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

尽管近几十年来新生儿重症监护有所改善，但缺氧缺血的围产期脑 损伤仍然是足月儿和早产儿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能 制作精准，直到2-3岁。目前的技术水平没有提供对大脑的客观功能测量 新生儿的损伤，预示着长期的认知和行为缺陷。显然，有必要及早 非侵入性测量，可以预测后期发育中的认知问题，并提供 提供早期干预的机会。 在少数几种可用于评估大脑功能发育的方法中，静息状态功能磁共振成像是其中的一种 (RsfMRI)。这种方法特别适合于新生儿和婴儿的研究，因为它只需要最少的研究对象 协作，易于实施，持续时间短，可以在自然睡眠中完成。然而，机制和 RsfMRI信号的来源尚不清楚。微血管张力调节的新细胞机制 我们的初步观察表明，GABA能中间神经元的活动，而不是初级神经元， 可能在早期局部rsfMRI连接中起重要作用。发育向更高频率和 在这一范围内rsfmri BOLD振荡的幅度增加与脑内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信号的特性在 更高范围的rsfMRI和局部rsfMRI连通性在很大程度上由中间神经元的活动决定，因此 反映正常围产期和损伤后皮质中间神经元的成熟进程。 该提案的总体目标是探索rsfmri调节的细胞机制，发现和 验证rsfMRI连接中的细胞特定信息，以告知我们功能成熟的状态 兔出生后早期皮质中间神经元的变化。利用神经元活动的同步记录， 在AIM 1中，在MRI采集过程中局部组织氧波动我们将描述生理机制 兔出生后发育过程中皮层静息状态fmri信号的调制。中间神经元的作用将是 探索使用药物干预选择性阻断中间神经元和/或锥体细胞的活动 神经元。神经元间对rsfMRI信号的贡献和局部连通性的特异性特征 相邻体素将在正常的出生后发育过程中确定，并应用于预测 产前缺氧缺血损伤兔模型中AIM 2的中间神经元和认知异常。

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 injury.