Circuit Mechanisms Governing the Default Mode Network

项目总结 无创功能磁共振成像(FMRI)使我们的 对宏观脑功能网络的理解。然而，当前功能磁共振成像的固有限制 人类的方法论限制了我们探索这些网络背后的机制的能力。这个 这个项目的首要目标是阐明 默认模式网络(DMN)的功能组织--这是一个至关重要的大规模大脑网络 行为的范围很广。虽然在啮齿动物身上的新技术允许我们在实验中揭示 DMN的因果控制，啮齿动物DMN拓扑结构仅使用静息状态fMRI定义，而不是 在功能上激活或抑制大脑活动，以响应行为相关 显著的刺激。这是一个严重的障碍，阻碍了在 啮齿动物和人类DMN的研究成果。为了解决这个问题，我们开发了一种新型的无声零回声- Time(中兴通讯)fMRI技术，支持清醒的啮齿动物成像和使用听觉怪胎 范式，其中在一系列重复的控制刺激中出现异常奇怪的刺激 可以引起注意并抑制DMN。我们还开发了一种与MR兼容的四通道 光谱分辨光纤光度测量系统，允许同时记录地面真实神经元 在功能磁共振成像期间的活动。为了阐明管理DMN的电路机制，我们提出了 两个相辅相成的研究目的是建立在我们严格的先前研究的基础上。在目标1中，我们将确定 使用新的中兴通讯光度法研究对显著刺激的关注如何改变DMN的活性和连接性 站台。在目标2中，我们将介绍定义细胞类型的时间锁定光遗传学 操纵前脑岛的活动--被认为负责DMN动态变化的大脑区域 切换到大量的fMRI因果建模研究中。啮齿动物DMN的功能解剖 体系结构对于理解DMN过渡机制至关重要，这将使我们能够 因果建模，并对大脑状态进行预测，深入了解 人类行为和神经精神/神经紊乱。 1

PROJECT SUMMARY Non-invasive functional magnetic resonance imaging (fMRI) has revolutionized our understanding of macroscopic functional brain networks. However, inherent constraints of current fMRI methodologies in humans limit our ability to probe the mechanisms underlying these networks. The overarching goal of this project is to shed light on cellular and circuit mechanisms underlying the functional organization of the default-mode network (DMN) – a large-scale brain network that is crucial for a wide range of behaviors. While the new technologies in rodents allows us to experimentally reveal causal control of DMN, rodent DMN topology has only been defined using resting-state fMRI, but not functionally in terms of activation or suppression of brain activity in response to behaviorally relevant salient stimuli. This represents a critical barrier preventing any straightforward translation between rodent and human DMN research findings. To address this, we developed a novel silent zero-echo- time (ZTE) fMRI technique, enabling awake rodent imaging and the use of an auditory oddball paradigm, wherein deviant oddball stimuli presented amongst a sequence of repetitive control stimuli can drive attention and suppress DMN. We also developed an MR-compatible, four-channel, spectrally-resolved fiber-photometry system, allowing concurrent recording of ground-truth neuronal activities during fMRI. To shed light on the circuit mechanisms governing the DMN, we proposed two complementary research Aims building on our rigorous prior research. In Aim 1, we will determine how attention to salient stimuli alters DMN activity and connectivity using the novel ZTE-photometry platform. In Aim 2, we will introduce time-locked optogenetics on defined cell types to causally manipulate the activity of anterior insula – the brain region assumed to be responsible for DMN dynamic switching in numerous fMRI causal modeling studies. Functionally dissecting the rodent DMN architecture is critical to the understanding of DMN transition mechanisms, which will enable us to causally model, and make predictions about brain states, bringing insight into the network basis of human behavior and neuropsychiatric/neurological disorders. 1