Evidence that Prolactin acts on a relatively small subpopulation of RFRP-3 Neurons to suppress their activity and stress responses (#237)
At
the end of pregnancy, elevated prolactin levels stimulate milk production.
During lactation, elevated circulating prolactin also feeds back to the brain
to suppress stress responses, but the neuroanatomical pathways involved remain
unknown. The hypothalamic-pituitary-adrenal axis is controlled by
corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus
(PVN) of the hypothalamus. RFamide-related peptide-3 (RFRP-3) neurons project
to this region from the dorsomedial hypothalamus. Our recent results indicate
that RFRP-3 administration promotes anxiety-related behaviours and
restraint-induced corticosterone secretion in female rats and mice, and
conversely overcomes prolactin-induced anxiolytic behaviour and suppression of
restraint-induced corticosterone secretion by prolactin. Moreover,
centrally-administered RFRP-3 increases Crh mRNA expression and serum ACTH
concentrations. These effects are overcome by co-treatment with RFRP-3 receptor
antagonists, such that antagonist-treated animals are more anxiolytic than
untreated controls. In addition, RFRP-3 fibres make close appositions with
paraventricular CRH neurons, a subgroup of which was found to express the gene
for the RFRP-3 receptor, Gpr147. These observations led us to hypothesise
that RFRP-3 neurons form a conduit between prolactin’s site of action and the
stress axis. In the present study, we show that during lactation,
prolactin suppresses RFRP-3 cell numbers and Rfrp mRNA levels. Using an
immunomagnetic separation method, we found that prolactin receptor-long form
mRNA is present, albeit in low levels, in purified RFRP-3 cells from rats and
mice. To quantify the percentage of RFRP-3 neurons expressing this receptor, we
performed double in situ hybridization for Rfrp and prolactin receptor-long form. In diestrus rats, just under
10% of Rfrp cells co-expressed prolactin receptor. Taken together, these
results indicate that the RFRP-3 system may directly convey prolactin’s effects
to the HPA axis but, given the relatively low prolactin receptor
colocalisation, indirect prolactin inputs may also be involved.