Neuron Phenotype Changes During Lactation

为了提供哺乳所必需的催乳素，哺乳刺激释放出紧张性抑制的脑下垂体促乳素。调节催乳素的漏斗状多巴胺(TIDA)神经元的适应性变化似乎通过使其递质从多巴胺(DA)转变为脑啡肽(Enk)来促进这一过程。这种“表型”转换是通过抑制DA合成限速酶酪氨酸羟化酶(TH)的mRNA的合成和诱导脑啡肽(Enk)的合成来完成的。抑制TH的刺激似乎主要是神经性的，但提供这种抑制的途径尚不清楚。这一建议将确定从乳头到下丘脑的通路是否最初通过室旁核中的刺激性继电器调节TIDA神经元，该继电器在抑制TIDA细胞之前延伸到腹弓状核。下一组实验将检验抑制信号是强啡肽的假设。然后，实验将集中在如何区分间歇性哺乳和断奶的问题上；特别是，如果幼崽在TH完全上调之前被送回它们该死的地方，TH表达的上调是否会中断，以及Enk在哺乳后是否会持续？最后，虽然高催乳素血症对哺乳是适应的，但在其他时间它可能是不适应的。为了理解这一过程，实验将检验这样的假设，即间歇给予催乳素会引起与哺乳相同的Enk(但不是TH)递质变化，以及非习惯性应激诱导TIDA神经元的递质表型变化，类似于TH和Enk的哺乳期变化。这些研究不仅将提供对支持哺乳的神经可塑性的了解，还将为了解应激过程中催乳素调节系统的神经内分泌失调提供基础。

To provide the prolactin necessary for lactation, the suckling stimulus releases pituitary lactotropes from tonic inhibition. Adaptive changes in the tuberoinfundibular dopamine (TIDA) neurons regulating prolactin appear to promote this process by producing a shift in their transmitter from dopamine (DA) to enkephalin (Enk). This "phenotype" switch is accomplished by curbing synthesis of mRNA for the rate limiting enzyme of DA synthesis tyrosine hydroxylase (TH) and by inducing enkephalin (Enk) synthesis. The stimulus to suppress the TH appears to be principally neural, but the pathways that provide that suppression are not known. This proposal will determine if the pathways from the nipples to the hypothalamus initially regulate the TIDA neurons through a stimulatory relay in the peripenduncular n. that extends to the ventral arcuate before inhibiting TIDA cells. The next set of experiments will test the hypothesis that the inhibitory signal is dynorphin. Experiments will then focus on the question of what distinguishes intermittent suckling form weaning; particularly,, can the up-regulation of TH expression be interrupted if pups are returned to their damns before TH fully up-regulates, and does Enk persist after suckling cases? Lastly while hyperprolactinemia is adaptive for lactation, it can be maladaptive at other times. To understand this process, experiments will test the hypothesis that intermittent prolactin administration causes the same transmitter changes as lactation for Enk (but not TH) and that non- habituating stress induces transmitter phenotype changes in TIDA neurons that resemble those of lactation for both TH and Enk. These studies will not only provide understanding of the neural plasticity that supports lactation, but will also provides a basis for understanding neuroendocrine dysregulation of the prolactin regulating system during stress.