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，包括唤醒调节。我们的研究表明，雌激素增加三个独立的组成部分的觉醒;运行轮和家庭笼运动活动，感觉反应（主要是触觉刺激）和情绪（恐惧条件反射）都增加雌二醇治疗的动物相比，石油治疗的动物。微阵列研究显示，脂质运载蛋白型前列腺素D合成酶（L-PGDS）在雌激素治疗小鼠的选定脑区发生特异性改变。L-PDGS催化前列腺素D2（PGD 2）的形成。PGD 2是一种内源性睡眠激素，可诱导腹外侧视前区（VLPO）睡眠活跃神经元表达c-FOS。PGD 2的睡眠促进作用是通过VLPO神经元中增加的A2 A受体结合介导的。A2 A激动剂可以直接兴奋VLPO神经元的亚群。综上所述，我们假设PGD 2和腺苷是参与雌激素增加唤醒的信号级联的关键分子。具体来说，我们将测试是否通过抑制VLPO中的A2 A信号转导介导的雌激素的唤醒促进作用。拟议的实验将提供关键的洞察信号级联潜在的雌激素介导的增加觉醒，并可能揭示新的治疗途径，在治疗疾病的警觉和觉醒。

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.