Brain Energetics Research Articles

Thioredoxin interacting protein drives astrocytic glucose hypometabolism in corticosterone-induced depressive state.

Brain energetics disturbance is a hypothesized cause of depression. Glucose isthepredominantfuel of brain energy metabolism; however, the cell-specific change of glucose metabolism and underlying molecular mechanism in depression remains unclear. In this study, we firstly applied 18 F-FDG PET and observed brain glucose hypometabolism in the prefrontal cortex (PFC) of corticosterone-induced depression of rats. Next, astrocytic glucose hypometabolism was identified in PFC slices in both corticosterone-induced depression of rats and cultured primary astrocytes from newborn rat PFC after stress-level corticosterone (100nM) stimulation. Furthermore, we found the blockage of glucose uptake and the decrease of plasma membrane (PM) translocation of glucose transporter 1 (GLUT1) in astrocytic glucose hypometabolism under depressive condition. Interestingly, thioredoxin interacting protein (TXNIP), a glucose metabolism sensor and controller, was found to be over-expressed in corticosterone-stimulated astrocytes in vivo and in vitro. High TXNIP level could restrict GLUT1-mediated glucose uptake in primary astrocytes in vitro. Adeno-associated virus vector-mediated astrocytic TXNIP over-expression in rat medial PFC suppressed GLUT1 PM translocation, consequently developed depressive-like behavior. Conversely, TXNIP siRNA facilitated GLUT1 PM translocation to recover glucose hypometabolism in corticosterone-exposed cultured astrocytes. Notably, astrocyte-specific knockdown of TXNIP in medial PFC of rats facilitated astrocytic GLUT1 PM translocation, showing obvious antidepressant activity. These findings provide a new astrocytic energetic perspective in the pathogenesis of depression and, more importantly, provide TXNIP as a promising molecular target for novel depression therapy.

Energy metabolism in childhood neurodevelopmental disorders.

Whereas energy function in the aging brain and their related neurodegenerative diseases has been explored in some detail, there is limited knowledge about molecular mechanisms and brain networks of energy metabolism during infancy and childhood. In this review we describe current insights on physiological brain energetics at prenatal and neonatal stages, and in childhood. We then describe the main groups of inborn errors of energy metabolism affecting the brain. Of note, scarce basic neuroscience research in this field limits the opportunity for these disorders to provide paradigms of energy utilization during neurodevelopment. Finally, we report energy metabolism disturbances in well-known non-metabolic neurodevelopmental disorders. As energy metabolism is a fundamental biological function, brain energy utilization is likely altered in most neuropediatric diseases. Precise knowledge on mechanisms of brain energy disturbance will open the possibility of metabolic modulation therapies regardless of disease etiology.

Astrocyte-Neuron Metabolic Crosstalk in Neurodegeneration: A Mitochondrial Perspective.

Converging evidence made clear that declining brain energetics contribute to aging and are implicated in the initiation and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Indeed, both pathologies involve instances of hypometabolism of glucose and oxygen in the brain causing mitochondrial dysfunction, energetic failure and oxidative stress. Importantly, recent evidence suggests that astrocytes, which play a key role in supporting neuronal function and metabolism, might contribute to the development of neurodegenerative diseases. Therefore, exploring how the neuro-supportive role of astrocytes may be impaired in the context of these disorders has great therapeutic potential. In the following, we will discuss some of the so far identified features underlining the astrocyte-neuron metabolic crosstalk. Thereby, special focus will be given to the role of mitochondria. Furthermore, we will report on recent advancements concerning iPSC-derived models used to unravel the metabolic contribution of astrocytes to neuronal demise. Finally, we discuss how mitochondrial dysfunction in astrocytes could contribute to inflammatory signaling in neurodegenerative diseases.

Dual-process brain mitochondria isolation preserves function and clarifies protein composition

The brain requires continuously high energy production to maintain ion gradients and normal function. Mitochondria critically undergird brain energetics, and mitochondrial abnormalities feature prominently in neuropsychiatric disease. However, many unique aspects of brain mitochondria composition and function are poorly understood. Developing improved neuroprotective therapeutics thus requires more comprehensively understanding brain mitochondria, including accurately delineating protein composition and channel-transporter functional networks. However, obtaining pure mitochondria from the brain is especially challenging due to its distinctive lipid and cell structure properties. As a result, conflicting reports on protein localization to brain mitochondria abound. Here we illustrate this problem with the neuropsychiatric disease-associated L-type calcium channel Cav1.2α1 subunit previously observed in crude mitochondria. We applied a dual-process approach to obtain functionally intact versus compositionally pure brain mitochondria. One branch utilizes discontinuous density gradient centrifugation to isolate semipure mitochondria suitable for functional assays but unsuitable for protein localization because of endoplasmic reticulum (ER) contamination. The other branch utilizes self-forming density gradient ultracentrifugation to remove ER and yield ultrapure mitochondria that are suitable for investigating protein localization but functionally compromised. Through this process, we evaluated brain mitochondria protein content and observed the absence of Cav1.2α1 and other previously reported mitochondrial proteins, including the NMDA receptor, ryanodine receptor 1, monocarboxylate transporter 1, excitatory amino acid transporter 1, and glyceraldehyde 3-phosphate dehydrogenase. Conversely, we confirmed mitochondrial localization of several plasma membrane proteins previously reported to also localize to mitochondria. We expect this dual-process isolation procedure will enhance understanding of brain mitochondria in both health and disease.

The PIONEER Study: A multi‐center, randomized, double‐blind, placebo‐controlled phase 2 trial of the effects of T3D‐959 on safety, cognition, function and plasma biomarkers in mild to moderate Alzheimer’s disease subjects: Rationale and study design

AbstractBackgroundDysfunctional glucose and lipid metabolism are key drivers underlying pathological pathways ultimately resulting in Alzheimer’s disease (AD). T3D‐959 is a small molecule, orally delivered, brain penetrating, novel PPAR delta agonist with 15‐fold lower PPAR gamma potency that acts to maintain homeostasis of glucose and lipid metabolism. Ubiquitous brain expression of PPAR‐delta, its critical role in regulating glucose and lipid metabolism and phenotype of PPAR‐delta null mice, coupled with a promising safety profile and multiple efficacy signals in an exploratory Phase 2a clinical trial (NCT02560753) in patients with mild‐to‐moderate AD, provide the foundation for the next Phase 2 clinical trial, the PIONEER Study [Prospective therapy to Inhibit and Overcome Alzheimer's Disease Neurodegeneration via Brain EnErgetics and Metabolism Restoration].MethodsPIONEER is a randomized, double‐blind, placebo‐controlled, Phase 2 trial involving 256 mild to moderate AD patients (MMSE=16‐26) dosed orally once‐a‐day for 24‐weeks in 4 parallel arms (T3D‐959 active arms of 15mg, 30mg and 45mg QD and a placebo arm in a 1:1:1:1 ratio). Co‐primary outcome measures include the ADAS‐cog11 cognition and global function CGIC measures. Secondary and exploratory outcome measures include change from baseline in plasma Aβ 42/40 ratio, NfL and tau between subjects treated with T3D‐959 compared to placebo, evaluation of the effect of T3D‐959 compared with placebo on apathy as measured by the NPI, on functional decline as measured with ADCS‐ADL, on executive function as measured using the DSCT, on verbal fluency, on plasma metabolomic and proteomic biomarkers and change in absolute regional, and whole brain, cerebral metabolic rate for glucose (CMRgl) as assayed by FDG‐PET.ResultsCognitive and functional endpoints, as well safety data will be presented and discussed.ConclusionsPIONEER is designed to evaluate the efficacy and safety of multiple dose strengths of T3D‐959 in patients with mild to moderate severity AD.

Improved brain energetics and cognition after a 6‐month ketogenic intervention in mild cognitive impairment: Final results of the Benefic Trial

AbstractBackgroundKetones can partially substitute for glucose as a brain fuel and may be beneficial for cognition in older people. The objective of the randomized, placebo‐controlled Benefic Trial (NCT02551419) was to assess whether counteracting the brain energy (glucose) deficit with a ketogenic medium chain triglyceride (kMCT) supplement could improve cognitive performance in mild cognitive impairment (MCI).MethodsA cognitive battery was used to screen for MCI and cognitive outcomes after the intervention. Cognitive outcomes pre‐ and post‐intervention were obtained for the active arm (15 g kMCT twice/day in a lactose‐free skim milk emulsion; n=39 completers) and placebo arm (non‐ketogenic vegetable oil of equivalent energy value and formulation as for the kMCT; n=44 completers). Brain ketone and glucose PET were done before and at the end of the 6‐month intervention on a sub‐group of both arms (n=19/group).ResultsSeveral cognitive domains improved post‐intervention in the kMCT group (p≤0.01; ANCOVA; age and education as covariates). Specifically, Trial 1 of the Free and Cued Recall Test showed a +1 word improvement on kMCT (+0.5 Δ Z‐score), correct answers on the Verbal Fluency Test increased by 2 words on kMCT (+0.3 Δ Z‐score) but decreased by 1 word on placebo (‐0.1 Δ Z‐score), correct answers on the Boston Naming Test increased by 1.1 on kMCT only, time taken on the Stroop Colour Naming Test decreased by 1 sec on the kMCT (p=0.09), and errors on the Trail Making Test decreased by 0.9 on kMCT but increased by 0.8 on placebo (p=0.02). Brain ketone uptake increased in the kMCT arm only and directly as the increase in plasma ketones (r = 0.87, p<0.01). Average drop‐out rate on both arms was 31% and, in completers, protocol adherence was 89% over six months.ConclusionsIn MCI, a kMCT supplement had a clinically meaningful effect on some cognitive outcomes directly related to risk of progression toward Alzheimer’s disease, and significantly improved brain energy supply. It is feasible for an MCI population to consume a kMCT supplement daily for six months. Acknowledgements: Financial support was provided by the Alzheimer Association USA, FRQS, Université de Sherbrooke and Nestlé Health Science.

The impact of aging in dementia: It is time to refocus attention on the main risk factor of dementia

Alzheimer’s disease (AD) represents the most common form of dementia among old age subjects, and despite decades of studies, the underlying etiopathogenetic mechanisms remain unsolved, and no cure is available. The amyloid hypothesis has been recently questioned due to the failure of amyloid-centered treatments. The fact that cognitively normal old age subjects have substantial amyloid deposition in the brain comparable to the levels observed in AD patients suggests that amyloid accumulation may enter into the normal process of aging and what really triggers neuronal death and clinical manifestation is the loss of function due to an energetic failure. With this viewpoint article, we aim to challenge the traditional view of amyloid as the leading cause of AD. Conversely, we propose the core feature of aging, that is the progressive brain energy decline, as the main risk factor for dementia in older persons. Thus, a bioenergetic deficit secondary to mitochondrial dysfunction may lead to progressive neuronal death and clinical expression of dementia. The optimization of brain energetics should become a key component in future strategies for preventing and treating dementia.

Persistent changes in extracellular lactate dynamics following synaptic potentiation

A diverse array of neurometabolic coupling mechanisms exist within the brain to ensure that sufficient metabolite availability is present to meet both acute and chronic energetic demands.Excitatory synaptic activity, which produces the majority of the brain’s energetic demands, triggers a rapid metabolic response including a characteristic shift towards aerobic glycolysis. Herein, astrocytically derived lactate appears to serve as an important metabolite to meet the extensive metabolic needs of activated neurons. Despite a wealth of literature characterizing lactate’s role in mediating these acute metabolic needs, the extent to which lactate supports chronic energetic demands of neurons remains unclear. We hypothesized that synaptic potentiation, a ubiquitous brain phenomenon that can produce chronic alterations in synaptic activity, could necessitate persistent alterations in brain energetics. In freely-behaving rats, we induced long-term potentiation (LTP) of synapses within the dentate gyrus through high-frequency electrical stimulation (HFS) of the medial perforant pathway. Before, during, and after LTP induction, we continuously recorded extracellular lactate concentrations within the dentate gyrus to assess how changes in synaptic strength alter local glycolytic activity. Synaptic potentiation 1) altered the acute response of extracellular lactate to transient neuronal activation as evident by a larger initial dip and subsequent overshoot and 2) chronically increased local lactate availability. Although synapses were potentiated immediately following HFS, observed changes in lactate dynamics were only evident beginning ~24 h later. Once observed, however, both synaptic potentiation and altered lactate dynamics persisted for the duration of the experiment (~72 h). Persistent alterations in synaptic strength, therefore, appear to be associated with metabolic plasticity in the form of persistent augmentation of glycolytic activity.

Metabolomic and Imaging Mass Spectrometric Assays of Labile Brain Metabolites: Critical Importance of Brain Harvest Procedures

Metabolomic technologies including imaging mass spectrometry (IMS; also called mass spectrometry imaging, MSI, or matrix-assisted laser desorption/ionization-mass spectrometry imaging, MALDI MSI) are important methods to evaluate levels of many compounds in brain with high spatial resolution, characterize metabolic phenotypes of brain disorders, and identify disease biomarkers. ATP is central to brain energetics, and reports of its heterogeneous distribution in brain and regional differences in ATP/ADP ratios reported in IMS studies conflict with earlier studies. These discordant data were, therefore, analyzed and compared with biochemical literature that used rigorous methods to preserve labile metabolites. Unequal, very low regional ATP levels and low ATP/ADP ratios are explained by rapid metabolism during postmortem ischemia. A critical aspect of any analysis of brain components is their stability during and after tissue harvest so measured concentrations closely approximate their physiological levels in vivo. Unfortunately, the requirement for inactivation of brain enzymes by freezing or heating is not widely recognized outside the neurochemistry discipline, and procedures that do not prevent postmortem autolysis, including decapitation, brain removal/dissection, and 'snap freezing' are commonly used. Strong emphasis is placed on use of supplementary approaches to calibrate metabolite abundance in units of concentration in IMS studies and comparison of IMS results with biochemical data obtained by different methods to help identify potential artifacts.

Mitochondrial Supercomplexes: Physiological Organization and Dysregulation in Age-Related Neurodegenerative Disorders.

Several studies suggest that the assembly of mitochondrial respiratory complexes into structures known as supercomplexes (SCs) may increase the efficiency of the electron transport chain, reducing the rate of production of reactive oxygen species. Therefore, the study of the (dis)assembly of SCs may be relevant for the understanding of mitochondrial dysfunction reported in brain aging and major neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Here we briefly reviewed the biogenesis and structural properties of SCs, the impact of mtDNA mutations and mitochondrial dynamics on SCs assembly, the role of lipids on stabilization of SCs and the methodological limitations for the study of SCs. More specifically, we summarized what is known about mitochondrial dysfunction and SCs organization and activity in aging, AD and PD. We focused on the critical variables to take into account when postmortem tissues are used to study the (dis)assembly of SCs. Since few works have been performed to study SCs in AD and PD, the impact of SCs dysfunction on the alteration of brain energetics in these diseases remains poorly understood. The convergence of future progress in the study of SCs structure at high resolution and the refinement of animal models of AD and PD, as well as the use of iPSC-based and somatic cell-derived neurons, will be critical in understanding the biological relevance of the structural remodeling of SCs.

Increased Glutamate concentrations during prolonged motor activation as measured using functional Magnetic Resonance Spectroscopy at 3T

Recent implications of glutamatergic signaling in a wide range of psychiatric disorders has highlighted the need to study the dynamics of glutamate (Glu) in the brain outside of steady state. A promising modality for doing so is functional Magnetic Resonance Spectroscopy (fMRS). Recent human studies at high magnetic fields (7T) have reported small but consistent changes in metabolite concentrations, in particular a 2–4% increase in Glu during visual and motor stimulation. While the origins of these changes remain the topic of ongoing research, the ability of fMRS to observe metabolites directly associated with neurotransmission and brain energetics could potentially aid our understanding of brain pathophysiology and the interpretation of functional imaging experiments. For this to happen, the current ultrahigh field results must be reproduced at lower, widely available clinical field strengths, in response to a wide variety of stimuli classes. Our goal herein was to investigate metabolite changes during a hand-clenching motor task at 3T, and to investigate the effect of the stimulation's temporal characteristics on the magnitude of the fMRS changes; specifically, we compared two block-designed functional activation paradigms, using short- and long-cycled clenching designs. Small but statistically significant increases in Glx=Glutamate+Glutamine (3.8%) and Glu (4.0%) concentrations were detected during the long-cycled design, while no statistically significant changes were observed during the short-cycled design. Activation during the long-cycled tasks was correlated to the frequency of clenching. We have also shown that using subject-level analysis in combination with a linear mixed model increases the observed effect size, and could help analyzing the weak MRS signals. Our results are in good agreement with the previous reports acquired at higher field systems, and support the viability of fMRS as a research tool at clinical field strengths, while also emphasizing the importance of the functional paradigm itself.

Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing.

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner - a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.

Optical measurement of microvascular oxygenation and blood flow responses in awake mouse cortex during functional activation

The cerebral cortex has a number of conserved morphological and functional characteristics across brain regions and species. Among them, the laminar differences in microvascular density and mitochondrial cytochrome c oxidase staining suggest potential laminar variability in the baseline O2 metabolism and/or laminar variability in both O2 demand and hemodynamic response. Here, we investigate the laminar profile of stimulus-induced intravascular partial pressure of O2 (pO2) transients to stimulus-induced neuronal activation in fully awake mice using two-photon phosphorescence lifetime microscopy. Our results demonstrate that stimulus-induced changes in intravascular pO2 are conserved across cortical layers I–IV, suggesting a tightly controlled neurovascular response to provide adequate O2 supply across cortical depth. In addition, we observed a larger change in venular O2 saturation (ΔsO2) compared to arterioles, a gradual increase in venular ΔsO2 response towards the cortical surface, and absence of the intravascular “initial dip” previously reported under anesthesia. This study paves the way for quantification of layer-specific cerebral O2 metabolic responses, facilitating investigation of brain energetics in health and disease and informed interpretation of laminar blood oxygen level dependent functional magnetic resonance imaging signals.

Lactate dehydrogenase expression modulates longevity and neurodegeneration in Drosophila melanogaster.

Lactate dehydrogenase (LDH) catalyzes the conversion of glycolysis-derived pyruvate to lactate. Lactate has been shown to play key roles in brain energetics and memory formation. However, lactate levels are elevated in aging and Alzheimer’s disease patients, and it is not clear whether lactate plays protective or detrimental roles in these contexts. Here we show that Ldh transcript levels are elevated and cycle with diurnal rhythm in the heads of aged flies and this is associated with increased LDH protein, enzyme activity, and lactate concentrations. To understand the biological significance of increased Ldh gene expression, we genetically manipulated Ldh levels in adult neurons or glia. Overexpression of Ldh in both cell types caused a significant reduction in lifespan whereas Ldh down-regulation resulted in lifespan extension. Moreover, pan-neuronal overexpression of Ldh disrupted circadian locomotor activity rhythms and significantly increased brain neurodegeneration. In contrast, reduction of Ldh in neurons delayed age-dependent neurodegeneration. Thus, our unbiased genetic approach identified Ldh and lactate as potential modulators of aging and longevity in flies.

Metabolic changes in human brain evolution.

Because the human brain is considerably larger than those of other primates, it is not surprising that its energy requirements would far exceed that of any of the species within the order. Recently, the development of stem cell technologies and single-cell transcriptomics provides novel ways to address the question of what specific genomic changes underlie the human brain's unique phenotype. In this review, we consider what is currently known about human brain metabolism using a variety of methods from brain imaging and stereology to transcriptomics. Next, we examine novel opportunities that stem cell technologies and single-cell transcriptomics provide to further our knowledge of human brain energetics. These new experimental approaches provide the ability to elucidate the functional effects of changes in genetic sequence and expression levels that potentially had a profound impact on the evolution of the human brain.

Redistribution of Monocarboxylate 1 and 4 in Hippocampus and Spatial Memory Impairment Induced by Long-term Ketamine Administration.

The monocarboxylate transporters (MCTs) MCT1, MCT2, and MCT4 are essential components of the astrocyte-neuron lactate shuttle (ANLS), which is a fundamental element of brain energetics. Decreased expression of MCTs can induce cognitive dysfunction of the brain. In the present study, we established a mouse model of long-term ketamine administration by subjecting mice to a 6-month course of a daily intraperitoneal injection of ketamine. These mice demonstrated learning and memory deficits and a significant decline in MCT1 and MCT4 proteins in the hippocampal membrane fraction, while cytoplasmic MCT1 and MCT4 protein levels were significantly increased. In contrast, the levels of global MCT2 protein were significantly increased. Analysis of mRNA levels found no changes in MCT1/4 transcripts, although the expression of MCT2 mRNA was significantly increased. We suggest that redistribution of hippocampal MCT1 and MCT4, but not MCT2 up-regulation, may be related to learning and memory deficits induced by long-term ketamine administration.

Lafora Disease: Differential Metabolic Disturbances in Neurons and Astrocytes

The brain is an incredible energy‐demanding organ and even small disturbances in brain energetics may have fatal consequences. Lafora disease (LD) is a rare metabolic and neurodegenerative disorder clinically presenting with tonic‐clonic epileptic seizures and myoclonic jerks. LD patients experience rapid neurodegeneration starting in early adolescence and the disease is indisputable fatal typically within 10 years of onset. LD is caused by mutations in the genes EPM2A or EPM2B encoding the proteins Laforin and Malin, both implicated in glycogen metabolism. However, the mechanism of disease is poorly understood, though emerging evidence suggests that neurons and glial cells are affected differently in LD. This study aims to elucidate the effect of laforin on central carbon metabolism in different cellular compartments. We employed a systematic characterization of glucose metabolism in cerebral brain slices from 3‐months old Epm2a−/− and wildtype animals in addition to primary cultures of neurons and astrocytes utilizing [U‐13C]glucose and subsequent analysis by gas chromatography‐mass spectroscopy. Furthermore, slices were incubated with [U‐13C]glutamine and [U‐13C]glutamate to assess neuronal and astrocytic metabolic compartmentation, since glutamine is predominantly taken up and metabolized by neurons, and glutamate by astrocytes. The results of this study revealed complex disturbances of central carbon metabolism in the LD brain with clear metabolic distinctions between cerebral cell types. Disturbed oxidative glucose metabolism was observed in both primary cultures of neurons and astrocytes and in acutely isolated brain slices. Interestingly, the results indicate a compartmentalized glucose metabolism where neuronal glucose metabolism is downregulated, and astrocytic glucose metabolism upregulated in Epm2A−/− mice. Furthermore, neuronal glutamine metabolism was increased whereas glial glutamate metabolism was unaffected. Overall, this study provides evidence of altered glucose and neurotransmitter metabolism in LD related to loss of laforin and hereby dysfunctional glycogen metabolism. Further investigation of metabolic alterations in cerebral cell types may provide important insights into the mechanism of disease and targeted treatment.

Excitatory/inhibitory neuronal metabolic balance in mouse hippocampus upon infusion of [U-13C6]glucose

Hippocampus plays a critical role in linking brain energetics and behavior typically associated to stress exposure. In this study, we aimed to simultaneously assess excitatory and inhibitory neuronal metabolism in mouse hippocampus in vivo by applying 18FDG-PET and indirect 13C magnetic resonance spectroscopy (1H-[13C]-MRS) at 14.1 T upon infusion of uniformly 13C-labeled glucose ([U-13C6]Glc). Improving the spectral fitting by taking into account variable decoupling efficiencies of [U-13C6]Glc and refining the compartmentalized model by including two γ-aminobutyric acid (GABA) pools permit us to evaluate the relative contributions of glutamatergic and GABAergic metabolism to total hippocampal neuroenergetics. We report that GABAergic activity accounts for ∼13% of total neurotransmission (VNT) and ∼27% of total neuronal TCA cycle (VTCA) in mouse hippocampus suggesting a higher VTCA/VNT ratio for inhibitory neurons compared to excitatory neurons. Finally, our results provide new strategies and tools for bringing forward the developments and applications of 13C-MRS in specific brain regions of small animals.

Brain energetics, mitochondria, and traumatic brain injury.

We review current thinking about, and draw connections between, brain energetics and metabolism, and between mitochondria and traumatic brain injury. Energy is fundamental to proper brain function. Its creation in a useful form for neurons and glia, and consistently in response to the brain's high energy needs, is critical for physiological pathways. Dysfunction in the mechanisms of energy production is at the center of neurological and neuropsychiatric pathologies. We examine the connections between energetics and mitochondria - the organelle responsible for almost all the energy production in the cell - and how secondary pathologies in traumatic brain injury result from energetic dysfunction. This paper interweaves these topics, a necessity since they are closely coupled, and identifies where there exist a lack of understanding and of data. In addition to summarizing current thinking in these disciplines, our goal is to suggest a framework for the mathematical modeling of mechanisms and pathways based on optimal energetic decisions.

The development of executive function in early childhood is inversely related to change in body mass index: Evidence for an energetic tradeoff?

A well-established literature demonstrates executive function (EF) deficits in obese children and adults relative to healthy weight comparisons. EF deficits in obesity are associated with overeating and impulsive consumption of high calorie foods leading to excess weight gain and to problems with metabolic regulation and low-grade inflammation that detrimentally affect the structure and function of prefrontal cortex. Here, we test a complementary explanation for the relation between EF and body mass index (BMI) grounded in the energy demand of the developing brain. Recent work shows that the brain accounts for a lifetime peak of 66% of resting metabolic rate in childhood and that developmental changes in brain energetics and normative changes in body weight gain are closely inversely related. This finding suggests a trade-off in early childhood between energy used to support brain development versus energy used to support physical growth and fat deposition. To test this theorized energetic trade-off, we analyzed data from a large longitudinal sample (N=1,292) and found that change in EF from age 3 to 5years, as a proxy for brain development in energetically costly prefrontal cortex, is inversely related to change in BMI from age 2 to 5years. Greater linear decline in BMI predicted greater linear increase in EF. We interpret this finding as tentative support for a brain-body energetic trade-off in early childhood with implications for lifetime obesity risk.