Role of adenosine in estrogen-mediated increased arousal

描述（由申请人提供）：雌激素参与多种生理过程，包括觉醒的调节。我们的研究表明，雌激素增加了唤醒的三个独立组成部分；与油处理过的动物相比，雌二醇处理过的动物的跑步轮和家庭笼运动活动、感觉反应（主要是对触觉刺激）和情绪（恐惧条件反射）都有所增加。微阵列研究显示，脂钙素型前列腺素D合成酶（L-PGDS）在雌激素治疗小鼠的特定脑区特异性改变。L-PDGS催化前列腺素D2 （PGD2）的形成。PGD2是一种内源性睡眠激素，可诱导腹外侧视前区（VLPO）睡眠活跃神经元上c-FOS的表达。PGD2促进睡眠的作用是通过VLPO神经元中A2A受体结合增加介导的。A2A激动剂可以直接激活VLPO神经元亚群。综上所述，我们假设PGD2和腺苷是参与信号级联反应的关键分子，通过这些信号级联反应，雌激素会增加觉醒。具体来说，我们将测试雌激素的唤醒促进作用是否通过抑制VLPO中的A2A信号来介导。这些实验将为雌激素介导的觉醒增加背后的信号级联提供重要的见解，并可能为治疗警觉性和觉醒障碍提供新的治疗途径。

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.