Oxytocin Modulation of Neural Circuit Function and Behavior - Revision - 3

催产素对神经回路功能和行为的调节 - 修订版 - 3

• 批准号: 10601831
• 负责人: RICHARD W TSIEN
• 金额: $ 9.8万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601831
• 关键词: Address; Adult; Animals; Antibodies; Area; Auditory area; Behavior; Behavioral; Brain; Child; Child Care; Child Rearing; Childbirth; Data; Foundations; Hippocampus (Brain); Hormones; Human; Hypothalamic structure; Interdisciplinary Study; Knowledge; Literature; Longevity; Maternal Behavior; Mental disorders; Molecular; Monitor; Mothers; Mus; Neuraxis; Neuropeptides; Oxytocin; Oxytocin Receptor; Parents; Performance; Physiological; Reporting; Reproduction; Research Personnel; Retrieval; Signal Transduction; Social Behavior; Social Environment; Social Interaction; Structure; System; Therapeutic; Trust; autism spectrum disorder; comparative; experience; experimental study; gain of function; improved; information processing; interest; loss of function; neglect; neural circuit; optogenetics; peptide hormone; pup; receptor; receptor expression; social; social cognition; social deficits; treatment strategy

Project Summary Oxytocin is a peptide hormone synthesized and released from the hypothalamus for reproduction and maternal behavior. Recent studies have tagged oxytocin as a “trust” hormone, promising to improve social deficits in various mental disorders, such as autism. Despite the enthusiasm for oxytocin, contradictory results in the efficacy of oxytocin in improving human social behaviors have been reported. Such inconsistency in literature is likely due to our poor understanding of complexity of oxytocin action, which likely varies with behavioral state, experience and brain structures. We believe that a better understanding of the endogenous action of oxytocin is the key to unleash the therapeutic potential of this highly evolutionary conserved neuropeptide. Advancing our understanding requires cross-level and comparative inter-disciplinary studies by an group of investigators with overlapping interests and the technical capability to analyze oxytocin signaling across molecular, physiological, systems behavioral and levels. This includes multi-animal interactions, as many mental disorders are impactful on social behavior, over the lifespan and throughout the brain. Oxytocin action in maternal brain is especially important as it represents the most ancient and important function of oxytocin under a social context. Here we will address this critical knowledge gap. Recently, we generated the first specific antibodies to the mouse oxytocin receptor, used these antibodies to determine where these receptors are localized, and examined how oxytocin can enable pup retrieval behavior in maternal mice. Those previous studies provide a robust foundation for the current Project, in which our team aims to understand which target neural circuits are modulated by oxytocin, and if there are behavioral episodes that might be sensitive to oxytocin modulation during brief periods of social interaction. The central hypothesis is that oxytocin is absolutely necessary to initiate maternal behaviors in key areas including auditory cortex and hippocampus, but may be dispensable in experienced mothers. We will perform behavioral, optogenetic, and circuit mapping studies in adult mice to determine where and when oxytocin modulates neural circuits to enhance social information processing and subsequently improve maternal behavior. In Aim 1 we will build a new behavioral recording system to continuously monitor social interactions for days to weeks. In Aim 2, we profile oxytocin projections and oxytocin receptor expression throughout the entire adult brain to find potential hotspots of modulation. Finally in Aims 3 and 4, we perform optogenetic loss-of-function and gain-of-function type experiments to determine where and when oxytocin modulation is needed for maternal behavior or at what points might additional oxytocin release accelerate maternal behavior onset or improve steady-state performance.

项目摘要 催产素是一种由下丘脑合成和释放的肽类激素，用于生殖和母体 行为最近的研究将催产素标记为“信任”激素，有望改善社交缺陷， 各种精神疾病，如自闭症。尽管人们对催产素很感兴趣， 已经报道了催产素在改善人类社会行为中的功效。文学中的这种矛盾是 这可能是由于我们对催产素作用的复杂性理解不足，催产素作用可能随行为状态而变化， 经验和大脑结构。我们相信，更好地理解催产素的内源性作用是 释放这种高度进化保守的神经肽的治疗潜力的关键。推进我们 理解需要一组调查人员进行跨层次和跨学科的比较研究， 重叠的兴趣和技术能力，分析催产素信号在分子，生理， 系统行为和水平。这包括多动物的相互作用，因为许多精神障碍是有影响的 对社会行为的影响，在整个生命周期和整个大脑中。催产素在母体大脑中的作用尤其 因为它代表了催产素在社会背景下最古老和最重要的功能。 在这里，我们将解决这一关键的知识差距。最近，我们产生了第一个特异性抗体， 小鼠催产素受体，使用这些抗体来确定这些受体的定位， 研究了催产素是如何使母鼠的幼崽恢复行为的。这些先前的研究提供了一个 为当前项目奠定了坚实的基础，我们的团队旨在了解哪些目标神经回路是 如果有行为事件可能对催产素调制敏感， 短暂的社会交往。中心假设是催产素对于启动是绝对必要的 母亲的行为在关键区域，包括听觉皮层和海马体，但可能被忽视， 经验丰富的母亲我们将在成年小鼠中进行行为、光遗传学和电路映射研究， 确定催产素在何时何地调节神经回路以增强社会信息处理， 从而改善母性行为。在目标1中，我们将建立一个新的行为记录系统， 持续数天至数周监控社交互动。在目标2中，我们分析了催产素投射和催产素 受体表达在整个成人大脑中，以找到潜在的热点调制。最后，目标3 和4，我们进行了光遗传学功能丧失和功能获得型实验，以确定其中和 当母性行为需要催产素调节时，或者在什么时候额外的催产素会释放 加速母性行为发作或改善稳态性能。