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

项目摘要 催产素是一种从下丘脑合成和释放的多肽激素，用于生殖和母体 行为。最近的研究表明，催产素是一种“信任”荷尔蒙，有望改善老年人的社会缺陷 各种精神障碍，如自闭症。尽管人们对催产素充满热情，但矛盾的结果是 催产素在改善人类社会行为方面的疗效已有报道。文学中的这种不一致是 可能是因为我们对催产素作用的复杂性缺乏了解，催产素的作用可能会随着行为状态的不同而变化， 经验和大脑结构。我们认为，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。推进我们的 理解需要由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，以跨分子，生理， 系统行为和级别。这包括多种动物之间的相互作用，因为许多精神障碍是有影响的。 在整个生命周期和整个大脑中对社会行为的影响。催产素在母体大脑中的作用尤其明显 这很重要，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，我们研制出了第一批特异性抗体 小鼠催产素受体使用这些抗体来确定这些受体的定位，并 研究了催产素如何能够使母鼠的幼崽取回行为。这些先前的研究提供了一种 为当前项目奠定了坚实的基础，在该项目中，我们的团队旨在了解哪些目标神经回路 是否存在可能对催产素调节敏感的行为事件 短暂的社会互动阶段。中心假设是催产素是启动 母亲在关键区域的行为，包括听觉皮质和海马体，但在 经验丰富的母亲。我们将在成年小鼠身上进行行为、光遗传学和电路映射研究，以 确定催产素何时何地调节神经回路，以增强社会信息处理和 随之而来的是改善产妇行为。在目标1中，我们将构建一个新的行为记录系统来 持续监控几天到几周的社交互动。在目标2中，我们分析了催产素投射和催产素 受体在整个成人大脑中的表达，寻找潜在的调制热点。《终极目标3》 和4，我们进行光遗传功能损失和功能增益型实验，以确定在哪里和 何时需要对母亲的行为进行催产素调节，或者在什么时候可能会额外释放催产素 加速母亲行为的开始或改善稳定状态下的表现。

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.