Environmental regulation of estrogen dependent aggression

雌激素依赖性攻击行为的环境调节

• 批准号: 8079858
• 负责人: BRIAN C TRAINOR
• 金额: $ 0.92万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079858
• 关键词: Affect; Aggressive behavior; Animals; Automobile Driving; Behavior; Behavioral; Bipolar Disorder; Borderline Personality Disorder; Brain; Brain region; California; Cell Nucleus; Cells; Clinical Trials; Complex; Cyclic AMP-Responsive DNA-Binding Protein; Cycloheximide; Cytoplasm; Data; Environment; Estradiol; Estrogen Receptors; Estrogens; Extracellular Signal Regulated Kinases; Feedback; Gene Expression; Genetic Transcription; Genomics; Gonadal Hormones; Gonadotropin Hormone Releasing Hormone; Hippocampus (Brain); Hormones; House mice; Human; Hypothalamic structure; Immunohistochemistry; Injection of therapeutic agent; Light; Measurement; Mediating; Melatonin; Membrane; Memory; Mental disorders; Modeling; Molecular; Mus; Ovulation; Pathway interactions; Pattern; Peripheral; Peromyscus; Phase; Phosphorylation; Photoperiod; Process; Protein Synthesis Inhibitors; Receptor Signaling; Regulation; Reproduction; Research; Research Personnel; Schizophrenia; Signal Pathway; Social Interaction; Stream; Testing; Time; Western Blotting; Woman; base; dimer; gene environment interaction; insight; male; men; non-genomic; public health relevance; receptor; response; steroid hormone

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.

描述（由申请人提供）：雌激素会影响大脑中的各种过程以及行为的许多方面，包括社交互动，繁殖和记忆。多种雌激素受体（ER）和信号通路构成了一个复杂的调节网络，该网络会产生有趣的功能可塑性例子。例如，在排卵时，雌激素从对促性腺激素释放激素的负反馈转换为发挥阳性反馈。负反馈部分是通过雌激素的快速作用非原始组作用来介导的，而正反馈则取决于雌激素的持续增加，显然会导致基因表达的变化。关于peromyscus的最新研究确定了男性行为的相似模式。雌激素会在长时间内（16L：8D）内降低侵略行为，但在短天（8L：16d）内增加了侵略性行为。这种功能可塑性似乎是由ERS下游效应的基本变化介导的。在漫长的日子里，激素的操作仅在10天后就会影响行为。微阵列分析表明，与短日相比，在漫长的几天内，雌激素调节的转录增加了。这表明雌激素可以通过驱动转录来降低侵略性。在短时间内的雌二醇注射量在15分钟内增加了攻击性，这表明这些作用是由非根源途径介导的。该提案由新研究者提交，研究了光周期如何调节雌激素对侵略性的影响。使用侵略行为的行为，细胞和分子分析，我们概述了不同环境如何在雌激素调节行为中诱导功能可塑性。失调的侵略是精神障碍的组成部分，包括躁郁症，精神分裂症和边缘性人格障碍。相关和临床试验数据表明，雌激素会影响男性和女性的侵略行为。但是，几乎所有研究雌激素对人类行为的影响的研究都利用外周激素的操纵或测量。越来越多的理解是，在下丘脑和海马等大脑区域中，类固醇激素是从头合成的。最近的数据表明，大脑中的雌激素合成是通过瞬间的社会相互作用调节的。这强烈表明，在大脑中合成的雌激素的快速作用对于行为至关重要。这些观察结果要求我们重新评估我们如何看待人类中的雌激素与行为之间的关系，因为绝大多数人类研究仅考虑源自性腺激素的雌激素。在我们的研究中，我们可以仅通过操纵光周期来研究攻击的慢速（基因组）和快速（非原始体）机制，从而为我们提供了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差异作用是由基因组和非基因组激活的差异介导的。在第一个具体目的中，我们将确认雌激素是否通过非牙科作用来增加侵略性。在第二个特定目的中，我们将使用免疫组织化学和蛋白质印迹来识别细胞内信号传导途径，这些途径可以介导雌激素对侵略性的快速影响。最后，我们将使用激素操纵和实时PCR来测试褪黑激素是否抑制脑中雌激素依赖性基因表达，从而阻断短时小鼠的基因组作用。拟议的研究将确定涉及调节侵略性的细胞内信号传导途径，并应为制定管理夸张的侵略行为的新策略提供见解。 公共卫生相关性：雌激素会影响大脑中的各种过程以及行为的许多方面，包括社交互动，繁殖和记忆。一只雄性加利福尼亚小鼠每天暴露的光量决定了雌激素是增加还是减少侵略性。拟议的研究将研究这种基因环境相互作用的基础的细胞机制，影响与许多精神疾病相关的行为。