Brain energy metabolism: A roadmap for future research.

Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+, as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research.

Emerging connections between cerebellar development, behaviour and complex brain disorders.

The human cerebellum has a protracted developmental timeline compared with the neocortex, expanding the window of vulnerability to neurological disorders. As the cerebellum is critical for motor behaviour, it is not surprising that most neurodevelopmental disorders share motor deficits as a common sequela. However, evidence gathered since the late 1980s suggests that the cerebellum is involved in motor and non-motor function, including cognition and emotion. More recently, evidence indicates that major neurodevelopmental disorders such as intellectual disability, autism spectrum disorder, attention-deficit hyperactivity disorder and Down syndrome have potential links to abnormal cerebellar development. Out of recent findings from clinical and preclinical studies, the concept of the 'cerebellar connectome' has emerged that can be used as a framework to link the role of cerebellar development to human behaviour, disease states and the design of better therapeutic strategies.

High Doses of ANA12 Improve Phenobarbital Efficacy in a Model of Neonatal Post-Ischemic Seizures.

Phenobarbital (PB) remains the first-line medication for neonatal seizures. Yet, seizures in many newborns, particularly those associated with perinatal ischemia, are resistant to PB. Previous animal studies have shown that in postnatal day P7 mice pups with ischemic stroke induced by unilateral carotid ligation, the tyrosine receptor kinase B (TrkB) antagonist ANA12 (N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide, 5 mg/kg) improved the efficacy of PB in reducing seizure occurrence. To meet optimal standards of effectiveness, a wider range of ANA12 doses must be tested. Here, using the unilateral carotid ligation model, we tested the effectiveness of higher doses of ANA12 (10 and 20 mg/kg) on the ability of PB to reduce seizure burden, ameliorate cell death (assessed by Fluoro-Jade staining), and affect neurodevelopment (righting reflex, negative geotaxis test, open field test). We found that a single dose of ANA12 (10 or 20 mg/kg) given 1 h after unilateral carotid ligation in P7 pups reduced seizure burden and neocortical and striatal neuron death without impairing developmental reflexes. In conclusion, ANA12 at a range of doses (10-20 mg/kg) enhanced PB effectiveness for the treatment of perinatal ischemia-related seizures, suggesting that this agent might be a clinically safe and effective adjunctive agent for the treatment of pharmacoresistant neonatal seizures.

Oxidative Stress-Induced Damage to the Developing Hippocampus Is Mediated by GSK3ß.

Neonatal brain injury renders the developing brain vulnerable to oxidative stress, leading to cognitive deficit. However, oxidative stress-induced damage to hippocampal circuits and the mechanisms underlying long-term changes in memory and learning are poorly understood. We used high oxygen tension or hyperoxia (HO) in neonatal mice of both sexes to investigate the role of oxidative stress in hippocampal damage. Perinatal HO induces reactive oxygen species and cell death, together with reduced interneuron maturation, inhibitory postsynaptic currents, and dentate progenitor proliferation. Postinjury interneuron stimulation surprisingly improved inhibitory activity and memory tasks, indicating reversibility. With decreased hippocampal levels of Wnt signaling components and somatostatin, HO aberrantly activated glycogen synthase kinase 3 ß activity. Pharmacological inhibition or ablation of interneuron glycogen synthase kinase 3 ß during HO challenge restored progenitor cell proliferation, interneuron development, inhibitory/excitatory balance, as well as hippocampal-dependent behavior. Biochemical targeting of interneuron function may benefit learning deficits caused by oxidative damage.SIGNIFICANCE STATEMENT Premature infants are especially vulnerable to oxidative stress, as their antioxidant defenses are underdeveloped. Indeed, high oxygen tension is associated with poor neurologic outcomes. Because of its sustained postnatal development and role in learning and memory, the hippocampus is especially vulnerable to oxidative damage in premature infants. However, the role of oxidative stress in the developing hippocampus has yet to be explored. With ever-rising rates of neonatal brain injury and no universally viable approach to maximize functional recovery, a better understanding of the mechanisms underlying neonatal brain injury is needed. Addressing this need, this study uses perinatal hyperoxia to study cognitive deficits, pathophysiology, and molecular mechanisms of oxidative damage in the developing hippocampus.

Infantile Cocktail of Erythropoietin and Melatonin Restores Gait in Adult Rats with Preterm Brain Injury.

Cerebral palsy (CP) is the most common cause of physical disability for children worldwide. Many infants and toddlers are not diagnosed with CP until they fail to achieve obvious motor milestones. Currently, there are no effective pharmacologic interventions available for infants and toddlers to substantially improve their trajectory of neurodevelopment. Because children with CP from preterm birth also exhibit a sustained immune system hyper-reactivity, we hypothesized that neuro-immunomodulation with a regimen of repurposed endogenous neurorestorative medications, erythropoietin (EPO) and melatonin (MLT), could improve this trajectory. Thus, we administered EPO + MLT to rats with CP during human infant-toddler equivalency to determine whether we could influence gait patterns in mature animals. After a prenatal injury on embryonic day 18 (E18) that mimics chorioamnionitis at ∼25 weeks human gestation, rat pups were born and raised with their dam. Beginning on postnatal day 15 (P15), equivalent to human infant ∼1 year, rats were randomized to receive either a regimen of EPO + MLT or vehicle (sterile saline) through P20. Gait was assessed in young adult rats at P30 using computerized digital gait analyses including videography on a treadmill. Results indicate that gait metrics of young adult rats treated with an infantile cocktail of EPO + MLT were restored compared to vehicle-treated rats (p < 0.05) and similar to sham controls. These results provide reassuring evidence that pharmacological interventions may be beneficial to infants and toddlers who are diagnosed with CP well after the traditional neonatal window of intervention.

Comparison of in vivo and in situ detection of hippocampal metabolites in mouse brain using 1 H-MRS.

The study of cerebral metabolites relies heavily on detection methods and sample preparation. Animal experiments in vivo require anesthetic agents that can alter brain metabolism, whereas ex vivo experiments demand appropriate fixation methods to preserve the tissue from rapid postmortem degradation. In this study, the metabolic profiles of mouse hippocampi using proton magnetic resonance spectroscopy (1 H-MRS) were compared in vivo and in situ with or without focused beam microwave irradiation (FBMI) fixation. Ten major brain metabolites, including lactate (Lac), N-acetylaspartate (NAA), total choline (tCho), myo-inositol (mIns), glutamine (Gln), glutamate (Glu), aminobutyric acid (GABA), glutathione (GSH), total creatine (tCr) and taurine (Tau), were analyzed using LCModel. After FBMI fixation, the concentrations of Lac, tCho and mIns were comparable with those obtained in vivo under isoflurane, whereas other metabolites were significantly lower. Except for a decrease in NAA and an increase in Tau, all the other metabolites remained stable over 41 hours in FBMI-fixed brains. Without FBMI, the concentrations of mIns (before 2 hours), tCho and GABA were close to those measured in vivo. However, higher Lac (P < .01) and lower NAA, Gln, Glu, GSH, tCr and Tau were observed (P < .01). NAA, Gln, Glu, GSH, tCr and Tau exhibited good temporal stability for at least 20 hours in the unfixed brain, whereas a linear increase of tCho, mIns and GABA was observed. Possible mechanisms of postmortem degradation are discussed. Our results indicate that a proper fixation method is required for in situ detection depending on the targeted metabolites of specific interests in the brain.

Intranasal epidermal growth factor treatment rescues neonatal brain injury.

There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.

Differential neuronal susceptibility and apoptosis in congenital Zika virus infection.

To characterize the mechanism of Zika virus (ZIKV)-associated microcephaly, we performed immunolabeling on brain tissue from a 20-week fetus with intrauterine ZIKV infection. Although ZIKV demonstrated a wide range of neuronal and non-neuronal tropism, the infection rate was highest in intermediate progenitor cells and immature neurons. Apoptosis was observed in both infected and uninfected bystander cortical neurons, suggesting a role for paracrine factors in induction of neuronal apoptosis. Our results highlight differential neuronal susceptibility and neuronal apoptosis as potential mechanisms in the development of ZIKV-associated microcephaly, and may provide insights into the design and best timing of future therapy. Ann Neurol 2017;82:121-127.

Increased cerebral blood flow on arterial spin labeling magnetic resonance imaging can localize to seizure focus in newborns: A report of 3 cases.

Arterial spin labeling (ASL) magnetic resonance imaging (MRI) can assess cerebral blood flow (CBF) without using radiolabeled tracers. It is unknown whether regional increases in CBF on ASL MRI correlate with seizure location in newborns. We report 3 newborns with focal seizures localized on continuous video electroencephalogram (cEEG), anatomical brain MRI, and ASL MRI. Each patient underwent pseudocontinuous ASL with segmented 3-dimensional fast spin echo readout as part of standard care. Case 1 is a term male infant presenting with left temporal status epilepticus and recurrent cEEG seizures from an idiopathic large left intraventricular hemorrhage. ASL images demonstrated left mesial temporal lobe increased CBF. Case 2 is a late preterm male infant presenting with recurrent cEEG seizures due to focal right megalencephaly. Ictal EEG and ASL images coincided with the focal dysplasia. Case 3 is a dysmorphic term female infant with nonconvulsive partial status epilepticus identified by focal increased CBF of the left temporal lobe on ASL images. The area of increased CBF was within an area of extensive left hemisphere dysplasia. To our knowledge, this is the first report of regional increases in CBF on ASL MRI correlating with ictal cEEG in newborns.

Stem cells and cell-based therapies for cerebral palsy: a call for rigor.

Cell-based therapies hold significant promise for infants at risk for cerebral palsy (CP) from perinatal brain injury (PBI). PBI leading to CP results from multifaceted damage to neural cells. Complex developing neural networks are injured by neural cell damage plus unique perturbations in cell signaling. Given that cell-based therapies can simultaneously repair multiple injured neural components during critical neurodevelopmental windows, these interventions potentially offer efficacy for patients with CP. Currently, the use of cell-based interventions in infants at risk for CP is limited by critical gaps in knowledge. In this review, we will highlight key questions facing the field, including: Who are optimal candidates for treatment? What are the goals of therapeutic interventions? What are the best strategies for agent delivery, including timing, dosage, location, and type? And, how are short- and long-term efficacy reliably tracked? Challenges unique to treating PBI with cell-based therapies, and lessons learned from cell-based therapies in closely related neurological disorders in the mature central nervous system, will be reviewed. Our goal is to update pediatric specialists who may be counseling families about the current state of the field. Finally, we will evaluate how rigor can be increased in the field to ensure the safety and best interests of this vulnerable patient population.

A novel mutation in the promoter of RARS2 causes pontocerebellar hypoplasia in two siblings.

Pontocerebellar hypoplasia (PCH) is characterized by hypoplasia and atrophy of the cerebellum, variable pontine atrophy, microcephaly, severe mental and motor impairments and seizures. Mutations in 11 genes have been reported in 8 out of 10 forms of PCH. Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase gene (RARS2) have been recently associated with PCH type 6, which is characterized by early-onset encephalopathy with signs of oxidative phosphorylation defect. Here we describe the clinical presentation, neuroimaging findings and molecular characterizations of two siblings with a clinical diagnosis of PCH who displayed a novel variant (c.-2A>G) in the 5'-UTR of the RARS2 gene in the homozygous state. This variant was identified through next-generation sequencing testing of a panel of nine genes known to be involved in PCH. Gene expression and functional studies demonstrated that the c.-2A>G sequence change directly leads to a reduced RARS2 messenger RNA expression in the patients by decreasing RARS2 promoter activity, thus providing evidence that mutations in the RARS2 promoter are likely to represent a new causal mechanism of PCH6.

Effects of preoperative hypoxia on white matter injury associated with cardiopulmonary bypass in a rodent hypoxic and brain slice model.

BACKGROUND: White matter (WM) injury is common after cardiopulmonary bypass or deep hypothermic circulatory arrest in neonates who have cerebral immaturity secondary to in utero hypoxia. The mechanism remains unknown. We investigated effects of preoperative hypoxia on deep hypothermic circulatory arrest-induced WM injury using a combined experimental paradigm in rodents. METHODS: Mice were exposed to hypoxia (prehypoxia). Oxygen-glucose deprivation was performed under three temperatures to simulate brain conditions of deep hypothermic circulatory arrest including ischemia-reperfusion/reoxygenation under hypothermia. RESULTS: WM injury in prenormoxia was identified after 35 °C-oxygen-glucose deprivation. In prehypoxia, injury was displayed in all groups. Among oligodendrocyte stages, the preoligodendrocyte was the most susceptible, while the oligodendrocyte progenitor was resistant to insult. When effects of prehypoxia were assessed, injury of mature oligodendrocytes and oligodendrocyte progenitors in prehypoxia significantly increased as compared with prenormoxia, indicating that mature oligodendrocytes and progenitors that had developed under hypoxia had greater vulnerability. Conversely, damage of oligodendrocyte progenitors in prehypoxia were not identified after 15 °C-oxygen-glucose deprivation, suggesting that susceptible oligodendrocytes exposed to hypoxia are protected by deep hypothermia. CONCLUSION: Developmental alterations due to hypoxia result in an increased WM susceptibility to injury. Promoting WM regeneration by oligodendrocyte progenitors after earlier surgery using deep hypothermia is the most promising approach for successful WM development in congenital heart disease patients.

Oligodendrocyte regeneration after neonatal hypoxia requires FoxO1-mediated p27Kip1 expression.

Diffuse white matter injury (DWMI) caused by hypoxia is associated with permanent neurodevelopmental disabilities in preterm infants. The cellular and molecular mechanisms producing DWMI are poorly defined. Using a mouse model of neonatal hypoxia, we demonstrate a biphasic effect on oligodendrocyte development, resulting in hypomyelination. Oligodendrocyte death and oligodendrocyte progenitor cell (OPC) proliferation during the week after hypoxia were followed by delayed oligodendrocyte differentiation and abnormal myelination, as demonstrated by electron microscopy. Cdk2 activation was essential for the regenerative OPC response after hypoxia and was accompanied by reduced FoxO1-dependent p27(Kip1) expression. p27(Kip1) was also reduced in OPCs in human infant white matter lesions after hypoxia. The negative effects of hypoxia on oligodendrogenesis and myelination were more pronounced in p27(Kip1)-null mice; conversely, overexpression of FoxO1 or p27(Kip1) in OPCs after hypoxia promoted oligodendrogenesis. Our studies demonstrate for the first time that neonatal hypoxia affects the Foxo1/p27(Kip1) pathway during white matter development. We also show that molecular manipulation of this pathway enhances oligodendrocyte regeneration during a critical developmental time window after DWMI. Thus, FoxO1 and p27(Kip1) may serve as promising target molecules for promoting timely oligodendrogenesis in neonatal DWMI.

White matter protection in congenital heart surgery.

BACKGROUND: Neurodevelopmental delays in motor skills and white matter (WM) injury have been documented in congenital heart disease and after pediatric cardiac surgery. The lack of a suitable animal model has hampered our understanding of the cellular mechanisms underlying WM injury in these patients. Our aim is to identify an optimal surgical strategy for WM protection to reduce neurological injury in congenital heart disease patients. METHODS AND RESULTS: We developed a porcine cardiopulmonary bypass model that displays area-dependent WM maturation. In this model, WM injury was identified after cardiopulmonary bypass-induced ischemia-reperfusion injury. The degree of injury was inversely correlated with the maturation stage, which indicates maturation-dependent vulnerability of WM. Within different oligodendrocyte developmental stages, we show selective vulnerability of O4+ preoligodendrocytes, whereas oligodendrocyte progenitor cells were resistant to insults. This indicates that immature WM is vulnerable to cardiopulmonary bypass-induced injury but has an intrinsic potential for recovery mediated by endogenous oligodendrocyte progenitor cells. Oligodendrocyte progenitor cell number decreased with age, which suggests that earlier repair allows successful WM development. Oligodendrocyte progenitor cell proliferation was observed within a few days after cardiopulmonary bypass-induced ischemia-reperfusion injury; however, by 4 weeks, arrested oligodendrocyte maturation and delayed myelination were detected. Logistic model confirmed that maintenance of higher oxygenation and reduction of inflammation were effective in minimizing the risk of injury at immature stages of WM development. CONCLUSIONS: Primary repair in neonates and young infants potentially provides successful WM development in congenital heart disease patients. Cardiac surgery during this susceptible period should avoid ischemia-reperfusion injury and minimize inflammation to prevent long-term WM-related neurological impairment.

Neonatal exposure to hypoxia induces early arterial stiffening via activation of lysyl oxidases.

Hypoxia in the neonatal period is associated with early manifestations of adverse cardiovascular health in adulthood including higher risk of hypertension and atherosclerosis. We hypothesize that this occurs due to activation of lysyl oxidases (LOXs) and the remodeling of the large conduit vessels, leading to early arterial stiffening. Newborn C57Bl/6 mice were exposed to hypoxia (FiO2  = 11.5%) from postnatal day 1 (P1) to postnatal day 11 (P11), followed by resumption of normoxia. Controls were maintained in normoxia. Using in vivo (pulse wave velocity; PWV) and ex vivo (tensile testing) arterial stiffness indexes, we determined that mice exposed to neonatal hypoxia had significantly higher arterial stiffness compared with normoxia controls by young adulthood (P60), and it increased further by P120. Echocardiography performed at P60 showed that mice exposed to hypoxia displayed a compensated dilated cardiomyopathy. Western blotting revelated that neonatal hypoxia accelerated age-related increase in LOXL2 protein expression in the aorta and elevated LOXL2 expression in the PA at P11 with a delayed decay toward normoxic controls. In the heart and lung, gene and protein expression of LOX/LOXL2 were upregulated at P11, with a delayed decay when compared to normoxic controls. Neonatal hypoxia results in a significant increase in arterial stiffness in early adulthood due to aberrant LOX/LOXL2 expression. This suggests an acceleration in the mechanical decline of the cardiovascular system, that contributes to increased risk of hypertension in young adults exposed to neonatal hypoxia that may increase susceptibility to further insults.

Biomarkers of brain injury in neonatal encephalopathy treated with hypothermia.

OBJECTIVE: To determine if early serum S100B and neuron-specific enolase (NSE) levels are associated with neuroradiographic and clinical evidence of brain injury in newborns with encephalopathy. STUDY DESIGN: Patients who received therapeutic whole-body hypothermia were prospectively enrolled in this observational study. Serum specimens were collected at 0, 12, 24, and 72 hours of cooling. S100B and NSE levels were measured by enzyme linked immunosorbent assay. Magnetic resonance imaging was performed in surviving infants at 7-10 days of life. Standardized neurologic examination was performed by a child neurologist at 14 days of life. Multiple linear regression analyses were performed to evaluate the association between S100B and NSE levels and unfavorable outcome (death or severe magnetic resonance imaging injury/significant neurologic deficit). Cutoff values were determined by receiver operating curve analysis. RESULTS: Newborns with moderate to severe encephalopathy were enrolled (n = 75). Median pH at presentation was 6.9 (range, 6.5-7.35), and median Apgar scores of 1 at 1 minute, 3 at 5 minutes, and 5 at 10 minutes. NSE and S100B levels were higher in patients with unfavorable outcomes across all time points. These results remained statistically significant after controlling for covariables, including encephalopathy grade at presentation, Apgar score at 5 minutes of life, initial pH, and clinical seizures. CONCLUSION: Elevated serum S100B and NSE levels measured during hypothermia were associated with neuroradiographic and clinical evidence of brain injury in encephalopathic newborns. These brain-specific proteins may be useful immediate biomarkers of cerebral injury severity.

Environmental enrichment rescues postnatal neurogenesis defect in the male and female Ts65Dn mouse model of Down syndrome.

Down syndrome (DS), the most frequent genetic cause of intellectual disability and developmental delay, results from impaired neural stem cell proliferation and differentiation. Impaired neurogenesis in the neocortex, hippocampus and cerebellum is believed to be the underlying cause of learning and behavioral deficits in the Ts65Dn mouse model of DS. Aggressive sensorimotor and cognitive therapies have shown promise in mitigating the cognitive disabilities in DS but these behavioral therapies have not yet been investigated at the cellular level. Here, using the Ts65Dn mouse model of DS, we demonstrate that a combination of environmental enrichment and physical exercise starting in juvenile mice (postnatal day 18) markedly increases cell proliferation, neurogenesis and gliogenesis in the hippocampal dentate gyrus (DG) and the forebrain subventricular zone (SVZ) of both male and female mice. Enrichment and exercise increased the rate of Ts65Dn DG neurogenesis to be comparable to that of the nonenriched euploid group, while the effect on SVZ neurogenesis was reduced and seen only after prolonged exposure. These results clearly indicate that in a comprehensive stimulatory environment, the postnatal DS brain has the intrinsic capability of improving neurogenesis and gliogenesis to the levels of normal matched controls and that this cellular response underlies the cognitive improvement seen following behavioral therapies.

Subclasses of oligodendrocytes populate the mouse hippocampus.

Oligodendrocytes are the myelin-forming cells of the central nervous system that facilitate transmission of axonal electrical impulses. Using transgenic mice expressing 2',3' cyclic nucleotide 3' phosphodiesterase (CNPase)-enhanced green fluorescent protein, a three-dimensional reconstruction tool and analysis, we illustrate that three morphologically different oligodendrocyte types exist in the hippocampus. Those of the ramified type have the most numerous processes, the largest cell body, occupy the largest area and form beaded-like structures, due to mitochondria aggregates, along the processes. Stellar-shaped oligodendrocytes have smaller cell bodies and their processes cover a significantly smaller area. Those of the smooth subtype have a small cell body with at most two processes. In addition to these types, a large number of oligodendrocytes were found that faintly express CNPase-enhanced green fluorescent protein. More than 50% of the faint type colocalized with NG2 and 91% with oligodendrocyte transcription factor-2, whereas 94% of NG2-immunoreactive and 45% of oligodendrocyte transcription factor-2-immunoreactive cells were faintly CNPase-enhanced green fluorescent protein positive. Based on the complexity of the overall structure, the three types probably represent stages of a maturation process such that one subtype can morph into another. Thus, the least complex 'smooth' cell would represent the youngest oligodendrocyte that matures into the stellar type and eventually progresses to become the most complex ramified oligodendrocyte. Investigation of the distribution pattern revealed that the highest density of oligodendrocytes was found in the stratum lacunosum-moleculare and the hilar region. The distribution analysis of oligodendrocyte subclasses revealed a tendency for different cell types to segregate in large non-overlapping areas. This observation suggests that morphologically, and possible functionally, different oligodendrocytes are topographically segregated.

Environmental enrichment ameliorates perinatal brain injury and promotes functional white matter recovery.

Hypoxic damage to the developing brain due to preterm birth causes many anatomical changes, including damage to the periventricular white matter. This results in the loss of glial cells, significant disruptions in myelination, and thereby cognitive and behavioral disabilities seen throughout life. Encouragingly, these neurological morbidities can be improved by environmental factors; however, the underlying cellular mechanisms remain unknown. We found that early and continuous environmental enrichment selectively enhances endogenous repair of the developing white matter by promoting oligodendroglial maturation, myelination, and functional recovery after perinatal brain injury. These effects require increased exposure to socialization, physical activity, and cognitive enhancement of surroundings-a complete enriched environment. Using RNA-sequencing, we identified oligodendroglial-specific responses to hypoxic brain injury, and uncovered molecular mechanisms involved in enrichment-induced recovery. Together, these results indicate that myelin plasticity induced by modulation of the neonatal environment can be targeted as a therapeutic strategy for preterm birth.

Metabolic perturbations after pediatric TBI: It's not just about glucose.

Improved patient survival following pediatric traumatic brain injury (TBI) has uncovered a currently limited understanding of both the adaptive and maladaptive metabolic perturbations that occur during the acute and long-term phases of recovery. While much is known about the redundancy of metabolic pathways that provide adequate energy and substrates for normal brain growth and development, the field is only beginning to characterize perturbations in these metabolic pathways after pediatric TBI. To date, the majority of studies have focused on dysregulated oxidative glucose metabolism after injury; however, the immature brain is well-equipped to use alternative substrates to fuel energy production, growth, and development. A comprehensive understanding of metabolic changes associated with pediatric TBI cannot be limited to investigations of glucose metabolism alone. All energy substrates used by the brain should be considered in developing nutritional and pharmacological interventions for pediatric head trauma. This review summarizes post-injury changes in brain metabolism of glucose, lipids, ketone bodies, and amino acids with discussion of the therapeutic potential of altering substrate utilization to improve pediatric TBI outcomes.