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.

项目概要 催产素是一种肽激素，由下丘脑合成并释放，用于生殖和母体 行为。最近的研究将催产素标记为一种“信任”激素，有望改善社会缺陷 各种精神障碍，例如自闭症。尽管人们对催产素充满热情，但研究结果却相互矛盾 催产素在改善人类社会行为方面的功效已有报道。文学中的这种矛盾是 可能是由于我们对催产素作用的复杂性了解甚少，而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，更好地了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。推进我们的 理解需要一组研究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来分析分子、生理、 系统行为和级别。这包括多动物互动，因为许多精神障碍都会产生影响 影响整个生命周期和整个大脑的社会行为。催产素对母体大脑的作用尤其明显 重要的是，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位置，以及 研究了催产素如何使母鼠恢复幼崽行为。之前的那些研究提供了 当前项目的坚实基础，我们的团队旨在了解哪些目标神经回路 受催产素调节，并且在治疗期间是否存在可能对催产素调节敏感的行为发作 短暂的社交互动。中心假设是催产素对于启动 包括听觉皮层和海马体在内的关键区域的母亲行为，但在以下区域可能是可有可无的： 有经验的妈妈们。我们将对成年小鼠进行行为、光遗传学和电路图谱研究，以 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和 随后改善母亲的行为。在目标 1 中，我们将建立一个新的行为记录系统 持续监控社交互动数天至数周。在目标 2 中，我们分析了催产素预测和催产素 整个成人大脑中的受体表达，以找到潜在的调节热点。终于进入目标3 4，我们进行光遗传学功能丧失和功能获得类型的实验，以确定在哪里和 当母亲行为需要催产素调节时，或者在什么时候可能会额外释放催产素 加速母亲行为的发生或改善稳态表现。