Impaired prolactin transport into the brain and functional responses to prolactin in aged male mice

Abstract

Ageing is related to changes in a number of endocrine systems that impact on the central actions of hormones. The anterior pituitary hormone prolactin is present in the circulation in both males and females, with widespread expression of the prolactin receptor throughout the forebrain. We aimed to investigate prolactin transport into the brain, as well as circulating levels of prolactin and functional responses to prolactin, in aged male mice (23 months). Transport of 125I‐labelled prolactin (125I‐prolactin) from the peripheral circulation into the brain was suppressed in aged compared to young adult (4 months) male mice, with no significant transport into the brain occurring in aged males. We subsequently investigated changes in the negative‐feedback regulation of prolactin secretion and prolactin‐induced suppression of luteinising hormone (LH) pulsatile secretion in aged male mice. Feedback regulation of prolactin secretion appeared to be unaffected in aged males, with no change in levels of circulating prolactin, and normal prolactin‐induced phosphorylated signal transducer and activator of transcription 5(pSTAT5) immunoreactivity in tuberoinfundibular dopaminergic (TIDA) neurones in the arcuate nucleus. There were, however, significant impairments in the ability of prolactin to suppress LH pulsatile secretion in aged males. In young adult males, acute prolactin administration significantly decreased LH pulses from 1.5 ± 0.19 pulses of LH in 4 hours to 0.5 ± 0.27 pulses. In contrast, prolactin did not suppress LH pulse frequency in aged males, with prolactin leading to an increase in mean LH concentration. These data demonstrate the emergence of impairments in prolactin transport into the brain and deficits in specific functional responses to prolactin with ageing.

Transient loss of satiety effects of leptin in middle‐aged male mice

“…This lack of ageing effect on leptin transport is distinct from other hormone systems such as prolactin where ageing markedly reduces the transport of prolactin into the brain. 15 Our findings are also in contrast to that of Banks et al, where 12-month-old CD-1 male mice showed impaired leptin transport, 43 which was accompanied by impaired leptin suppression of food intake. 44 Importantly, in that study, disrupted leptin transport and the satiety effects of leptin were specifically related to adiposity rather than ageing.…”

“…Multiple-time regression analysis was used to determine the unidirectional influx constant (K i ) from blood to brain as previously described for movement of protein into the brain. 5,15,16,25,26 An intravenous (i.v.) injection of 0.2 mL 10 6 counts per minute (cpm) of 125 I-leptin was administered into the left jugular vein of ketamine/ domitor anesthetised mice.…”

“…Supporting a potential role for age-related changes in leptin, we have previously reported markedly impaired prolactin transport into the brain in aged male mice. 15 Interestingly, there were no differences in the rate of leptin clearance from the blood (Figure 3A; difference between slopes, linear regression, F = 0.0945, p = .9101) or in the rate of leptin transport into the brain between 3-month-old, 12-month-old or 22-24-month-old male mice (Figure 3B; difference between slopes, linear regression, F = 0.7299, p = .4896). This suggests that altered transport does not contribute to the loss of leptin-induced satiety in middle-aged mice.…”

“…We have previously reported alterations in prolactin transport into the brain with ageing, where transport of the pituitary-derived prolactin, and some central actions of this hormone were suppressed in 24-month-old male mice. 15 Additionally, in female mice, we have shown that leptin transport into the brain can be profoundly altered in different physiological states, with pregnancy accompanied by marked suppression of leptin transport into the brain. 16 The prevalence of obesity in humans increases with ageing, 17 and studies have identified specific increases around mid-life.…”

Prolactin Action Is Necessary for Parental Behavior in Male Mice

“…In male mice, prolactin is the only identified lactogen to act through the Prlr, with growth hormone failing to bind to the Prlr in mice (Bartke and Kopchick, 2015) and placental lactogen only relevant in female mice during pregnancy (Cohick et al, 1996). It has also been confirmed that circulating prolactin can be transported past the blood brain barrier to access central Prlrs (Brown et al, 2016b;Barad et al, 2020), with bromocriptine treatment significantly eliminating pSTAT5 expression in the brain (Brown et al, 2010). Therefore, we can be confident that prolactin acting at the Prlr is mediating the observed effect on paternal behavior in these mice.…”