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，包括社会互动，繁殖和记忆。多种雌激素受体（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，雌激素对促性腺激素释放激素的反馈从负反馈转变为正反馈。负反馈部分是由雌激素的快速非基因组效应介导的，而正反馈依赖于雌激素的持续增加，而雌激素的持续增加显然会驱动基因表达的变化。最近对Peromyscus的研究发现了男性行为的类似模式。雌激素减少了长日饲养小鼠的攻击行为（16L:8D），但增加了短日饲养小鼠的攻击行为（8L:16D）。这种功能可塑性似乎是由内质网下游效应的根本变化所介导的。在漫长的日子里，激素操作只会在10天后影响行为。微阵列分析显示，与短时间相比，长时间的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减少攻击性。在短时间内，雌二醇注射在15分钟内增加攻击性，表明这些影响是由非基因组途径介导的。这个提议，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。通过对攻击行为的行为、细胞和分子分析，我们概述了不同的环境如何诱导雌激素调节行为的功能可塑性。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，几乎所有检查雌激素对人类行为影响的研究都使用外周激素操作或测量。越来越多的人认识到，类固醇激素是在大脑的下丘脑和海马体等区域重新合成的。最近的数据显示，大脑中雌激素的合成是由每时每刻的社会互动所调节的。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与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慢速（基因组）和快速（非基因组）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以影响行为。我们假设雌激素对攻击的不同影响是由基因组和非基因组激活的差异介导的。在第一个具体目标中，我们将确认雌激素是否通过非基因组作用增加攻击性。在第二个特定目标中，我们将使用免疫组织化学和western blots来识别可能介导雌激素对攻击的快速作用的细胞内信号通路。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大脑中雌激素依赖基因的表达，从而阻断短日小鼠的基因组作用。该研究将确定参与调节攻击的细胞内信号通路，并为开发管理夸大攻击行为的新策略提供见解。

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.