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得到了改善，但围产期脑缺氧缺血性疾病仍是新生儿脑损伤的主要原因。 损伤仍然是足月儿和早产儿神经发育障碍主要原因，包括 运动、行为和认知缺陷。认知和行为异常的诊断不能 准确地制作，直到2-3岁。现有技术没有提供脑的客观功能测量 新生儿损伤可预测长期认知和行为缺陷。显然，有必要尽早 一种非侵入性的测量方法，可以在以后的发展中解释认知问题， 早期干预的机会。 在少数可用的方式来评估功能性大脑发育是静息状态功能磁共振成像 （rsfMRI）。这种模式特别适合新生儿和婴儿研究，因为它需要最少的受试者 合作，易于实施，持续时间短，并且可以在自然睡眠中进行。然而，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能中间神经元的活性，而不是初级神经元， 可能在早期局部rsfMRI连接中发挥重要作用。向更高频率的发展转变， 在这个范围内，rsfMRI BOLD振荡幅度的增加与中间神经元的成熟相一致， 围产期早期体感皮层。我们假设rsfMRI信号的性质在 更高范围的rsfMRI和局部rsfMRI连接性在很大程度上由中间神经元的活动决定，因此 反映了正常围产期发育期间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连接中的细胞特异性信息，告知我们功能成熟的状态 家兔生后早期皮层中间神经元的变化。使用神经元活动的同步记录， 在目标1的MRI采集过程中，我们将描述生理机制 在出生后发育过程中调节家兔大脑皮层静息状态fMRI信号。中间神经元的作用将是 探索了使用药理学干预来选择性地阻断中间神经元和/或锥体神经元的活性， 神经元中间神经元对rsfMRI信号的贡献的特异性特征和局部连接 将在正常的出生后发育期间确定相邻的体素， 在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.