Neural circuits regulating brain-wide effects of oxytocin neurons

项目摘要（项目4，共同PI：Buzsaki、Froemke、Lin、Tsien） 中枢神经系统中催产素（OXT）调节的时空尺度尚不清楚， 对下游目标和上游控制机制的作用了解甚少，特别是与 其他调制器。在这里，我们测量来自下一代调制GRAB传感器的信号。我们的试点数据 确定OXT水平在明显的清醒行为和睡眠期间波动很大， 在REM睡眠期间最少。因此，OXT的释放不仅发生在社会行为中，也发生在其他环境中， 好.因此，项目4的目标是问a）OXT神经元如何受到上游脑区的调节， 涉及各种行为，以及B）OXT如何影响目标区域中的特定网络计算。我们将 还将其作用与一种特征明显的神经调节剂乙酰胆碱（ACh）联系起来，并讨论了人工 睡眠期间OXT和特定电路模式之间的（“病理性”）耦合影响清醒时的社会行为。 在第一组实验中，我们将确定亚型的范式独立生理特征， 并将它们与范式特异性（例如，父母行为，社会等级）行为。 潜在的OXT亚型（使用由Molecular Tools Core通过交叉切片生成的小鼠系进行评估） 方法）将通过生理学和脑状态依赖性表征进行光遗传学鉴定。 使用大规模的电生理学方法，我们将建立放电模式之间的关系， 海马、丘脑和新皮质中的OXT神经元类型和特征性群体模式。反过来， 这些特征化的放电模式将用于将它们在社会互动期间观察到的尖峰活动 和母性关怀。第二组实验致力于揭示OXT神经元的差异影响 在室旁核和视上核的靶电路模式，并比较这些影响的那些 一种不同的调节剂（这里是乙酰胆碱）。我们将研究神经调节对临界海马的影响， （theta，gamma，尖波波纹）和新皮层（gamma，上下状态）网络模式和内部 区域沟通。我们还将建立OXT和 啊。最后一组实验将人为地改变快速眼动和非快速眼动之间的时间关系 海马体和OXT释放的模式。这些实验的目的是为了了解 睡眠模式可能是动物之间长期互动的社会学习和记忆所必需的， 以及这些机制的特定扰动是否会影响清醒动物随后的社会行为。 总之，本项目旨在发现OXT的网络控制及其对电路的影响，并比较 区分OXT信号传导的非社会性与社会性方面的条件和电路机制。这是一 在核心的支持下，四个PI的实验室之间的合作努力。我们的合作不断增加 提高生产力，并保证对参与这些项目的学生和博士后进行跨学科培训。

Project Summary (Project 4, Co-PIs: Buzsaki, Froemke, Lin, Tsien) The spatiotemporal scales of oxytocin (OXT) modulation in the central nervous system remain unclear, and the actions on downstream targets and mechanisms of upstream control are poorly understood especially compared to other modulators. Here we measure signals from next-generation modulatory GRAB sensors. Our pilot data established that OXT levels fluctuate extensively during both overt waking behaviors and sleep, reaching its minimum during REM sleep. Thus OXT release occurs not only during social behaviors but in other contexts as well. Therefore, the goal of Project 4 is to ask how a) OXT neurons are regulated by upstream brain regions, involved in a variety of behaviors, and how b) OXT affects specific network computations in target areas. We will also relate its actions to a well-characterized neuromodulator, acetylcholine (ACh) and address how artificial (“pathological”) coupling between OXT and specific circuit patterns during sleep impacts waking social behavior. In the first set of experiments, we will identify paradigm-independent physiological features of subtypes of OXT neurons and relate them to paradigm-specific (e.g., parental behavior, social hierarchy) behaviors. Potential OXT subtypes (assessed with mouse lines generated by the Molecular Tools Core via intersectional approaches) will be identified optogenetically, with by physiological and brain state-dependent characterization. Using large-scale electrophysiological methods, we will establish the relationship between the firing patterns of OXT neuron types and characteristic population patterns in the hippocampus, thalamus and neocortex. In turn, these characterized firing patterns will serve to relate their spiking activity observed during social interactions and maternal care. The second set of experiments are devoted to reveal the differential impact of OXT neurons in the paraventricular and supraoptic nuclei on their target circuit patterns and compare these effects to those of a different modulator (here, ACh). We will examine the influence of neuromodulation on critical hippocampal (theta, gamma, sharp wave ripples) and neocortical (gamma, UP-DOWN states) network patterns and inter- regional communication. We will also establish the state-dependent temporal relationships between OXT and ACh. The final set of experiments will artificially alter the temporal relationship between REM and non-REM patterns in the hippocampus and OXT release. The goal of these experiments is to gain knowledge how potential sleep patterns might be required for social learning and memory over extended interactions between animals, and if specific perturbations of these mechanisms impact subsequent social behavior in the waking animal. In sum, this project aims to discover the network control of OXT and its impact on circuits, and compare the conditions and circuit mechanisms distinguishing non-social vs social aspects of OXT signaling. This is a collaborative effort across laboratories of the four PIs, supported by the Cores. Our collaboration increases productivity and guarantees interdisciplinary training of students and postdocs participating in these projects.