding behaviour in rats. For example, relaxin-3-positive projections and RXFP3 are present within hypothalamic feeding circuits, and icv injection of human relaxin-3 (-0.2 to 1.

Consequences of relaxin-3 null mutation in mice on food-entrainable arousal.

Relaxin-3/RXFP3 networks have been hypothesised to influence behavioural state based on their anatomical distribution and recent experimental findings in rat and mouse. Two arousal-related behaviours altered by changes in relaxin-3/RXFP3 signalling are feeding and voluntary running wheel activity. In particular, relaxin-3 null mutation (knockout) mice display a 'dark-phase hypoactivity' phenotype, reflected by reduced voluntary running wheel activity and increased sleeping behaviour, with no other major changes in basal behavioural profile.

Relaxin-3 systems in the brain--the first 10 years.

The relaxin-3 gene was identified in 2001 by searching the human genome database for homologues of the relaxin hormone, and was subsequently discovered to encode a highly conserved neuropeptide in mammals and lower species. In the decade since its discovery there have been significant advances in our knowledge of the peptide, including the identification of its cognate receptor (a type 1 G-protein coupled receptor, GPCR135 or RXFP3), an understanding of its structure-activity and associated cellular signalling, and the elucidation of key neuroanatomical aspects of relaxin-3/RXFP3 networks in mammalian brain. The latter studies revealed that relaxin-3 is expressed within GABA neurons of the brainstem including an area known as the nucleus incertus, and that ascending relaxin-3 projections innervate a broad range of RXFP3-rich forebrain areas.