POWRE: Neural Substrates for Glucoprivic Regulation of Reproductive Hormone Secretion

Briski，K.P.IBN 98-05789这项研究的目标是探索能量平衡和生殖之间的联系。这个项目特别适合于POWRE奖，因为它将允许探索性工作来确定新的调查路线的可行性。充足的代谢燃料是雌性哺乳动物成功繁殖所必需的。由于代谢失衡会启动生理和行为反应，恢复能量平衡，并为维持生命的过程分配可用的燃料，因此生殖等高能活动经常受到损害。虽然能量缺乏时生殖激素分泌减少反映了下丘脑促性腺激素释放激素(GnRH)功能障碍，但将底物燃料稳态与神经内分泌功能联系起来的神经机制尚不清楚。最近的研究表明，脑内给予葡萄糖抗代谢产物2-脱氧葡萄糖(2DG)，可抑制血浆黄体生成素(LH)浓度，从而暗示中枢葡萄糖受体参与生殖激素的调节。有报道称，向第四脑室注射2DG可抑制循环中的黄体生成素，这表明对生殖功能具有重要功能的受体间存在于该传递部位的扩散范围内，但这些受体在大脑这一部分的具体位置(S)尚不清楚。下丘脑腹内侧核(VMN)和下丘脑外侧区(LHA)可能存在更多的葡萄糖敏感神经元，但这些基因座在葡萄糖底物失衡时生殖激素分泌代偿性减少中的作用尚未被研究。本研究旨在确定抑制排卵前促黄体激素分泌的中枢葡萄糖受体在正常雌性大鼠中的神经解剖分布，并确定下丘脑结构中含有对葡萄糖底物失衡的生殖内分泌反应至关重要的神经元。PI建议通过研究在完整的成年雌性大鼠中将2DG特异性地注入不同的脑部位对排卵前黄体生成素高峰的开始、幅度和持续时间的影响，来确定抑制促性腺激素分泌的中枢性高血糖信号的来源。她还将通过研究秋水仙碱对局部细胞功能的可逆药理抑制是否减弱葡萄糖抗代谢产物对促性腺激素分泌的抑制作用，来研究下丘脑几个离散结构的功能完整性是否对葡聚糖抑制生殖神经内分泌轴至关重要。其他实验将确定特定的神经肽神经元是否对促性腺激素对2DG的反应至关重要。

BRISKI, K.P. IBN 98-05789 The goal of the research to be performed with this NSF POWRE funding is to explore the link between energy balance and reproduction. This project is particularly suited for a POWRE award because it will allow exploratory work to determine the feasibility of a new line of inquiry. Sufficient metabolic fuels are necessary for successful reproduction in female mammals. Because metabolic imbalance initiates physiological and behavioral responses that restore energy homeostasis and allocate available fuels for life-sustaining processes, high-energy activities such as reproduction are often impaired. While decreases in reproductive hormone secretion during energy deficits reflect hypothalamic gonadaotropin-releasing hormone (GnRH) dysfunction, the neural mechanisms that link substrate fuel homeostasis with neuroendocrine function are not clear. Recent studies show that intracerebral administration of the glucose anti-metabolite, 2-deoxy-glucose (2DG), inhibits plasma luteinizing hormone (LH) concentrations, thus implicating central glucoprivic receptors in the regulation of reproductive hormones. Reports that circulating LH is inhibited by infusion of 2DG into the fourth ventricle suggest that interoreceptors of functional significance for reproductive function occur within a diffusion range of this delivery site, but the specific location(s) of these receptors in this part of the brain are unknown. Glucose- sensitive neurons may exist more rostrally within the ventromedial hypothalamus nucleus (VMN) and lateral hypothalamic area (LHA), but the role of these loci in compensatory reductions in reproductive hormone secretion during glucose substrate imbalance has not been studied. This proposal seeks to characterize the neuroanatomical distribution of central glucoprivic receptors that inhibit preovulatory LH secretion in intact female rats, and to identify hypothalamic structures that contain neurons critical for reproductive endocr ine responses to glucose substrate imbalance. The PI proposes to identifity the origin of central glucoprivic signals that inhibit phasic gonadotropin secretion by investigating the effects of site- specific infusion of 2DG into discrete brain loci on the onset, magnitude, and duration of the preovulatory LH surge in intact, adult female rats. She will also investigate whether the functional integrity of several discrete hypothalamic structures is critical for glucoprivic inhibition of the reproductive neuroendocrine axis by examining whether reversible pharmacological inhibition of local cellular function by colchicine attenuates inhibitory effects of glucose anti-metabolites on gonadotropin secretion. Other experiments will determine if specific neuropeptide neurons are critical for gonadotropin responses to 2DG.