Sex Differences In Anxiety: Role of Zif268

描述（由申请人提供）：本提案的目的是调查社会互动行为的性别差异，并检查内侧前额叶皮层（mPFC）中的立即早期基因zif 268在调节雄性和雌性大鼠这些行为中的作用。本研究的另一个重点是确定zif 268的上游和下游分子靶点，这些分子靶点与社会交往中的性别差异有关。我们的初步数据表明，雄性大鼠表现出更高的社会互动（SI）比雌性大鼠-无论他们的发情周期-。有趣的是，zif 268在内侧前额叶皮层（mPFC）的基础表达在性别之间变化，因为与女性相比，男性在该区域具有更高水平的zif 268表达。通过使用zif 268反义寡脱氧核苷酸（zif 268阿索），我们诱导了暂时下调zif 268表达的mPFC的雄性大鼠和比较他们的SI行为的控制男性和女性注入zif 268错义寡脱氧核苷酸（zif 268 MSO）。在这样做时，我们发现zif 268阿索雄性显示出比对照雄性显著更少的SI（并且因此更焦虑），并且事实上，显示出与对照雌性相似的SI水平。从本质上讲，下调雄性大鼠mPFC中的zif 268表达消除了先前在SI测试中发现的焦虑样行为的性别差异。我们的新发现使我们假设mPFC中的性二态zif 268表达是介导SI测试中性别特异性焦虑样行为的关键分子因素，SI测试具有很强的社会成分。在这个应用程序中，我们想进一步探讨的假设，内侧前额叶皮层的zif 268发挥了重要作用，在确定性别差异的社会互动和确定的上游和下游目标zif 268在mPFC中发挥了重要作用，这些性别差异的焦虑。

DESCRIPTION (provided by applicant): The aim of this proposal is to investigate sex differences in social interaction behavior and to examine the role of the immediate early gene zif268 in the medial prefrontal cortex (mPFC) in mediating these behaviors in male and female rats. Another focus of this study is to determine the upstream and downstream molecular targets of zif268 that are relevant to sex differences in social interaction. Our preliminary data show that male rats exhibit higher social interaction (SI) than female rats -regardless of their estrus cycle-. Interestingly, the basal expression of zif268 in the medial prefrontal cortex (mPFC) varied between the sexes in that males had higher levels of zif268 expression in this region when compared to females. Through the use of zif268 antisense oligodeoxynucleotides (zif268 ASO), we induced a temporary down-regulation of zif268 expression in the mPFC of male rats and compared their SI behavior to both control males and females infused with zif268 missense oligodeoxynucleotides (zif268 MSO). Upon doing this, we found that zif268 ASO males displayed significantly less SI (and therefore, were more anxious) than control males and, in fact, displayed levels of SI which were similar to control females. In essence, down-regulation of zif268 expression in the mPFC of male rats eliminated the sex differences previously found in anxiety-like behavior in the SI test. Our novel findings have led us to hypothesize that sexually-dimorphic zif268 expression in the mPFC is a key molecular factor in mediating sex-specific anxiety-like behavior in the SI test, which has a strong social component. In this application we would like to explore further the hypothesis that zif268 in the medial prefrontal cortex play a major role in determining sex differences in social interaction and determine the upstream and downstream targets of zif268 in the mPFC that play a major role in these sex differences in anxiety.