Fatty acids (FAs) are essential in the developing brain for myelination, neurogenesis, and lipid membrane
turnover. During fetal and early postnatal brain development, FA synthesis in the brain is necessary for rapid
structural brain growth. However, FAs can also serve as a source of energy. Recent evidence suggests that
neural stem and progenitor cells rely largely on FA oxidation for energy. The question is whether the balance
between FA synthesis and oxidation (FA metabolism) in the brain shifts after injury. Neonatal brain injury is a
major contributor to long-term neurodevelopmental delays. The response to injury and endogenous recovery
phase is metabolically expensive, imposing additional energy demands and disrupting the highly orchestrated
process of brain development and maturation. Therefore, there is a critical need to delineate acute and long-
term metabolic adaptations after neonatal brain injury. Our preliminary results show that the neonatal injured
brain from intermittent hypoxia has decreased FA composition, increased dependency on FAs as a fuel
compared to other substrates and increased FA oxidation. In addition, FA mobilization for oxidation is increased
days after injury. Based on these results, we hypothesize that metabolic adaptations after neonatal brain injury
directly perturb the balance of FA synthesis and oxidation, thereby disrupting the timely developmental trajectory
of brain growth and maturation. We will test our hypothesis in three aims. In the first aim, we will determine
temporal and spatial contributions of FA metabolism after neonatal brain injury. This aim will delineate time- and
region-specific FA composition in the hippocampus, white matter, and subventricular zone. The region-specific
composition of FAs and substrates will be measured with tandem mass spectrometry and MALDI- mass
spectrometry imaging. We will measure protein, RNA, and metabolic flux in region- and cell-specific populations.
Studies will be performed that will measure dependency, capacity, and flexibility to utilize FAs and other
substrates from different brain regions and time points after injury. In the second aim, we will determine whether
time-specific alteration of FA metabolism in progenitor cells disrupts their normal developmental trajectory. We
will specifically remove an obligate gene responsible for FA synthesis or oxidation in neural progenitor cells to
answer the question whether FA metabolism regulates neural progenitor cell activity in the neurogenic niches.
In the third aim, we will test whether brain FA oxidation after neonatal brain injury is adaptive or maladaptive.
This aim will study the role of FA oxidation in the developing brain and after neonatal brain injury using pan-
brain-specific loss of either the obligate gene in FA oxidation or the gene responsible for the rate-limiting step of
FA translocation into the mitochondria. Overall, this project will delineate the time-course and contribution of FAs
toward metabolic flexibility. The outcomes of this study will inform the science of FA metabolism and guide
development of new therapeutic targets aimed at balancing metabolic demands after neonatal brain injury.