Sex Differences In Anxiety: Role of Zif268

描述(申请人提供)：这项建议的目的是调查社会互动行为的性别差异，并研究内侧前额叶皮质(MPFC)中的即刻早期基因Zif268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Zif268基因上游和下游与社会交往中性别差异相关的分子靶点。我们的初步数据显示，无论发情周期如何，雄性大鼠表现出比雌性大鼠更高的社交互动(SI)。有趣的是，Zif268在内侧前额叶皮质(MPFC)的基础表达在性别之间存在差异，因为与女性相比，男性在该区域的Zif268表达水平更高。通过使用Zif268反义寡核苷酸(Zif268 ASO)诱导雄性大鼠mPFC中Zif268表达的暂时下调，并比较其SI行为与注入Zif268错义寡核苷酸(Zif268 MSO)的雄性和雌性大鼠的SI行为。通过这样做，我们发现Zif268 ASO雄性比对照雄性表现出明显更少的SI(因此，更焦虑)，事实上，表现出与对照雌性相似的SI水平。本质上，下调雄性大鼠mPFC中Zif268的表达消除了以前在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中性二态Zif268的表达是在SI测试中调节性别特定焦虑样行为的关键分子因素，SI测试具有很强的社会成分。在这一应用中，我们将进一步探索这一假设，即内侧前额叶皮质的Zif268在决定社会互动中的性别差异方面发挥着重要作用，并确定在焦虑中发挥这些性别差异的mPFC中Zif268的上游和下游靶点。 公共卫生相关性：这项建议的目的是调查社会互动行为的性别差异，并研究内侧前额叶皮质(MPFC)中的即刻早期基因Zif268在调节雄性和雌性大鼠的这些行为中的作用。我们的初步数据表明Zif268与焦虑的性别差异有关，并导致我们假设在mPFC中性别二态的Zif268表达是调节性别特异性焦虑的关键分子因素。在这一应用中，我们将进一步探索这一假设，即内侧前额叶皮质的Zif268在决定焦虑的性别差异中发挥重要作用，并确定在焦虑的性别差异中发挥主要作用的mPFC中Zif268的上游和下游靶点。

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. PUBLIC HEALTH RELEVANCE: 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. Our preliminary data implicate zif268 in sex differences in anxiety and led us to hypothesize that sexually-dimorphic zif268 expression in the mPFC is a key molecular factor in mediating sex-specific anxiety. 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 anxiety and determine the upstream and downstream targets of zif268 in the mPFC that play a major role in these sex differences in anxiety.