Oxytocin modulation of a distributed neural circuit for maternal behavior

项目摘要（项目 1，联合负责人：Froemke、Lin、Buzsaki） 催产素是一种对社会行为很重要的神经肽，例如母性护理和伴侣关系。现在是 相信轴突催产素直接释放到各个前脑目标对于社会行为至关重要，但它 目前尚不清楚何时何地需要催产素调节来增强社会信息处理和 规范母亲的行为。催产素对于哺乳至关重要，但尚不清楚产妇的其他方面 母亲或无关的共同照顾动物的行为取决于催产素系统。催产素给药 也可能在临床上有希望，改善自闭症谱系障碍、社交焦虑和后遗症的结果 产妇抑郁症。然而，必须了解功能解剖学和全脑神经 催产素影响行为变化的电路，包括何时释放催产素，以及是否 催产素调节存在差异，具体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。 总之，在这里我们将研究社会互动和母亲行为的出现 使用我们将建立的新行为监测系统，在多只动物共同饲养期间自然表达。 然后，我们将使用该系统来确定何时何地需要催产素调节以及最有效的调节 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.