Functional analysis of prolactin-sensitive neural circuits in the arcuate nucleus.

综合生理学目前面临的最大挑战之一是理解大脑如何解码波动的激素水平，以精确协调地控制复杂的多方面生理过程，如繁殖、哺乳和新陈代谢。催乳激素影响广泛的生理功能，帮助母亲适应怀孕和随后的哺乳的生理需求。然而，大脑中调节催乳素作用的神经回路和单个神经元还没有被很好地理解。垂体前叶乳性细胞分泌PRL被认为主要受单一脑输出信号即多巴胺（DA）的调节，多巴胺（DA）由下丘脑弓状核（ARC）中的结节基底多巴胺能（TIDA）神经元释放，并对PRL的自发分泌施加抑制张力。这种对PRL分泌的看似简单的调节与PRL影响极其广泛的功能的多效性作用形成鲜明对比（迄今已描述的输出超过300个！）。最近的实验证据表明，PRL功能可能由ARC内PRL敏感神经元的特定亚群控制。下丘脑的这个区域被认为是PRL作用的主要靶点，因为它包含大量的PRL敏感神经元，这些神经元可以通过开孔毛细血管快速进入循环的PRL水平。ARC的神经元多样性使其成为解释PRL作用多样性的主要候选。基于这些假设，我们的DFG-ANR联盟将研究下丘脑中的特殊神经回路如何解码波动的激素水平并将其转化为适当的生理和行为反应。本研究的具体目的是解剖和功能分析在下丘脑弓状核催乳素敏感的神经回路。为了做到这一点，我们将利用最近开发的动物模型来获得这些细胞的遗传途径。我们将探索雄性小鼠与未交配和哺乳期雌性小鼠之间的这种内分泌-脑对话，以解决长期存在的大脑回路如何适应哺乳期生理需求的问题。

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 neural circuits in the hypothalamic arcuate nucleus. 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.