Functional analysis of prolactin-sensitive neural circuits in the arcuate nucleus – Prol-Hyp

One of the great challenges remaining in integrative physiology today is to understand how the brain decodes fluctuating hormone levels to orchestrate precise and coordinated control over complex multifaceted physiological processes such as reproduction, lactation and metabolism. The hormone prolactin influences a wide range of physiological functions helping the mother adapt to the physiological demands of pregnancy and subsequent lactation. However, the neural circuits and individual neurons mediating prolactin actions in the brain are not well understood. PRL secretion by lactotrope cells in the anterior pituitary gland is thought to be primarily regulated by a single brain output signal, i.e. dopamine (DA), released by tuberoinfundibular dopaminergic (TIDA) neurons in the hypothalamic arcuate nucleus (ARC) and exerting an inhibitory tone on spontaneous PRL secretion. This seemingly simple regulation of PRL secretion is in stark contrast to the pleiotropic actions of PRL influencing an extremely wide range of functions (more than 300 described outputs so far!). Recent experimental evidence suggests that PRL functions may be controlled by specialized subsets of PRL-sensitive neurons within the ARC. This area of the hypothalamus is poised to serve as a prime target for PRL action since it contains a large number of PRL-sensitive neurons which have fast access to circulating PRL levels via fenestrated capillaries. The neuronal diversity of the ARC makes it a prime candidate to explain the diversity of PRL actions. Based on these hypotheses, our DFG-ANR consortium will investigate how specialized neural circuits in the hypothalamus decode fluctuating hormone levels and translate those into appropriate physiological and behavioral responses. The specific aim of the present study is to dissect and functionally analyze prolactin-sensitive DA neural circuits in the hypothalamic arcuate nucleus with a special focus on dopaminergic cells. To do this, we will capitalize on recently developed animal models giving us genetic access to these cells. We will explore this endocrine-brain dialog in male versus virgin and lactating female mice to address the long-standing question of how brain circuits adapt to the physiological demands during lactation.