Oxytocin modulation of a distributed neural circuit for maternal behavior

项目摘要（项目1，共同PI：Froemke、Lin、Buzsaki） 催产素是一种对社会行为很重要的神经肽，如母性关怀和伴侣关系。现在 认为轴突催产素直接释放到各种前脑靶点对社会行为至关重要，但它 尚不清楚催产素调节在何时何地需要增强社会信息处理， 规范母性行为催产素是必不可少的护理，但目前还不清楚其他方面的产妇 母亲或不相关的共同照顾动物的行为取决于催产素系统。催产素给药 也可能是临床上有前途的，改善自闭症谱系障碍，社交焦虑和后 产后抑郁症然而，必须了解功能解剖学和全脑神经系统， 催产素影响行为变化的回路，包括催产素何时释放，以及是否 催产素调节存在差异，这取决于性别或社会背景。 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。核心假设是催产素是启动 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。 总之，在这里，我们将研究社会互动和母性行为的出现， 在多个动物共同圈养期间自然表达，使用我们将建立的新行为监测系统。 然后，我们将使用这个系统来确定何时何地需要催产素调节，并且最有效 促进亲社会互动和儿童保育。

Project Summary (Project 1, Co-PIs: Froemke, Lin, Buzsaki) Oxytocin is a neuropeptide important for social behavior, such as maternal care and pair bonding. It is now believed that direct axonal oxytocin release into various forebrain targets is critical for social behavior, but it remains unclear where and when oxytocin modulation is required to enhance social information processing and regulate maternal behavior. Oxytocin is essential for nursing, but it is unclear what other aspects of maternal behavior by mothers or unrelated co-caring animals depend on the oxytocin system. Oxytocin administration might also be clinically promising, improving outcomes in autism spectrum disorders, social anxiety, and post- partum depression. However, it is imperative to understand the functional anatomy and whole-brain neural circuitry by which oxytocin affects behavioral changes, including when oxytocin might be released, and whether there are differences in oxytocin modulation that depend on gender or 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. In summary, here we will study the emergence of social interactions and maternal behaviors as they are naturally expressed during multiple animal co-housing, using a new behavioral monitoring systems we will build. We will then use this system to determine when and where oxytocin modulation is required and most effective at promoting pro-social interactions and child care.