Role of interneurons in resting state fMRI connectivity during normal development and after perinatal brain injury

正常发育期间和围产期脑损伤后中间神经元在静息态 fMRI 连接中的作用

• 批准号: 10263546
• 负责人: Alexander Drobyshevsky
• 金额: $ 53.29万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263546
• 关键词: 3 year old; Adult; Age; Agonist; Animals; Behavior Disorders; Behavioral; Biological Markers; Blood flow; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Brain region; Cannulas; Cell Count; Cells; Cognition Disorders; Cognitive; Cognitive deficits; Data; Development; Diagnosis; Early Intervention; Electrodes; Electrophysiology (science); Equilibrium; Frequencies; Functional Magnetic Resonance Imaging; GABA Receptor; Glutamate Receptor; Goals; Growth; Human; Hyperactive behavior; Hypoxia; Hypoxic-Ischemic Brain Injury; Impaired cognition; Impairment; Implant; Infant; Injury; Interneurons; Intervention; Lasers; Learning; Magnetic Resonance Imaging; Measures; Microinjections; Modality; Modeling; Motor; Neonatal; Neonatal Intensive Care; Neurodevelopmental Impairment; Neurons; Newborn Infant; Oryctolagus cuniculus; Outcome Study; Oxygen; Pacemakers; Pattern; Perfusion; Perinatal Brain Injury; Perinatal Hypoxia; Pharmacology; Physiological; Play; Premature Infant; Property; Regulation; Reporting; Rest; Role; Shapes; Signal Transduction; Sleep; Somatosensory Cortex; Testing; Time; Tissues; Western Blotting; antenatal; base; behavioral impairment; biomarker development; blood oxygen level dependent; early detection biomarkers; experience; fetal; field study; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; insight; interest; ischemic injury; neonate; neuronal circuitry; patch clamp; perinatal development; perinatal period; postnatal development; postnatal period; prognostic; prognostic assays; prognostic value; sensor; serial imaging

Despite improvements of neonatal intensive care over recent decades, hypoxic-ischemic perinatal brain injury remains a major cause of neurodevelopmental impairment among term and preterm infant, including motor, behavioral and cognitive deficits. Diagnosis of cognitive and behavioral abnormalities cannot be accurately made until 2-3 years old. Current state of the art provides no objective functional measures of brain injury in newborns that predict long term cognitive and behavioral deficits. Clearly there is a need for an early non-invasive measure that can prognosticate for cognitive problems in later development and provide an opportunity for early intervention. Among few available modalities to assess functional brain development is resting state functional MRI (rsfMRI). This modality is particularly suited for neonatal and infant studies since it requires minimal subject cooperation, easy to implement, short in duration, and can be done in natural sleep. However, mechanism and origins of rsfMRI signal are poorly understood. Emerging cellular mechanisms of microvascular tone regulation and our preliminary observations suggest that activity of GABAergic interneurons, and not primary neurons, may play a significant role in early local rsfMRI connectivity. Developmental shift to higher frequencies and increased amplitudes of rsfMRI BOLD oscillations in this range coincides with the maturation of interneurons in somatosensory cortexes in early perinatal period. We hypothesized that properties of rsfMRI signal in the higher range of rsfMRI and local rsfMRI connectivity is largely determined by activity of interneurons and thus reflect maturation progression of cortical interneurons during normal perinatal development and after injury. The overall goals of the proposal are to explore cellular mechanisms of rsfMRI regulation, discover and validate cell specific information in rsfMRI connectivity that informs us about the state of functional maturation of cortical interneurons in early postnatal period in rabbit. Using simultaneous recording of neuronal activity, local tissue oxygen fluctuations during MRI acquisition in Aim 1 we will characterize physiological mechanisms modulating resting state fMRI signal in rabbit cortex during postnatal development. Role of interneurons will be explored using pharmacological interventions to selectively block activity of interneurons and and/or pyramidal neurons. Specific signature of interneuron contribution to rsfMRI signal and local connectivity between neighboring voxels will be determined during normal postnatal development and applied to predict injury to interneurons and cognitive abnormalities in Aim 2 in a rabbit model of antenatal hypoxic ischemic in jury.

尽管最近几十年的新生儿重症监护病得到了改善，但缺氧围产期大脑 受伤仍然是术语和早产儿中神经发育障碍的主要原因，包括 运动，行为和认知缺陷。认知和行为异常的诊断不可能 准确地制作到2-3岁。当前的最新状态没有提供大脑的客观功能度量 预测长期认知和行为缺陷的新生儿的伤害。显然需要早点 无创的措施可以预测以后发展的认知问题，并提供 早期干预的机会。 在评估功能大脑发展的少数可用方式中，静止状态功能性MRI （RSFMRI）。这种方式特别适合新生儿和婴儿研究，因为它需要最少的主题 合作，易于实施，持续时间短，可以在自然睡眠中完成。但是，机制和 RSFMRI信号的起源知之甚少。微血管张力调节的新兴细胞机制 我们的初步观察表明，GABA能中间神经元而不是原发性神经元的活性， 可能在早期本地RSFMRI连接性中发挥重要作用。发展到更高的频率和 在此范围内，RSFMRI BOLD振荡的幅度增加与中间神经元的成熟相吻合 围产期早期的体感皮质。我们假设RSFMRI信号在 较高的RSFMRI和局部RSFMRI连接性在很大程度上取决于中间神经元的活性，因此 反映正常围产期发育和损伤后皮质中间神经元的成熟进展。 该提案的总体目标是探索RSFMRI调节，发现和 在RSFMRI连接性中验证细胞特定信息，以告知我们功能成熟的状态 兔子早期早期的皮质中间神经元。使用同时记录神经元活动， AIM 1中MRI获取期间局部组织氧气波动1我们将表征生理机制 在产后发育过程中调节兔皮质中的静息状态fMRI信号。中间神经元的角色将是 使用药理学干预措施进行探索，以选择性地阻断中间神经元和/或金字塔的活性 神经元。中间神经元对RSFMRI信号的贡献和局部连通性的特定签名 在正常产后发育期间将确定相邻的体素，并应用于预测 在陪审团的兔子低氧缺血模型中，AIM 2中的中间神经元和认知异常。