Environmental regulation of estrogen dependent aggression

描述（由申请人提供）：雌激素影响大脑中的各种过程和行为的许多方面，包括社会交往，生殖和记忆。各种雌激素受体（ER）和信号通路组成了一个复杂的调节网络，产生了有趣的功能可塑性的例子。例如，在排卵期，雌激素从对促性腺激素释放激素施加负反馈转变为施加正反馈。负反馈部分由雌激素的快速作用的非基因组效应介导，而正反馈依赖于雌激素的持续增加，这显然驱动基因表达的变化。最近对Peromyscus的研究发现了一种类似的雄性行为模式。雌激素减少长日照（16 L：8 D）小鼠的攻击行为，但增加短日照（8 L：16 D）小鼠的攻击行为。这种功能可塑性似乎是介导的ER的下游效应的根本变化。在漫长的日子里，激素的操纵只会在10天后影响行为。微阵列分析显示，与短日照相比，长日照下大脑中雌激素调节的转录增加。这表明雌激素可能通过驱动转录来降低攻击性。在短时间内，雌二醇注射在15分钟内增加了攻击性，这表明这些作用是由非基因组途径介导的。这项提案由一位新的研究者提交，研究了光周期如何调节雌激素对攻击性的影响。使用行为，细胞和分子分析的侵略行为，我们概述了如何不同的环境可以诱导功能可塑性雌激素调节的行为。攻击性失调是包括双相情感障碍、精神分裂症和边缘型人格障碍在内的精神障碍的一个组成部分。相关和临床试验数据表明，雌激素影响男性和女性的攻击行为。然而，几乎所有研究雌激素对人类行为的影响，利用外周激素的操作或测量。越来越多的人认识到类固醇激素是在下丘脑和海马体等大脑区域重新合成的。最近的数据表明，大脑中雌激素的合成是由社会互动在每时每刻的基础上调节的。这有力地表明，大脑中合成的雌激素的快速作用可能对行为至关重要。这些观察结果要求我们重新评估我们如何看待雌激素和人类行为之间的关系，因为绝大多数人类研究只考虑来自性腺激素的雌激素。在我们的研究中，我们可以简单地通过操纵光周期来研究缓慢（基因组）和快速（非基因组）的攻击机制，这给了我们一个独特的机会来研究雌激素如何与环境相互作用来影响行为。我们假设雌激素对攻击性的不同影响是由基因组和非基因组激活的差异介导的。在第一个具体的目标，我们将确认是否雌激素增加侵略行为的非基因组。在第二个具体的目标，我们将使用免疫组织化学和蛋白质印迹法，以确定细胞内的信号转导途径，可以介导的快速影响雌激素的侵略。最后，我们将使用激素操作和实时PCR来测试褪黑激素是否抑制脑中雌激素依赖性基因的表达，从而阻断短日照小鼠的基因组作用。这项研究将确定参与调节攻击性的细胞内信号通路，并为开发管理夸大攻击性行为的新策略提供见解。 公共卫生相关性：雌激素影响大脑中的各种过程和行为的许多方面，包括社会交往，生殖和记忆。雄性加州小鼠每天暴露在阳光下的量决定了雌激素是增加还是减少攻击性。这项拟议的研究将调查这种基因-环境相互作用的细胞机制，这种相互作用影响与许多精神疾病相关的行为。

DESCRIPTION (provided by applicant): Estrogens affect a wide variety of processes in the brain and many aspects of behavior including social interactions, reproduction, and memory. A variety of estrogen receptors (ER) and signaling pathways make up a complex regulatory network that produces intriguing examples of functional plasticity. For example, at ovulation estrogens switch from exerting negative feedback on gonadotropin releasing hormone to exerting positive feedback. Negative feedback is mediated in part by rapid acting nongenomic effects of estrogens whereas positive feedback relies on a sustained increase in estrogens that apparently drives changes in gene expression. Recent studies on Peromyscus identified a similar pattern for male behavior. Estrogens decrease aggressive behavior in mice housed in long days (16L:8D) but increase aggressive behavior in mice housed in short days (8L:16D). This functional plasticity appears to be mediated by a fundamental change in the down-stream effects of ERs. In long days, hormone manipulations affect behavior only after 10 days. Microarray analyses showed increased estrogen-regulated transcription in the brain under long days compared to short days. This suggests that estrogens may decrease aggression by driving transcription. In short day's estradiol injections increase aggression within 15 minutes, suggesting these effects are mediated by nongenomic pathways. This proposal, submitted by a new investigator, examines how a photoperiod modulates the effects of estrogens on aggression. Using behavioral, cellular, and molecular analyses of aggressive behavior we outline how the different environments can induce functional plasticity in estrogen regulated behavior. Dysregulated aggression is a component of mental disorders including bipolar disorder, schizophrenia, and borderline personality disorder. Correlational and clinical trial data suggest that estrogens affect aggressive behavior in men and women. However, virtually all studies examining the effects of estrogens on human behavior utilize either peripheral hormone manipulations or measurements. There is growing appreciation that steroid hormones are synthesized de novo in brain regions such as the hypothalamus and hippocampus. Recent data show estrogen synthesis in the brain is modulated by social interactions on a moment-to- moment basis. This strongly suggests that rapid actions of estrogens synthesized in the brain may be of critical important for behavior. These observations require us to reassess how we view the relationships between estrogens and behavior in humans, because the vast majority of human studies only consider estrogens derived from gonadal hormones. In our studies we can investigate both slow (genomic) and rapid (nongenomic) mechanisms of aggression simply by manipulating photoperiod, giving us a unique opportunity to examine how estrogens interact with the environment to affect behavior. We hypothesize that the differential effects of estrogens on aggression are mediated by differences in genomic and nongenomic activation. In the first specific aim we will confirm whether estrogens increase aggression by acting nongenomically. In the second specific aim we will use immunohistochemistry and western blots to identify intracellular signaling pathways that could mediate the rapid effects of estrogens on aggression. Finally we will use hormone manipulations and real-time PCR to test whether melatonin inhibits estrogen-dependent gene expression in the brain, thereby blocking genomic action in short-day mice. The proposed research will identify intracellular signaling pathways involved in regulating aggression and should provide insights for developing new strategies for managing exaggerated aggressive behaviors. PUBLIC HEALTH RELEVANCE: Estrogens affect a wide variety of processes in the brain and many aspects of behavior including social interactions, reproduction, and memory. The amount of light a male California mouse is exposed to each day determines whether estrogens increase or decrease aggression. The proposed research will investigate the cellular mechanisms that underlie this gene-environment interaction that affects a behavior associated with many mental disorders.