Effects of estrogen and serotonin on anxiety

描述(申请人提供)：卵巢激素，如雌激素(E)，被认为在调节焦虑方面发挥重要作用，可能是通过调节中缝背核(DRN)发出的5-羟色胺(5-HT)系统。为了支持这一假说，我们最近发现，在去卵巢(OVX)大鼠中，慢性E治疗选择性地增加了腹内侧和尾侧DRN中色氨酸羟基酶-2(TPH2；5-羟色胺合成的限速酶和5-羟色胺能系统调节的关键控制点之一)的mRNA水平，并减少了在旷场中的焦虑样行为。特别是，DRN尾侧TPH2mRNA的增加与旷野中焦虑样行为的减少相关，而在吻侧DRN中TPH2mRNA的增加与焦虑行为的增加相关。这些结果提示，E可能通过增加尾侧DRN中5-羟色胺的合成能力来降低焦虑。这项拟议的研究将检验最重要的假设，即E增加尾侧DRN中的TPH2 mRNA，这反过来又可以减少焦虑。我将通过研究TPH2 mRNA在尾侧DRN中的下调或过表达是否会分别阻断或模仿E对开放场地和高架+迷宫中焦虑样行为的影响来检验这一假说。本研究试图阐明DRN 5-羟色胺系统在焦虑行为的激素调节中的作用。最重要的是，这项研究的发现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.