Circuit Mechanisms Governing the Default Mode Network

项目摘要 非侵入性功能磁共振成像（fMRI）彻底改变了我们的 理解宏观的大脑功能网络。然而，当前功能磁共振成像的固有限制 在人类中的方法限制了我们探测这些网络背后的机制的能力。的 这个项目的首要目标是阐明细胞和电路机制的基础上， 默认模式网络（DMN）的功能组织-一个大规模的大脑网络， for a wide宽range范围of behaviors行为.在啮齿类动物身上的新技术让我们可以通过实验揭示 DMN的因果控制，啮齿动物DMN拓扑结构仅使用静息态fMRI定义，但没有 在功能上，在响应行为相关的大脑活动的激活或抑制方面， 显著刺激这是一个关键的障碍，阻止了任何直接的翻译之间 啮齿动物和人类DMN研究结果。为了解决这个问题，我们开发了一种新型的无声零回声- 时间（中兴通讯）功能磁共振成像技术，使清醒的啮齿动物成像和使用的听觉oddball 范例，其中在一系列重复控制刺激中呈现异常的古怪刺激 可以吸引注意力并抑制DMN我们还开发了一种兼容MR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 功能磁共振成像中的活动为了阐明控制DMN的电路机制，我们提出了 两个互补的研究目标建立在我们严格的先前研究。在目标1中，我们将确定 使用新的ZTE光度法如何注意显著刺激改变DMN活动和连接 平台在目标2中，我们将在定义的细胞类型上引入时间锁定的光遗传学， 操纵前额叶的活动--被认为负责DMN动态的大脑区域 在众多的fMRI因果建模研究中切换。啮齿动物DMN的功能解剖 架构对于理解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，从而深入了解大脑的网络基础。 人类行为和神经精神/神经障碍。 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