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

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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.