Hypothalamic prolactin signaling protects against overheating in pregnancy

Abstract

Pregnancy involves physiological adaptations that optimize fetal development. Reduced maternal core temperature may protect offspring from the teratogenic effects of excess heat, but the mechanisms regulating body temperature during pregnancy remained largely unclear. In a recent study in mice, Ladyman and colleagues identified the prolactin receptor as a thermal switch lowering maternal core temperature and promoting offspring survival in warm environments.

Tight thermoregulatory control during pregnancy protects fetal development from the damaging effects of heat [1]. In many mammalian species, including mice, a gradual reduction in core body temperature is observed across pregnancy [2]. This maternal reduction in core temperature allows mothers to absorb excess heat from the womb [1]. This heat dissipation via the mother is critical given that the fetal thermoregulatory system is immature [1]. Until recently, the neurobiological origins of these maternal thermoregulatory adaptations were largely unknown. Recent work by Ladyman and colleagues aimed to address this knowledge gap and identified the hypothalamic prolactin receptor as a potential critical switch [3].

By combining genetic lineage tracing and immediate-early-gene immunohistochemical labeling, Ladyman and colleagues first showed that in both male and female mice, nearly a quarter of prolactin receptor (Prlr)-expressing neurons in the rostral preoptic area of the brain respond to ambient warmth [3]. Given that prolactin-sensitive neurons respond to heat, the authors then asked – do these neurons also modulate core body temperature? To address this question, Ladyman and colleagues chemogenetically activated Prlr-expressing neurons in the preoptic area (POA), which was found to reduce core temperature and energy expenditure in male and female mice [3]. This is similar to the torpor phenotype previously reported by activating estrogen receptor alpha-expressing cells in the medial POA [4]. Taken together, these studies indicate that hormone-sensitive neurons in the POA can decrease energy expenditure, including core temperature, in both sexes. Future studies should determine the degree of overlap in the estrogen- and prolactin-sensitive neuronal populations, as both receptors are widely expressed in these brain regions.

Circulating prolactin levels increase during pregnancy, so Ladyman and colleagues then asked – does hypothalamic prolactin signaling underlie the reduction in core body temperature observed in pregnancy? To test this, the authors first knocked out Prlr in the POA using floxed Prlr mice stereotaxically injected with AAV encoding Cre. Indeed, pregnant Prlr knockout (KO) mice had higher core temperature than controls, with a growing difference as pregnancy progressed and prolactin levels, presumably, increased [3]. This effect was not observed in non-pregnant females, suggesting a contextually specific role of hypothalamic prolactin signaling in thermoregulation during pregnancy.

Although Prlr is expressed in both GABAergic and glutamatergic neurons [5], glutamatergic neurons in the POA appear to be particularly important for heat dissipation in warm environments [6]. Therefore, Ladyman and colleagues asked whether prolactin signaling in glutamatergic neurons is required for dams to maintain thermal homeostasis and protect offspring health when exposed to mild warmth (30ºC) [3]. At 30ºC, Prlr KO in glutamatergic neurons led to higher maternal core temperature in late-pregnant mice compared to control mice [3]. While the core temperature elevation in late pregnant KO dams was subtle, offspring from the Prlr KO dams were more likely to perish after birth in warm conditions. Prlr KO dams appear to abandon their pups, but only at elevated temperatures; at standard housing temperatures (22 ºC), pup survival was largely similar between litters nursed by control and Prlr KO dams [3].

In summary, the findings by Ladyman and colleagues add important insights to a body of literature identifying prolactin as a potent driver of maternal physiology and behavior. The study raises a number of interesting questions to be addressed in future work. For instance, how does prolactin receptor expression map onto other neuronal populations that alter thermal preference in postpartum females [7] or promote torpor or maintain temperature balance outside of pregnancy [8]? More broadly, how does prolactin signaling protect fetal health in the context of elevated ambient temperatures? Was the increase in pup mortality observed in the study due to developmental aberrations, increased sensitivity to heat damage after birth, or due to the absence of maternal care? Lastly, nesting and nursing may trap heat, creating an additional thermal challenge. It is intriguing to consider if and how ambient warmth might lead Prlr KO moms to prioritize their thermal homeostasis over the survival of their offspring.

Overall, prolactin receptor signaling appears to play critical roles in pregnancy. These roles go beyond known roles in promoting lactation [5] and parental care postpartum [9], and include reducing physical activity [10] as well as protecting against the detrimental effects of warmth [3]. These findings and others [7] establish a link between hypothalamic neurons sensitive to rising maternal hormones and adaptive thermoregulatory changes that are essential for reproduction.