Investigating the neurophysiological basis of circuit-specific laminar rs-fMRI

研究电路特异性层流 rs-fMRI 的神经生理学基础

• 批准号: 10518479
• 负责人: EMERY N BROWN
• 金额: $ 214.12万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518479
• 关键词: Address; Anesthetics; Animals; Astrocytes; Axon; Bilateral; Biological Markers; Blood Vessels; Brain; Brain Diseases; Brain Injuries; Brain Mapping; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Chronic; Clinical; Corpus Callosum; Coupled; Coupling; Diagnostic; Disease; Etiology; Fiber; Foundations; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Hypotension; Impairment; Injury; Lesion; Measures; Mediating; Methods; Mus; Network-based; Neurons; Pathologic; Patients; Pattern; Photometry; Play; Regulation; Resolution; Rest; Role; Scanning; Scheme; Signal Transduction; Source; Specific qualifier value; Specificity; Techniques; Testing; To specify; Translating; Vascular Dementia; Vascular Diseases; Work; awake; base; bioimaging; blood oxygen level dependent; cerebrovascular; diagnostic tool; functional disability; hypoperfusion; imaging biomarker; improved; mouse model; multimodality; nervous system disorder; neurophysiology; neuroregulation; neurovascular; neurovascular coupling; novel; optogenetics; potential biomarker; response; tool; vascular cognitive impairment and dementia; white matter; white matter injury

Resting-state fMRI has emerged as a potential method to identify diagnostic bio-imaging markers of a broad spectrum of neurological disorders by measuring the low-frequency fluctuation (LFF) correlation features of diseased brains. Due to the fMRI signal’s indirect coupling to neuronal activity, a fundamental challenge of rs- fMRI mapping is how to extract the true “functional connectivity” feature across cortices with circuit specificity. Both direct corticocortical connections, e.g. callosal projections, and subcortical neuromodulatory projections can modulate rs-fMRI connectivity with converging effects on neuro-glio-vascular (NGV) interactions. Also, au- tonomic regulation on gliovascular dynamics further confounds rs-fMRI LFF when interpreting the brain dam- age with vascular impairment in various cerebrovascular diseases. We propose to implement line-scanning and single-vessel fMRI methods in a multi-modal platform to dissect laminar and vascular-specific rs-fMRI LFF and decipher NGV signaling underlying rs-fMRI LFF. Here, we will focus on elucidating the transcallosal circuit- based interhemispheric rs-fMRI LFF correlation in the normal and diseased mouse model with hypoperfusion- induced cerebrovascular white matter injury in the corpus callosum. Three aims will be addressed: 1). We will investigate the causal linkage between laminar-specific bilateral LFF and transcallosal projection. Two hypoth- eses will be tested: i). Layer-specific transcallosal projections determine bilateral LFF laminar correlation pat- terns, and ii). Callosal-driven laminar LFF holds distinct oscillation features from brain state-dependent global LFF. 2). We will differentiate the NGV signaling of callosal-specific and global vascular LFF using multi-modal fMRI. Also, we will test two hypotheses: i). Callosal projection neuron-specific oscillation mediates circuit-spe- cific bilateral LFF, and ii). Distinct astrocytic Ca2+ signals coupled to either callosal projection neuronal activity or global neuromodulation contribute to different forms of LFF correlation. 3). We will specify callosal-specific and global vascular LFF in the hypoperfusion-induced white matter injury mouse model. We will test if hy- poperfusion-induced cerebral flow changes alter global vascular LFF and hypoperfusion-induced injury in the corpus callosum leads to altered bilateral rs-fMRI connectivity. This proposal aims to reveal the mechanistic NGV regulation of circuit-specific rs-fMRI LFF and apply novel rs-fMRI methods in the diseased mouse model to set the foundation to translate specific LFF correlation patterns as potential biomarkers of circuit dysfunction or vascular impairment in pathological brains.

静息态功能磁共振成像已成为识别广泛的诊断生物成像标记物的潜在方法。 通过测量神经系统疾病的低频波动（LFF）相关特征来分析神经系统疾病的谱 有病的大脑。由于功能磁共振成像信号与神经元活动的间接耦合，RS- 功能磁共振成像映射是如何提取具有电路特异性的跨皮质的真正“功能连接”特征。 两者都是直接的皮质连接，例如胼胝体投射和皮质下神经调节投射 可以调节 rs-fMRI 连接性，并对神经胶质血管 (NGV) 相互作用产生聚合效应。另外，au- 在解释脑损伤时，神经胶质血管动力学的张力调节进一步混淆了 rs-fMRI LFF 各种脑血管疾病导致血管损伤的年龄。我们建议实施线扫描 和单血管功能磁共振成像方法在多模态平台上剖析层流和血管特异性 rs-fMRI LFF 并破译 rs-fMRI LFF 下的 NGV 信号传导。在这里，我们将重点阐明跨胼胝体回路—— 在正常和患病小鼠低灌注模型中基于半球间 rs-fMRI LFF 相关性 诱发胼胝体脑血管白质损伤。将解决三个目标：1）。我们将 研究层流特异性双侧 LFF 与经胼胝体投射之间的因果关系。两个假设—— 将测试 eses：i)。特定层的经胼胝体投影确定双边 LFF 层流相关性模式 燕鸥，以及 ii)。胼胝体驱动的层状 LFF 具有与大脑状态依赖的全局振荡特征不同的特征 LFF。 2）。我们将使用多模态区分胼胝体特异性和整体血管 LFF 的 NGV 信号传导 功能磁共振成像。此外，我们将测试两个假设：i)。胼胝体投射神经元特异性振荡介导电路特异性 具体的双边 LFF，以及 ii)。与胼胝体投射神经元活动耦合的独特星形细胞 Ca2+ 信号 或全局神经调节有助于不同形式的 LFF 相关性。 3）。我们将指定胼胝体特异性 和低灌注引起的白质损伤小鼠模型中的全局血管 LFF。我们将测试是否hy- 缺血引起的脑血流变化改变了整体血管 LFF 和低灌注引起的损伤 胼胝体导致双侧 rs-fMRI 连接改变。该提案旨在揭示机制 NGV 调节电路特异性 rs-fMRI LFF 并在患病小鼠模型中应用新型 rs-fMRI 方法 为将特定 LFF 相关模式转化为回路功能障碍的潜在生物标志物奠定基础 或病理性大脑中的血管损伤。