Sex Differences In Anxiety: Role of Zif268

描述（由申请人提供）：本提案的目的是研究雄性和雌性大鼠社会互动行为的性别差异，并研究内侧前额叶皮层（mPFC）中的即时早期基因zif268在调节这些行为中的作用。本研究的另一个重点是确定与社会交往中性别差异相关的zif268的上下游分子靶点。我们的初步数据表明，无论其发情周期如何，雄性大鼠比雌性大鼠表现出更高的社会互动（SI）。有趣的是，zif268在内侧前额叶皮层（mPFC）的基础表达在性别之间存在差异，男性在该区域的zif268表达水平高于女性。通过使用zif268反义寡脱氧核苷酸（zif268 ASO），我们诱导了雄性大鼠mPFC中zif268表达的暂时下调，并比较了注入zif268错义寡脱氧核苷酸（zif268 MSO）的对照雄性和雌性大鼠的SI行为。通过这样做，我们发现zif268 ASO男性的SI明显低于对照组男性（因此，他们更焦虑），事实上，他们的SI水平与对照组女性相似。实质上，雄性大鼠mPFC中zif268表达的下调消除了先前在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中性别二态的zif268表达是SI测试中介导性别特异性焦虑样行为的关键分子因素，这种行为具有很强的社会成分。在这个应用中，我们想进一步探索内侧前额叶皮层的zif268在决定社会互动的性别差异中起主要作用的假设，并确定mPFC中zif268的上游和下游靶点在焦虑的性别差异中起主要作用。

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.