The development of neurovascular coupling in the postnatal brain

In the adult brain, localized increases in neural activity almost always result in increases in local blood flow, a relationship essential for normal brain function. This coupling between neural activity and blood flow provides the basis for many neuroimaging techniques including functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS). However, functional brain imaging studies in newborns and children have detected a range of responses, including some entirely inverted with respect to those of the adult. Confusion over the properties of functional hemodynamics in the developing brain has made it challenging to interpret functional imaging data in infants and children. Additionally, developmental differences in functional hemodynamics would suggest postnatal neurovascular maturation and a unique metabolic environment in the developing brain. This thesis begins with a series of studies in which I tracked and characterized postnatal changes in functional hemodynamics in rodent models utilizing high-speed, high-resolution multi-spectral optical intrinsic and fluorescent signal imaging. I demonstrated that in early postnatal development increases in cortical blood flow do not occur in response to somatosensory stimulation. In fact, I observed stimulus-linked global vasoconstrictions in the brain. In slightly older age groups, I observed biphasic hemodynamic responses, with initial local hyperemia followed by global vasoconstriction, eventually progressing with age to recognizable adult-like hemodynamic responses. In these studies, I also found that the postnatal development of autoregulation is a potential confound in the study of early functional activation, and may account for some of the variability seen in prior human studies. Charting this progression led to the hypothesis that anomalous functional responses observed in human subjects are due to the postnatal development of neurovascular coupling itself. To directly assess neurovascular development, I performed a further set of studies in Thy1-GCaMP3 mice, permitting simultaneous observation of the development of neural function and connectivity along with functional hemodynamics. My results demonstrate that the spatiotemporal properties of neural development do not predict observed changes in the hemodynamic response, consistent with the parallel development of neural networks and neurovascular coupling. Confirming the presence of vascularly-uncoupled neural activity in the newborn brain led me to question how the brain supports its energy needs in the absence of evoked hyperemia, prompting the exploration of the potential metabolic bases and consequences of developmental changes in neurovascular coupling. Finally, I explore the cellular and vascular morphological and functional correlates of functional neurovascular development. My results confirm that neurovascular development occurs postnatally, which has critical implications for the interpretation of functional imaging studies in infants and children. My work also provides new insights into postnatal neural, metabolic, and vascular maturation and could have important implications for the care of infants and children, and for understanding the role of neurovascular development in the pathophysiology of developmental disorders.