Abstract
Complex neural circuits within the hypothalamus that govern essential autonomic processes and associated behaviors signal using amino acid and monoamine transmitters and a variety of neuropeptide (hormone) modulators, often via G-protein coupled receptors (GPCRs) and associated cellular pathways. Relaxin-3 is a recently identified neuropeptide that is highly conserved throughout evolution. Neurons expressing relaxin-3 are located in the brainstem, but broadly innervate the entire limbic system including the hypothalamus. Extensive anatomical data in rodents and non-human primate, and recent regulatory and functional data, suggest relaxin-3 signaling via its cognate GPCR, RXFP3, has a broad range of effects on neuroendocrine function associated with stress responses, feeding and metabolism, motivation and reward, and possibly sexual behavior and reproduction. Therefore, this article aims to highlight the growing appreciation of the relaxin-3/RXFP3 system as an important “extrinsic” regulator of the neuroendocrine axis by reviewing its neuroanatomy and its putative roles in arousal-, stress-, and feeding-related behaviors and links to associated neural substrates and signaling networks. Current evidence identifies RXFP3 as a potential therapeutic target for treatment of neuroendocrine disorders and related behavioral dysfunction.
Highlights
Precise regulation of complex neural circuits in the hypothalamus governs essential autonomic processes and associated behaviors, such as metabolism, growth, and feeding; stress responses, arousal, and locomotor activity; as well as reproduction and social/sexual behavior [1,2,3,4,5,6,7]
Using a recombinant adeno-associated virus engineered to locally secrete bioactive R3/I5, we demonstrated an increase in food intake in the R3/I5 expressing rats (∼5.2 g/day more than control) which was sustained for up to 2 months, leading to an ∼23% increase in cumulative body weight gain [43]
This study demonstrated that increased food seeking and consumption in response to GABA/agouti-related peptide (AgRP) neuron activation is induced by suppressing the activity of the PVN neurons that express the single-minded 1 (SIM1) transcription factor [23, 97]
Summary
Precise regulation of complex neural circuits in the hypothalamus governs essential autonomic processes and associated behaviors, such as metabolism, growth, and feeding; stress responses, arousal, and locomotor activity; as well as reproduction and social/sexual behavior [1,2,3,4,5,6,7]. The intracellular signaling pathway of the relaxin-3-RXFP3 interaction has been studied in the SN56 neuronal-like cell line, in which the Gαi/Gαo pathway was recruited, suggesting an inhibitory intracellular pathway may be activated in vivo when relaxin-3 binds to RXFP3-expressing neurons within the brain [63], an idea that can be tested in different functional networks [see Ref.
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