Relaxin-3

Relaxin-3 binds RXFP3 (Relaxin Family Peptide Receptor 3) with high affinity and RXFP4 with lower affinity. RXFP3 couples to Gi/o proteins, reducing cAMP and activating ERK/MAPK cascades. In hippocampal interneurons, RXFP3 activation modulates GABAergic inhibition and theta oscillations. In the hypothalamus, RXFP3 activation increases feeding behavior. RXFP3 distribution overlaps with stress and memory circuits, explaining relaxin-3's diverse central effects.

The nucleus incertus (NI), located in the dorsal tegmentum of the brainstem, contains the majority of relaxin-3-expressing neurons. NI neurons project widely to limbic structures including hippocampus, hypothalamus, septum, and amygdala. CRF (corticotropin-releasing factor) strongly activates NI neurons, triggering relaxin-3 release. This stress-gated release positions relaxin-3 as a brainstem-to-forebrain stress broadcast signal that coordinates arousal, food-seeking, and memory encoding during stress.

Relaxin-3 projections to the medial septum and hippocampus modulate theta rhythm generation (4-12 Hz oscillations essential for spatial navigation and memory consolidation). RXFP3 activation in the medial septum shifts hippocampal oscillatory states in a manner consistent with increased arousal and spatial exploration. Acute stress-induced theta acceleration may be partly mediated by NI relaxin-3 output. Both RXFP3 agonism and antagonism affect spatial memory performance depending on brain region and context.

Acute restraint stress, swim stress, and CRF injection all activate NI relaxin-3 neurons. ICV relaxin-3 increases anxiety-like behavior in some tests while reducing it in others, depending on dose and behavioral paradigm. RXFP3 antagonist (R3(B1-22)R) reduces stress-induced anxiety. Relaxin-3 knockout mice show altered HPA reactivity and anxiolytic phenotype in some paradigms, supporting a role in anxiogenic stress signaling.

ICV relaxin-3 increases food intake in satiated rats, effects blocked by RXFP3 antagonism. The orexigenic effect appears to involve hypothalamic NPY circuits, as relaxin-3 activates NPY neurons. RXFP3 knockout mice or NI-lesioned animals show reduced food intake and lower body weight, establishing tonic relaxin-3/RXFP3 signaling in normal appetite regulation.

Spatial learning in the Morris water maze is impaired by both NI lesions (reducing relaxin-3) and RXFP3 overactivation in the hippocampus, suggesting an optimal level of relaxin-3/RXFP3 signaling for hippocampal-dependent memory. In aging rodents with reduced NI function, relaxin-3 restoration improves hippocampal theta power and spatial memory performance.