title: Rapid Postnatal Expansion of Neural Networks Occurs in an Environment of Altered Neurovascular and Neurometabolic Coupling.
abstract: In the adult brain, increases in neural activity lead to increases in local blood flow. However, many prior measurements of functional hemodynamics in the neonatal brain, including functional magnetic resonance imaging (fMRI) in human infants, have noted altered and even inverted hemodynamic responses to stimuli. Here, we demonstrate that localized neural activity in early postnatal mice does not evoke blood flow increases as in the adult brain, and elucidate the neural and metabolic correlates of these altered functional hemodynamics as a function of developmental age. Using wide-field GCaMP imaging, the development of neural responses to somatosensory stimulus is visualized over the entire bilaterally exposed cortex. Neural responses are observed to progress from tightly localized, unilateral maps to bilateral responses as interhemispheric connectivity becomes established. Simultaneous hemodynamic imaging confirms that spatiotemporally coupled functional hyperemia is not present during these early stages of postnatal brain development, and develops gradually as cortical connectivity is established. Exploring the consequences of this lack of functional hyperemia, measurements of oxidative metabolism via flavoprotein fluorescence suggest that neural activity depletes local oxygen to below baseline levels at early developmental stages. Analysis of hemoglobin oxygenation dynamics at the same age confirms oxygen depletion for both stimulus-evoked and resting-state neural activity. This state of unmet metabolic demand during neural network development poses new questions about the mechanisms of neurovascular development and its role in both normal and abnormal brain development. These results also provide important insights for the interpretation of fMRI studies of the developing brain.
  
  
  
  This work demonstrates that the postnatal development of neuronal connectivity is accompanied by development of the mechanisms that regulate local blood flow in response to neural activity. Novel in vivo imaging reveals that, in the developing mouse brain, strong and localized GCaMP neural responses to stimulus fail to evoke local blood flow increases, leading to a state in which oxygen levels become locally depleted. These results demonstrate that the development of cortical connectivity occurs in an environment of altered energy availability that itself may play a role in shaping normal brain development. These findings have important implications for understanding the pathophysiology of abnormal developmental trajectories, and for the interpretation of functional magnetic resonance imaging data acquired in the developing brain.
authors.affiliation: Laboratory for Functional Optical Imaging, Departments of Biomedical Engineering and Radiology, Mortimer B. Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, New York 10027 mkozberg@gmail.com eh2245@columbia.edu.
authors.forename: Mariel G
authors.initials: MG
authors.lastname: Kozberg
authors.affiliation: Laboratory for Functional Optical Imaging, Departments of Biomedical Engineering and Radiology, Mortimer B. Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, New York 10027.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Laboratory for Functional Optical Imaging, Departments of Biomedical Engineering and Radiology, Mortimer B. Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, New York 10027.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Shaik
authors.affiliation: Laboratory for Functional Optical Imaging, Departments of Biomedical Engineering and Radiology, Mortimer B. Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, New York 10027.
authors.forename: Sharon H
authors.identifier: 0000-0002-5044-5177
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Laboratory for Functional Optical Imaging, Departments of Biomedical Engineering and Radiology, Mortimer B. Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, New York 10027 mkozberg@gmail.com eh2245@columbia.edu.
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Hillman
mesh_terms: D000344:Afferent Pathways / Q000502:physiology*; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000000981:diagnostic imaging / Q000254:growth & development* / Q000378:metabolism*; D001931:Brain Mapping; D002560:Cerebrovascular Circulation / Q000502:physiology*; D005260:Female; D006439:Hemodynamics; D006454:Hemoglobins / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009415:Nerve Net / Q000378:metabolism*; D000069336:Neurovascular Coupling / Q000502:physiology*; D010108:Oxyhemoglobins / Q000378:metabolism; D010812:Physical Stimulation
chemical_list: D006454:Hemoglobins; D008164:Luminescent Proteins; D010108:Oxyhemoglobins; C100003:deoxyhemoglobin
keywords: GCaMP imaging; fMRI; flavoprotein fluorescence; functional hyperemia; neurovascular coupling; oxygen consumption; postnatal neural development