The brain as a source and a target of prolactin in mammals

Abstract

Prolactin is a polypeptide hormone associated with an extensive variety of biological functions. Among the roles of prolactin in vertebrates, some were preserved throughout evolution. This is the case of its function in the brain, where prolactin receptors, are expressed in different structures of the central nervous system. In the brain, prolactin actions are principally associated with reproduction and parental behavior, and involves the modulation of adult neurogenesis, neuroprotection, and neuroplasticity, especially during pregnancy, thereby preparing the brain to parenthood. Prolactin is mainly produced by specialized cells in the anterior pituitary gland. However, during vertebrate evolution many other extrapituitary tissues do also produce prolactin, like the immune system, endothelial cells, reproductive structures and in several regions of the brain. This review summarizes the relevance of prolactin for brain function, the sources of prolactin in the central nervous system, as well as its local production and secretion. A highlight on the impact of prolactin in human neurological diseases is also provided.

Keywords: brain; brain disease; choroid plexus; neurogenesis; neuroplasticity; neuroprotection; prolactin; prolactin receptor.

Figure 1

Main signaling pathways elicited by the activation of the long and short prolactin receptor isoforms. The action of prolactin (PRL) is initiated by its binding to a prolactin receptor (PRLR) homodimer, forming a heterotrimeric complex. PRL binding to the long form of PRLR triggers distinct signaling cascades that ultimately culminate in the regulation of gene transcription. The main activation pathway of PRL is the JAK/STAT pathway, but prolactin is also able to induce the PI3K/AKT pathway. The MAPK/ERK is another signaling pathway triggered by prolactin binding to both PRLR isoforms. The activation of this pathway involves the SHC, Grb2, SOS, Ras and Raf cascades. It is also believed that the activation of the PRLR-short form inhibits the expression of FOXO3 and Galt, involved in the metabolism of galactose to glucose, possibly leading to developmental defects. However, the exact mechanism of action of this pathway remains unidentified. AKT: Protein kinase B; ERK: extracellular signal regulated kinase; FOXO3: forkhead transcription factor 3; Galt: galactose-1-phosphate uridyltransferase; Grb2: growth factor receptor-bound protein 2; JAK2: Janus kinase 2; MAPK: mitogen-activated protein kinase; MAPKK: MAPK kinase; PI3K: phosphatidylinositol 3-kinase; Raf: rapidly accelerated fibrosarcoma; Ras: Rat sarcoma; SHC: SHC-transforming protein 1; SOS: son of sevenless; Src: proto-oncogene tyrosine-protein kinase Src; STAT5: signal transducer and activator of transcription 5.

Figure 2

Schematic representation of the expression of prolactin and prolactin receptors in the brain. Reported sites of prolactin expression are signed by a blue square, while the expression of the long and the short form of the prolactin receptor (PRLR) are indicated in light green and dark green, respectively. Prolactin and PRLR expression are represented throughout several regions of the rat brain, since most of the available information is retrieved from studies conducted in rodents. ARC: Arcuate nucleus; BNST: bed nucleus of the stria terminalis; LV: lateral ventricle; MPOA: medial preoptic area; PVN: paraventricular nuclei; SVZ: subventricular zone; VMN: ventromedial hypothalamic nucleus.

Figure 3

Summary of the main prolactin-mediated effects in the modulation of adult neurogenesis. Prolactin (PRL) has been associated with modulatory actions in the two major neurogenic niches in adult brain, the subventricular zone (SVZ) and subgranular zone (SGZ) of the dentate gyrus (DG). In the SVZ, progenitor cells differentiate into interneurons that migrate throughout the rostral migratory stream (RMS) to the olfactory bulb. During the early stage of gestation and lactation, PRL increases the number of proliferating cells in the SVZ and raises the amount of new interneurons in the olfactory bulb. The role of PRL in hippocampal progenitor cells neurogenesis is not as consensual. Some evidences support that PRL favors DG cells proliferation, while others suggest that PRL has either no effect or that negatively impacts hippocampal neurogenesis. In addition, recent evidence suggested that the choroid plexus may also be an alternative source of PRL in the rat brain. However, further studies are necessary to understand if choroid plexus derived PRL has any effects in SVZ neurogenesis. LV: Lateral ventricle.