Neural circuits regulating brain-wide effects of oxytocin neurons

项目总结(项目4，合作项目：Buzsaki，Froemke，Lin，Tsien) 催产素(OXT)在中枢神经系统中的时空调节尚不清楚，而且 对下游目标和上游调控机制的作用了解较少，尤其是比较 传给其他调制器。在这里，我们测量来自下一代调制式抓取传感器的信号。我们的试点数据 确定了OXT水平在公开的清醒行为和睡眠期间都有很大的波动，达到了 至少在快速眼动睡眠期间。因此，oxt的释放不仅发生在社交行为中，而且发生在其他上下文中，如 井。因此，项目4的目标是研究a)OXT神经元是如何受到上游大脑区域的调节的， 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。我们会 还将其作用与一种特性良好的神经调节剂乙酰胆碱(ACh)联系起来，并阐述了人工 (“病理性”)睡眠时OXT和特定回路模式之间的耦合会影响清醒的社会行为。 在第一组实验中，我们将识别亚型的独立于范式的生理特征 并将其与特定范式(例如，父母行为、社会等级)行为联系起来。 潜在的OXT亚型(用分子工具核心通过交叉点生成的鼠线进行评估 方法)将通过生理和大脑状态依赖的特征从光遗传学上确定。 利用大规模电生理方法，我们将建立脑电活动模式之间的关系 OXT神经元类型和在海马体、丘脑和新皮质中的特征种群模式。反过来, 这些特征的放电模式将有助于联系在社交互动中观察到的它们的尖峰活动 和产妇护理。第二组实验致力于揭示oxt神经元的不同影响。 室旁核和视上核对其靶电路模式的影响，并将这些影响与 一个不同的调制器(这里是ACH)。我们将研究神经调节对关键海马区的影响 (Theta、Gamma、锐波纹波)和新皮质(Gamma、向上-向下状态)网络模式和 地区性沟通。我们还将建立OXT和OXT之间依赖于状态的时态关系 哎呀。最后一组实验将人为地改变REM和非REM之间的时间关系 海马体和OXT释放的模式。这些实验的目标是了解如何潜在地 在动物之间的长期互动中，社会学习和记忆可能需要睡眠模式， 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。 综上所述，本项目旨在发现OXT的网络控制及其对电路的影响，并比较 OXT信号的非社会性和社会性的条件和回路机制。这是一个 在核心的支持下，跨四个主要绩效指标的实验室开展协作工作。我们的合作增加了 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.