Temporal Phase Relation of Circadian Neural Oscillations Alters RFamide-Related Peptide-3 and Testicular Function in the Mouse

Abstract

In order to study the effect of the temporal synergism of neural oscillations on reproductive regulation and the response of RFamide-related peptide-3 (RFRP-3; a mammalian ortholog of avian gonadotropin-inhibitory hormone), expression of immunoreactive RFRP-3 in the neurons of the dorsomedial nucleus of the hypothalamus was monitored in sexually immature and mature laboratory mice (study I). In study II, the effects of serotonin and dopamine precursors (5-hydroxytryptophan and L-dihydroxyphenylalanine; injected daily, 8 or 12 h apart, for 13 days in 3-week-old mice) on testicular activity and immunoreactive RFRP-3 neurons were studied until 24 days after treatment. Results indicate high levels of expression of immunoreactive RFRP-3 in the sexually immature and 8-hour mice (simulating gonadal suppression), while a low level was noted in mature and 12-hour mice (simulating gonadal stimulation). These findings not only suggest the modulation of gonadal development in mice (during the course of puberty attainment) by changing the temporal phase relation of serotonergic and dopaminergic oscillations (as in some seasonally breeding species), but also demonstrate an inverse correlation of RFRP-3 neurons and gonadal activity in both control and experimental conditions.

Development, Sex Steroid Regulation, and Phenotypic Characterization of RFamide-Related Peptide (Rfrp) Gene Expression and RFamide Receptors in the Mouse Hypothalamus

“…Similar data obtained by quantifying RFRP-3-ir in male mice showed a decrease in RFRP-3-ir cell number after sexual maturation (20,21), but developmental changes in Rfrp mRNA were not measured in mice, and females were not studied. Moreover, to date, sex differences in developmental changes in Rfrp expression have not been directly assessed in any species.…”

Molecular, cellular, morphological, physiological and behavioral aspects of gonadotropin-inhibitory hormone

“…It was suggested that sexual maturation is characterized by a change in GnIH/GnRH receptor ratio, resulting in a switch in pituitary sensitivity from inhibitory by GnIH receptor to stimulatory by GnRH receptor in avian species (Shimizu and Bédécarrats, 2010). Sethi et al (2010) analyzed changes in the expression of RFRP-3 in the brain and the testicular activity of male mice after birth. Testicular activity increased progressively until 13 weeks of age and declined in the old mice.…”

“…Testicular activity increased progressively until 13 weeks of age and declined in the old mice. RFRP-3-ir neurons appeared in 1 week old mice, their number and size increased drastically at 3 weeks of age, and remained unaltered until 7 weeks of age followed by a progressive decline until 13 weeks and thereafter increased again in the old age (Sethi et al, 2010). Semaan and Kauffman (2015) detailed the daily pubertal profile from postnatal day (P) 15 to P30 of RFRP-3 gene expression and c-fos induction in developing female mice.…”

Temporal phase relation of circadian neural oscillations as the basis of testicular maturation in mice: A test of a coincidence model

“…Recently, for mice we reported that administering an 8-h temporal relation of 5-HTP and L-DOPA suppresses gonadal growth and a 12-h relation accelerates gonadal growth, whereas other relations (0-, 4-, 16-and 20-h) were ineffective (Sethi and Chaturvedi 2009). Further, the inhibitory effects of an 8-h phase relation and the stimulatory effects of a 12-h phase relation of neural oscillations on the gonadal growth of mice are inversely correlated with levels of RFRP-3, a mammalian ortholog of avian gonadotropin-inhibitory hormone (Sethi et al 2010). On the basis of numerous other reports, it is evidently not the amount of the serotonergic or dopaminergic drug that is injected which is most important in triggering either gonadal stimulation or inhibition, but, rather, it is the temporal phase relation between the two neural oscillations, as entrained by their precursor drugs, 5-HTP and L-DOPA, injected at specifi c intervals.…”