Distribution of relaxin-3 and RXFP3 within arousal, stress, affective, and cognitive circuits of mouse brain.
Relaxin-3 (RLN3) and its native receptor, relaxin family peptide 3 receptor (RXFP3), constitute a newly identified neuropeptide system enriched in mammalian brain. The distribution of RLN3/RXFP3 networks in rat brain and recent experimental studies suggest a role for this system in modulation of arousal, stress, metabolism, and cognition. In order to facilitate exploration of the biology of RLN3/RXFP3 in complementary murine models, this study mapped the neuroanatomical distribution of the RLN3/RXFP3 system in mouse brain. Adult, male wildtype and RLN3 knock-out (KO)/LacZ knock-in (KI) mice were used to map the central distribution of RLN3 gene expression and RLN3-like immunoreactivity (-LI). The distribution of RXFP3 mRNA and protein was determined using [(35)S]-oligonucleotide probes and a radiolabeled RXFP3-selective agonist ([(125)I]-R3/I5), respectively. High densities of neurons expressing RLN3 mRNA, RLN3-associated beta-galactosidase activity and RLN3-LI were detected in the nucleus incertus (or nucleus O), while smaller populations of positive neurons were observed in the pontine raphé, the periaqueductal gray and a region adjacent to the lateral substantia nigra. RLN3-LI was observed in nerve fibers/terminals in nucleus incertus and broadly throughout the pons, midbrain, hypothalamus, thalamus, septum, hippocampus, and neocortex, but was absent in RLN3 KO/LacZ KI mice. This RLN3 neural network overlapped the regional distribution of RXFP3 mRNA and [(125)I]-R3/I5 binding sites in wildtype and RLN3 KO/LacZ KI mice. These findings provide further evidence for the conserved nature of RLN3/RXFP3 systems in mammalian brain and the ability of RLN3/RXFP3 signaling to modulate "behavioral state" and an array of circuits involved in arousal, stress responses, affective state, and cognition.
Smith
Craig M
CM
Florey Neuroscience Institutes, The University of Melbourne, Victoria 3010, Australia.
Shen
Pei-Juan
PJ
Banerjee
Avantika
A
Bonaventure
Pascal
P
Ma
Sherie
S
Bathgate
Ross A D
RA
Sutton
Steven W
SW
Gundlach
Andrew L
AL
D000339:Affect / Q000502:physiology; D000818:Animals; D001143:Arousal / Q000502:physiology*; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D003071:Cognition / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009434:Neural Pathways / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012065:Relaxin / Q000378:metabolism*; D013312:Stress, Physiological
D043562:Receptors, G-Protein-Coupled; C505050:SALPR protein, mouse; C512898:relaxin-3 protein, mouse; D012065:Relaxin