High prolactin during pregnancy, which is essential for normal postpartum maternal behavior, increases neurogenesis in the subventricular zone of the lateral ventricle (SVZ) of the maternal brain. Because SVZ mitogenesis generates new olfactory neurons and may contribute to perception of novel odorants, we hypothesized that the prolactin-induced increase in SVZ mitogenesis during pregnancy might be important for normal maternal interactions with pups. To investigate this hypothesis, prolactin secretion was suppressed for 3 d early in pregnancy in mice, using a carefully timed dose of bromocriptine. The bromocriptine-induced reduction in prolactin prevented the normal increase in generation of neural progenitors in the SVZ of the maternal brain. Another group of bromocriptine-treated animals were allowed to continue their pregnancy until term, and then maternal behaviors were evaluated postpartum. Low prolactin during early pregnancy, and the consequent suppression of mitogenesis in the SVZ of the maternal brain, was subsequently followed by increased postpartum anxiety and markedly impaired maternal behavior. In another group of pregnant females, injections of the mitotic inhibitor methylazoxymethanol to specifically suppress neurogenesis in the mother during early pregnancy without affecting prolactin secretion also caused postpartum anxiety and impaired maternal behavior. These data demonstrate that prolactin-induced increase in generation of neural progenitors in the SVZ of the maternal brain during early pregnancy is required for normal expression of postpartum maternal behaviors.

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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