Analysis of Integrated Brain Functions Using Hemogenetic Imaging

使用血遗传学成像分析大脑的综合功能

• 批准号: 10553193
• 负责人: Alan Jasanoff
• 金额: $ 55.7万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553193
• 关键词: Address; Animals; Autopsy; Behavior; Biological Models; Biology; Blood flow; Brain; Brain imaging; Brain region; Calcium; Cells; Data; Detection; Disadvantaged; Elements; Family; Feedback; Fluorescence; Foundations; Functional Imaging; Functional Magnetic Resonance Imaging; Future; Gene Expression; Genetic; Human; Image; Injections; Investigation; Label; Lead; Maps; Measurement; Measures; Methods; Modeling; Molecular; Molecular Probes; Monitor; Neurons; Neurophysiology - biologic function; Neurosciences; Organ; Organism; Output; Pathway interactions; Performance; Peripheral; Population; Process; Property; Rattus; Reporter; Reporter Genes; Research; Research Personnel; Rest; Rewards; Rodent; Role; Sensory; Signal Transduction; Somatosensory Cortex; Source; Specificity; Structure; System; Techniques; Technology; Thalamic Nuclei; Time; Tracer; Viral; Viral Vector; cell type; experience; experimental study; hemodynamics; imaging modality; improved; insight; neural; neural circuit; neuroimaging; neuroregulation; neurovascular coupling; new technology; non-invasive imaging; novel therapeutics; personalized approach; pharmacologic; premonitory sensory phenomena; promoter; response; sensory input; sensory stimulus; somatosensory; spatiotemporal; stimulus processing; tool; ultra high resolution; ultrasound

Hemodynamic neuroimaging methods like functional magnetic resonance imaging (fMRI) have revolution- ized neuroscience by allowing researchers to characterize spatiotemporal features of brain-wide activity in hu- mans and animals. A major disadvantage of such approaches, however, is their lack of specificity for well-defined cellular and molecular sources; this limits their ability to yield explanatory insights into neural function. To address this problem, we recently developed an unprecedented family of genetically encodable molecular probes, called NOSTICs, that transduce intracellular calcium activity into artificial hemodynamic responses, permitting spatially comprehensive neuroimaging of genetically targeted cells and circuit elements. Hemogenetic signals arising from the NOSTICs may be differentiated from endogenous blood flow changes by pharmacological means and can be detected by any hemodynamic imaging modality. Our preliminary experiments indicate that cell-specific activity of even sparse neuronal populations can be identified using hemogenetic fMRI. These capabilities will enable hemogenetic imaging to confront some of the most outstanding problems in neuroscience, such as de- scribing functional properties of discrete cell populations on a brain-wide scale, defining input-output relation- ships among interacting brain regions and neural circuit components, and relating behavior and activity to plas- ticity and gene expression changes that occur throughout the brain. In this project, we will use hemogenetic imaging to address each of these broad problems in the context of sensory function in rodents, while at the same time refining the technology and laying a foundation for its wider application to many research topics and model systems in neuroscience. In Aim 1, we propose to use the technology for investigation of network-level processing in the somatosen- sory system. Anticipated results will inform a first-of-its-kind model of multiregional stimulus processing that con- stitutes a data-driven alternative to traditional correlative functional connectivity measures. We will use this model to examine the importance of feedback relationships and to help explain the phenomena of sensory adaptation and salience encoding at the network level. In Aim 2, we will exploit this capability by applying NOSTIC probes for genetically targeted fMRI of excitatory and inhibitory neural subtypes during forepaw stimulation and resting state dynamics in rats, addressing hypotheses about the functional roles of the different cell types. In addition, we will apply ultrahigh resolution fMRI to examine the relationships between single vessel-level hemodynamics and the cell type-specific distributions of NOSTIC expression, enabling a rich analysis that simultaneously in- forms interpretation of conventional fMRI results and rigorously characterizes performance of the hemogenetic technique itself. In Aim 3, we propose to improve the NOSTIC reporters themselves. Improvements we plan will enhance the detectability of hemogenetic signals and give rise to hemogenetic gene reporters that will be useful for mapping neural connectivity and plasticity in future applications.

血液动力学神经影像学方法（例如功能磁共振成像（fMRI））具有革命 - 通过允许研究人员表征HU-大脑活性的时空特征来表征神经科学 男人和动物。但是，这种方法的主要缺点是它们缺乏针对明确定义的特殊性 细胞和分子来源；这限制了他们产生对神经功能的解释性见解的能力。解决 这个问题，我们最近开发了一个前所未有的遗传编码分子探针家族，称为 Nostics，将细胞内钙活性转化为人造血液动力学反应，从而在空间上允许 遗传靶向细胞和电路元件的全面神经影像学。出现的血液遗传信号 从怀旧的药理性手段和 可以通过任何血液动力学成像方式检测到。我们的初步实验表明该细胞特异性 可以使用血液遗传fMRI鉴定稀疏神经元种群的活性。这些功能将 使血液遗传成像能够面对神经科学中一些最杰出的问题，例如 在大脑范围内的离散细胞群体的涂抹功能特性，定义输入输出关系 - 相互作用的大脑区域和神经回路组件之间的船只，以及将行为和活动与质量有关 整个大脑中发生的细胞性和基因表达变化。在这个项目中，我们将使用血液源 成像以在啮齿动物的感觉功能的背景下解决这些广泛问题 时间完善技术并为许多研究主题和模型奠定基础 神经科学的系统。 在AIM 1中，我们建议使用该技术来调查各个人的网络级处理 Sory系统。预期的结果将为多区域刺激处理的首个模型提供信息 认为是传统相关功能连接度量的数据驱动的替代方案。我们将使用此模型 检查反馈关系的重要性并帮助解释感觉适应现象 和在网络级别编码的显着性。在AIM 2中，我们将通过应用NOSTIC探针来利用此能力 对于遗传靶向兴奋性和抑制性神经亚型的遗传靶向fMRI，在刺激和静止期间 大鼠的状态动力学，解决了有关不同细胞类型的功能作用的假设。此外， 我们将应用超高分辨率fMRI来检查单血管级血流动力学之间的关系 以及怀旧表达的细胞类型特异性分布，实现了丰富的分析 形式的传统fMRI结果的解释，并严格地表征了血液遗传学的性能 技术本身。在AIM 3中，我们建议自己改善怀旧的记者。我们计划的改进将 增强血液遗传学信号的可检测性，并引起血液遗传学基因记者 用于在未来应用中绘制神经连通性和可塑性。