Prolactin has numerous biological actions in the brain, and transgenic mice are increasingly being used to investigate these actions. The present study aimed to provide a detailed mapping of the prolactin-responsive neurons in the female mouse forebrain by describing the distribution of prolactin receptor mRNA by in situ hybridization, and measuring prolactin-induced phosphorylation of signal transducer and activation of transcription 5 (pSTAT5) by immunohistochemistry. For in situ hybridization, a probe designed to detect both long and short receptor isoforms showed mRNA expression in a heterogeneous manner within the forebrain. Strong expression was observed in the rostral hypothalamus, particularly in periventricular regions, as well as in the arcuate and ventromedial nuclei of the mediobasal hypothalamus. There was also significant expression in some nonhypothalamic regions, notably high expression in the choroid plexus, and lower levels of expression in the medial amygdala, bed nucleus of the stria terminalis, and lateral septum. Prolactin-induced pSTAT5, detected by immunohistochemistry, provided a functional index of prolactin receptor activation in neurons. Prolactin-induced pSTAT5 was only observed in areas containing prolactin receptor mRNA, and was particularly prominent in the rostral and mediobasal hypothalamus. Most other areas that contained prolactin receptor mRNA also showed positive signal for prolactin-induced pSTAT5. The major exceptions were paraventricular nucleus and median preoptic nucleus, in which prolactin receptor mRNA was observed, but no induction of pSTAT5 by prolactin. The data provide key neuroanatomical information facilitating the use of the mouse model for furthering our understanding of prolactin actions in the brain.

The neuroendocrine control of prolactin secretion is unlike that of any other pituitary hormone. It is predominantly inhibited by the hypothalamus and, in the absence of a regulatory feedback hormone, it acts directly in the brain to suppress its own secretion. In addition to this short‐loop feedback action in the brain, prolactin has been reported to influence a wide range of other brain functions. There have been few attempts to rationalise why a single hormone might exert such a range of distinct and seemingly unrelated neuroendocrine functions. In this review, we highlight some of the original studies that first characterised the unusual features of prolactin neuroendocrinology, and then attempt to identify areas of new progress and/or controversy. Finally, we discuss a hypothesis that provides a unifying explanation for the pleiotrophic actions of prolactin in the brain.

Tuberoinfundibular dopamine (TIDA) neurons, known as neuroendocrine regulators of prolactin secretion from the pituitary gland, also release GABA within the hypothalamic arcuate nucleus. As these neurons express prolactin receptors (Prlr), prolactin may regulate GABA secretion from TIDA neurons, potentially mediating actions of prolactin on hypothalamic function. To investigate whether GABA is involved in feedback regulation of TIDA neurons, we examined the physiological consequences of conditional deletion of Prlr in GABAergic neurons. For comparison, we also examined mice in which Prlr were deleted from most forebrain neurons. Both neuron-specific and GABA-specific recombination of the Prlr gene occurred throughout the hypothalamus and in some extrahypothalamic regions, consistent with the known distribution of Prlr expression, indicative of knock-out of Prlr. This was confirmed by a significant loss of prolactininduced phosphorylation of STAT5, a marker of prolactin action. Several populations of GABAergic neurons that were not previously known to be prolactin-sensitive, notably in the medial amygdala, were identified. Approximately 50% of dopamine neurons within the arcuate nucleus were labeled with a GABA-specific reporter, but Prlr deletion from these dopamine/GABA neurons had no effect on feedback regulation of prolactin secretion. In contrast, Prlr deletion from all dopamine neurons resulted in profound hyperprolactinemia. The absence of coexpression of tyrosine hydroxylase, a marker for dopamine production, in GABAergic nerve terminals in the median eminence suggested that rather than a functional redundancy within the TIDA population, the dopamine/GABA neurons in the arcuate nucleus represent a subpopulation with a functional role distinct from the regulation of prolactin secretion.

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