Effects of estrogen and serotonin on anxiety

描述（由申请人提供）：卵巢激素，如雌激素（E），被认为在调节焦虑中起重要作用，可能通过调节中缝背核（DRN）发出的5-羟色胺（5-HT）系统。为了支持这一假设，我们最近发现，在卵巢切除（OVX）大鼠的慢性E治疗增加色氨酸羟化酶-2（TPH 2; 5-HT合成的限速酶和在调节多巴胺能系统的关键控制点之一）的mRNA水平选择性地在中腹内侧和尾部DRN，也减少了在开放领域的焦虑样行为。特别是，增加TPH 2 mRNA在尾侧DRN与减少焦虑样行为在开放领域，而在吻侧DRN与增加焦虑行为。这些结果表明，E可能通过增加尾侧DRN 5-HT的合成能力来减轻焦虑。这项研究将检验总体假设，即E增加尾侧DRN中的TpH 2 mRNA，这反过来又减少了焦虑。我将通过研究TPH 2 mRNA敲低或过表达在尾侧DRN中是否会分别阻断或模拟E对开放视野和高架十字迷宫中焦虑样行为的影响来验证这一假设。本研究旨在阐明DRN 5-HT系统在焦虑行为的激素调节中的作用。最重要的是，这项研究的结果对女性情绪障碍的治疗具有重要的临床意义。

DESCRIPTION (provided by applicant): Ovarian hormones, such as estrogen (E), are thought to play a significant role in regulation of anxiety, perhaps via modulating the serotonin (5-HT) system emanating from the dorsal raphe nucleus (DRN). In support of this hypothesis, we have recently found that chronic E treatment in ovariectomized (OVX) rats increases the mRNA level of tryptophan hydroxylase-2 (TPH2; the rate-limiting enzyme for 5-HT synthesis and one of the key control points in regulation of the serotonergic system) selectively in the mid-ventromedial and caudal DRN and also decreases anxiety-like behavior in the open field. In particular, increased TPH2 mRNA in the caudal DRN was correlated with decreased anxiety-like behavior in the open field, whereas in the rostral DRN was correlated with increased anxiety behavior. These results suggest that E may decrease anxiety by increasing the synthetic capacity of 5-HT in the caudal DRN. The proposed study will examine the overarching hypothesis that E increases TpH2 mRNA in caudal DRN, and this in turn reduces anxiety. I will test this hypothesis by investigating the whether TPH2 mRNA knockdown or overexpression in the caudal DRN will block or mimic, respectively, the effects of E on anxiety-like behavior in the open field and the elevated plus maze. This study seeks to elucidate the role of the DRN 5-HT system in hormone regulation of anxiety behaviors. Most importantly, findings from this study have significant clinical implications for treatment of mood disorders in women.