Role of adenosine in estrogen-mediated increased arousal

说明(申请人提供)：雌激素参与多种生理过程，包括调节唤醒。我们的研究表明，雌激素增加了唤醒的三个独立成分；与石油处理的动物相比，雌激素处理的动物的跑轮和家笼运动活动、感觉反应(主要是对触觉刺激)和情绪性(恐惧条件反射)都增加了。基因芯片研究显示，在雌激素治疗的小鼠的特定脑区，Lipocalin型前列腺素D合成酶(L-PGDS)发生了特异性的改变。L-PDGS催化前列腺素D2的形成。PGD2是一种内源性睡眠激素，可诱导视前区腹外侧区睡眠活跃神经元c-fos的表达。PGD2促进睡眠的作用是通过增加VLPO神经元上A2a受体的结合来实现的。A2a激动剂可直接兴奋VLPO神经元亚群。综上所述，我们假设PGD2和腺苷是参与雌激素提高唤醒的信号级联反应的关键分子。具体地说，我们将测试雌激素的促醒作用是否通过抑制VLPO中的A2A信号而介导。拟议的实验将为雌激素介导的觉醒增加背后的信号级联提供关键的洞察力，并可能揭示治疗警觉性和觉醒障碍的新的治疗途径。

DESCRIPTION (provided by applicant): Estrogens are involved in a variety of physiological processes, including regulation of arousal. Our studies indicate that estrogens increase three separate components of arousal; running wheel and home cage motor activity, sensory responsiveness (predominantly to tactile stimulation) and emotionality (fear conditioning) are all increased in estradiol-treated animals as compared to oil-treated animals. Microarray studies revealed that lipocalin-type prostaglandin D synthase (L-PGDS) is specifically altered in select brain regions of estrogen-treated mice. L-PDGS catalyses the formation of prostaglandin D2 (PGD2). PGD2 is an endogenous somnogen that induces c-FOS expression on sleep-active neurons in the ventrolateral preoptic area (VLPO). The sleep-promoting effects of PGD2 are mediated by increased A2A receptor binding in VLPO neurons. A2A agonists can directly excite a subpopulation of VLPO neurons. Taken together, we hypothesize that PGD2 and adenosine are key molecules involved in the signaling cascade by which estrogens increase arousal. Specifically, we will test whether the arousal-promoting effects of estrogen are mediated via a suppression of A2A signaling in the VLPO. The proposed experiments will provide critical insight into the signaling cascade underlying estrogen- mediated increases in arousal, and possibly reveal new therapeutic avenues in the treatment of disorders of vigilance and arousal.