Brain Energetics Research Articles

Astrocytic GLUT1 reduction paradoxically improves central and peripheral glucose homeostasis.

Astrocytes are considered an essential source of blood-borne glucose or its metabolites to neurons. Nonetheless, the necessity of the main astrocyte glucose transporter, i.e., GLUT1, for brain glucose metabolism has not been defined. Unexpectedly, we found that brain glucose metabolism was paradoxically augmented in mice with astrocytic GLUT1 reduction (GLUT1ΔGFAP mice). These mice also exhibited improved peripheral glucose metabolism especially in obesity, rendering them metabolically healthier. Mechanistically, we observed that GLUT1-deficient astrocytes exhibited increased insulin receptor-dependent ATP release, and that both astrocyte insulin signaling and brain purinergic signaling are essential for improved brain function and systemic glucose metabolism. Collectively, we demonstrate that astrocytic GLUT1 is central to the regulation of brain energetics, yet its depletion triggers a reprogramming of brain metabolism sufficient to sustain energy requirements, peripheral glucose homeostasis, and cognitive function.

Metabolic flexibility ensures proper neuronal network function in moderate neuroinflammation

Microglia, brain-resident macrophages, can acquire distinct functional phenotypes, which are supported by differential reprogramming of cell metabolism. These adaptations include remodeling in glycolytic and mitochondrial metabolic fluxes, potentially altering energy substrate availability at the tissue level. This phenomenon may be highly relevant in the brain, where metabolism must be precisely regulated to maintain appropriate neuronal excitability and synaptic transmission. Direct evidence that microglia can impact on neuronal energy metabolism has been widely lacking, however. Combining molecular profiling, electrophysiology, oxygen microsensor recordings and mathematical modeling, we investigated microglia-mediated disturbances in brain energetics during neuroinflammation. Our results suggest that proinflammatory microglia showing enhanced nitric oxide release and decreased CX3CR1 expression transiently increase the tissue lactate/glucose ratio that depends on transcriptional reprogramming in microglia, not in neurons. In this condition, neuronal network activity such as gamma oscillations (30–70 Hz) can be fueled by increased ATP production in mitochondria, which is reflected by elevated oxygen consumption. During dysregulated inflammation, high energy demand and low glucose availability can be boundary conditions for neuronal metabolic fitness as revealed by kinetic modeling of single neuron energetics. Collectively, these findings indicate that metabolic flexibility protects neuronal network function against alterations in local substrate availability during moderate neuroinflammation.

Sleep-stage-dependent alterations in cerebral oxygen metabolism quantified by magnetic resonance.

A key function of sleep is to provide a regular period of reduced brain metabolism, which is critical for maintenance of healthy brain function. The purpose of this work was to quantify the sleep-stage-dependent changes in brain energetics in terms of cerebral metabolic rate of oxygen (CMRO2 ) as a function of sleep stage using quantitative magnetic resonance imaging (MRI) with concurrent electroencephalography (EEG) during sleep in the scanner. Twenty-two young and older subjects with regular sleep hygiene and Pittsburgh Sleep Quality Index (PSQI) in the normal range were recruited for the study. Cerebral blood flow (CBF) and venous oxygen saturation (SvO2 ) were obtained simultaneously at 3 Tesla field strength and 2.7-s temporal resolution during an 80-min time series using OxFlow, an in-house developed imaging sequence. The method yields whole-brain CMRO2 in absolute physiologic units via Fick's Principle. Nineteen subjects yielded evaluable data free of subject motion artifacts. Among these subjects, 10 achieved slow-wave (N3) sleep, 16 achieved N2 sleep, and 19 achieved N1 sleep while undergoing the MRI protocol during scanning. Mean CMRO2 was 98 ± 7(μmol min-1 )/100 g awake, declining progressively toward deepest sleep stage: 94 ± 10.8 (N1), 91 ± 11.4 (N2), and 76 ± 9.0 μmol min-1 /100 g (N3), with each level differing significantly from the wake state. The technology described is able to quantify cerebral oxygen metabolism in absolute physiologic units along with non-REM sleep stage, indicating brain oxygen consumption to be closely associated with depth of sleep, with deeper sleep stages exhibiting progressively lower CMRO2 levels.

Ketogenic diet reduces a neurobiological craving signature in inpatients with alcohol use disorder.

Increasing evidence suggests that a ketogenic (high-fat, low-carbohydrate) diet (KD) intervention reduces alcohol withdrawal severity and alcohol craving in individuals with alcohol use disorder (AUD) by shifting brain energetics from glucose to ketones. We hypothesized that the KD would reduce a neurobiological craving signature when individuals undergoing alcohol detoxification treatment were exposed to alcohol cues. We performed a secondary analysis of functional magnetic resonance data of 33 adults with an AUD who were randomized to a KD (n = 19) or a standard American diet (SA; n = 14) and underwent 3 weeks of inpatient alcohol detoxification treatment. Once per week, participants performed an alcohol cue-reactivity paradigm with functional magnetic resonance imaging. We extracted brain responses to food and alcohol cues and quantified the degree to which each set of brain images shared a pattern of activation with a recently established 'Neurobiological Craving Signature' (NCS). We then performed a group-by-time repeated measures ANOVA to test for differences in craving signature expression between the dietary groups over the three-week treatment period. We also correlated these expression patterns with self-reported wanting ratings for alcohol cues. For alcohol relative to food cues, there was a main effect of group, such that the KD group showed lower NCS expression across all 3 weeks of treatment. The main effect of time and the group-by-time interaction were not significant. Self-reported wanting for alcohol cues reduced with KD compared to SA but did not correlate with the NCS score. A ketogenic diet reduces self-reported alcohol wanting, and induced lower NCS to alcohol cues during inpatient treatment for AUD. However, in the KD group alcohol wanting continued to decrease across the 3 weeks of abstinence while the NCS scores remained stable, suggesting that this cue-induced NCS may not fully capture ongoing, non-cue-induced alcohol desire.

Abstract 105: Sex Difference in Brain Energy Metabolism After Electronic Cigarette Vape Exposure May Contribute to Worsened Stroke Injury in Rats

Introduction: Electronic cigarettes (EC) are battery-powered nicotine delivery devices that have gained popularity as alternatives to tobacco cigarettes for young smokers and smokers trying to cease. Because of its relative novelty, our understanding about the effects of EC vaping on stroke outcome is limited. Here we aim to investigate the effects of EC on energy metabolism in the brain and on stroke outcome in animals of both sexes. Methods: Female and male Sprague-Dawley rats (2-3 months old; n=8) were randomly assigned to either air or EC vapor (5% nicotine Juul pods) exposure for 16 nights using the EcigAero-TM Aerosol Exposure Apparatus. After the exposure period, the rats were divided into two cohorts. The brains were collected from the first cohort of rats for unbiased metabolomic (Metabolon Inc.) or Western blot analysis. The second cohort underwent transient middle cerebral artery occlusion (tMCAO; 90 min) or sham surgery and was survived for 21 days. During the post-tMCAO/sham survival, cognition was assessed using the Morris water maze followed by brain collection for histopathological analysis. Results: Metabolomic analysis showed substantial changes in glycolytic metabolites in EC-exposed female rats in relation to air controls, implying altered brain energetics. In EC-exposed female animals, a significant increase (p<0.05) in glucose, glucose 6-phosphate, fructose-6-phosphate, and fructose 1-6 diphosphate was noted compared to air controls. However, such changes were not seen in EC-exposed male rats. Quantification of infarct volume demonstrated that, compared to air rats, EC-exposed rats displayed a significantly increased infarct volume in female rats while showing a trend of increase in male rats. In female rats, infarct volumes were 86 ± 19 mm 3 and 151 ± 25 mm 3 for air and EC groups, respectively, a significant difference (p<0.05). In the male rat air group, tMCAO resulted in an infarct volume of 80 ± 37 mm 3 , while EC yielded 130 ± 38 mm 3 . Behavioral testing showed worsened post-stroke cognitive outcome in EC groups compared to air groups in rats of both sexes. Conclusion: EC vape exposure, even for as short as two weeks, impacts glucose metabolism and worsens post-stroke cognitive deficits in female more than male rats.

Glucose dysregulation in antipsychotic-naive first-episode psychosis: in silico exploration of gene expression signatures

Antipsychotic (AP)-naive first-episode psychosis (FEP) patients display early dysglycemia, including insulin resistance and prediabetes. Metabolic dysregulation may therefore be intrinsic to psychosis spectrum disorders (PSDs), independent of the metabolic effects of APs. However, the potential biological pathways that overlap between PSDs and dysglycemic states remain to be identified. Using meta-analytic approaches of transcriptomic datasets, we investigated whether AP-naive FEP patients share overlapping gene expression signatures with non-psychiatrically ill early dysglycemia individuals. We meta-analyzed peripheral transcriptomic datasets of AP-naive FEP patients and non-psychiatrically ill early dysglycemia subjects to identify common gene expression signatures. Common signatures underwent pathway enrichment analysis and were then used to identify potential new pharmacological compounds via Integrative Library of Integrated Network-Based Cellular Signatures (iLINCS). Our search results yielded 5 AP-naive FEP studies and 4 early dysglycemia studies which met inclusion criteria. We discovered that AP-naive FEP and non-psychiatrically ill subjects exhibiting early dysglycemia shared 221 common signatures, which were enriched for pathways related to endoplasmic reticulum stress and abnormal brain energetics. Nine FDA-approved drugs were identified as potential drug treatments, of which the antidiabetic metformin, the first-line treatment for type 2 diabetes, has evidence to attenuate metabolic dysfunction in PSDs. Taken together, our findings support shared gene expression changes and biological pathways associating PSDs with dysglycemic disorders. These data suggest that the pathobiology of PSDs overlaps and potentially contributes to dysglycemia. Finally, we find that metformin may be a potential treatment for early metabolic dysfunction intrinsic to PSDs.

Recent Advances in MR Imaging-based Quantification of Brain Oxygen Metabolism.

The metabolic rate of oxygen (MRO2) is fundamental to tissue metabolism. Determination of MRO2 demands knowledge of the arterio-venous difference in hemoglobin-bound oxygen concentration, typically expressed as oxygen extraction fraction (OEF), and blood flow rate (BFR). MRI is uniquely suited for measurement of both these quantities, yielding MRO2 in absolute physiologic units of µmol O2 min-1/100 g tissue. Two approaches are discussed, both relying on hemoglobin magnetism. Emphasis will be on cerebral oxygen metabolism expressed in terms of the cerebral MRO2 (CMRO2), but translation of the relevant technologies to other organs, including kidney and placenta will be touched upon as well. The first class of methods exploits the blood's bulk magnetic susceptibility, which can be derived from field maps. The second is based on measurement of blood water T2, which is modulated by diffusion and exchange in the local-induced fields within and surrounding erythrocytes. Some whole-organ methods achieve temporal resolution adequate to permit time-series studies of brain energetics, for instance, during sleep in the scanner with concurrent electroencephalogram (EEG) sleep stage monitoring. Conversely, trading temporal for spatial resolution has led to techniques for spatially resolved approaches based on quantitative blood oxygen level dependent (BOLD) or calibrated BOLD models, allowing regional assessment of vascular-metabolic parameters, both also exploiting deoxyhemoglobin paramagnetism like their whole-organ counterparts.

Metabolic cross‐talk between astrocytes and neurons: implications for Alzheimer’s disease

AbstractBackgroundConverging evidence indicates that declining brain energetics contributes to the initiation and progression of neurodegenerative disorders, including Alzheimer’s disease (AD). Upstream events often characterizing AD include hypometabolism of glucose and oxygen in the brain, which may cause mitochondrial dysfunction, energetic failure, and oxidative stress (Moreira et al., 2010). Astrocytes, which have a main role in supporting neuronal function and metabolism, might contribute to the development of neurodegenerative diseases. By modulating the release of gliotransmitters (e.g. glutamate), they provide a fine control of neuronal metabolism and cell‐to‐cell communication, both of them involved in AD (Monterey et al., 2021). Impaired astrocytes metabolism may incite an inflammatory response that, in turn, negatively impacts neuronal viability.MethodPrimary rat cortical astrocytes were isolated from the cortex of Wistar rat pups. A metabolic stress was induced by using glyceraldehyde (GA) (Magi et al., 2021). We evaluated cell viability, the release of tumor necrosis factor alpha (TNFα) and the involvement of the nuclear factor‐kappa B (NF‐kB) pathway. In order to check the glutamate turnover, we analyzed the expression of GLAST and GLT1 and we evaluated the ATP content after glutamate exposure under physiological conditions. We also explored whether damaged astrocytes could elicit neuronal death in a co‐culture setting.ResultExposure to increasing concentrations of GA caused a concentration‐dependent cell injury in rat cortical astrocytes. GA (1mM) started to induce a significant cell damage after 24 h. After 48 h, GA exposure activated the NF‐kB pathway and the release of TNFα. GA treatment significantly increased GLAST and GLT1 levels after 48h. When injured astrocytes were co‐cultured with cortical neurons, neurons viability significantly decreased. Under physiological condition, glutamate significantly improved intracellular ATP levels after 4 and 8 hours of treatment, paving the way to the evaluation of its action in metabolic‐impaired setting, as induced by GA treatment.ConclusionOur results suggest that metabolically impaired astrocytes may damage neighboring neurons, suggesting astrocytes involvement in the pathophysiological development and progression of AD. Therefore, astrocytes can be considered a key therapeutic and neuroprotective target for future studies.

Potential role of creatine as an anticonvulsant agent: evidence from preclinical studies.

Epilepsy is one of the most common neurological disorders affecting people of all ages representing a significant social and public health burden. Current therapeutic options for epilepsy are not effective in a significant proportion of patients suggesting a need for identifying novel targets for the development of more effective therapeutics. There is growing evidence from animal and human studies suggesting a role of impaired brain energy metabolism and mitochondrial dysfunction in the development of epilepsy. Candidate compounds with the potential to target brain energetics have promising future in the management of epilepsy and other related neurological disorders. Creatine is a naturally occurring organic compound that serves as an energy buffer and energy shuttle in tissues, such as brain and skeletal muscle, that exhibit dynamic energy requirements. In this review, applications of creatine supplements in neurological conditions in which mitochondrial dysfunction is a central component in its pathology will be discussed. Currently, limited evidence mainly from preclinical animal studies suggest anticonvulsant properties of creatine; however, the exact mechanism remain to be elucidated. Future work should involve larger clinical trials of creatine used as an add-on therapy, followed by large clinical trials of creatine as monotherapy.

Brain energetics and the connectionist concept in cognitive neuroscience.

One of the central paradigms of modern neuroscience is the connectionist concept suggesting that the brain's cognitive functions are carried out at the level of neural networks through complex interactions among neurons. This concept considers neurons as simple network elements whose function is limited to generating electrical potentials and transmitting signals to other neurons. Here, I focus on the neuroenergetic aspect of cognitive functions and argue that many findings from this field challenge the concept that cognitive functions are performed exclusively at the level of neural circuits. Two of these findings are particularly foretelling. First, activation of the cerebral cortex in humans (sensory stimulation or solving cognitive problems) is not associated with a significant increase in energy demand. Second, the energetic cost of the brain per unit mass in primates, including Homo sapiens, is approximately proportional to the number of cerebral neurons but not to the number of synapses, the complexity of neural networks, or the level of brain's intellectual abilities. These findings contradict the predictions of the connectionist concept. Rather, they suggest that cognitive functions are generated by intraneuronal mechanisms that do not require much energy. In this context, interactions among neurons would serve to coordinate activities of neurons performing elementary cognitive functions. This function of the network mechanisms also does not require much energy.

The left-lateralisation of citrate synthase activity in the anterior cingulate cortex of male violent suicide victims

The anterior cingulate cortex (AC) as a part of prefrontal cortex plays a crucial role in behavioural regulation, which is profoundly disturbed in suicide. Citrate synthase (CS) is a key enzyme of tricarboxylic acid cycle fundamental for brain energetics and neurotransmitter synthesis, which are deteriorated in suicidal behaviour. However, CS activity has not been yet studied in brain structures of suicide victims. CS activity assay was performed bilaterally on frozen samples of the rostral part of the AC of 24 violent suicide completers (21 males and 3 females) with unknown psychiatric diagnosis and 24 non-suicidal controls (20 males and 4 females). Compared to controls, suicide victims revealed decreased CS activity in the right AC, however, insignificant. Further statistical analysis of laterality index revealed the left-lateralisation of CS activity in the AC in male suicides compared to male controls (U-test P = 0.0003, corrected for multiple comparisons). The results were not confounded by postmortem interval, blood alcohol concentration, age, and brain weight. Our findings suggest that disturbed CS activity in the AC plays a role in suicide pathogenesis and correspond with our previous morphological and molecular studies of prefrontal regions in suicide.

Phosphorus metabolism in the brain of cognitively normal midlife individuals at risk for Alzheimer's disease

BackgroundNeurometabolic abnormalities and amyloid-beta plaque deposition are important early pathophysiologic changes in Alzheimer's disease (AD). This study investigated the relationship between high-energy phosphorus-containing metabolites, glucose uptake, and amyloid plaque using phosphorus magnetic resonance spectroscopy (31P-MRS) and positron emission tomography (PET). MethodsWe measured 31P-MRS, fluorodeoxyglucose (FDG)-PET, and Pittsburgh Compound B (PiB)-PET in a cohort of 20 cognitively normal middle-aged adults at risk for AD. We assessed 31P-MRS reliability by scanning a separate cohort of 13 healthy volunteers twice each. We calculated the coefficient-of-variation (CV) of metabolite ratios phosphocreatine-to-adenosine triphosphate (PCr/α-ATP), inorganic phosphate (Pi)-to-α-ATP, and phosphomonoesters-to-phosphodiesters (PME/PDE), and pH in pre-defined brain regions. We performed linear regression analysis to determine the relationship between 31P measurements and tracer uptake, and Dunn's multiple comparison tests to investigate regional differences in phosphorus metabolism. Finally, we performed linear regression analysis on 31P-MRS measurements in both cohorts to investigate the relationship of phosphorus metabolism with age. ResultsMost regional 31P metabolite ratio and pH inter- and intra-day CVs were well below 10%. There was an inverse relationship between FDG-SUV levels and metabolite ratios PCr/α-ATP, Pi/α-ATP, and PME/PDE in several brain regions in the AD risk group. There were also several regional differences among 31P metabolites and pH in the AD risk group including elevated PCr/α-ATP, depressed PME/PDE, and elevated pH in the temporal cortices. Increased PCr/α-ATP throughout the brain was associated with aging. ConclusionsPhosphorus spectroscopy in the brain can be performed with high repeatability. Phosphorus metabolism varies with region and age, and is related to glucose uptake in adults at risk for AD. Phosphorus spectroscopy may be a valuable approach to study early changes in brain energetics in high-risk populations.

Comparative analysis of astrocytes in the prefrontal cortex of primates: Insights into the evolution of human brain energetics.

Astrocytes are the main homeostatic cell of the brain involved in many processes related to cognition, immune response, and energy expenditure. It has been suggested that the distribution of astrocytes is associated with brain size, and that they are specialized in humans. To evaluate these, we quantified astrocyte density, soma volume, and total glia density in layer I and white matter in Brodmann's area 9 of humans, chimpanzees, baboons, and macaques. We found that layer I astrocyte density, soma volume, and ratio of astrocytes to total glia cells were highest in humans and increased with brain size. Overall glia density in layer I and white matter were relatively invariant across brain sizes, potentially due to their important metabolic functions on a per volume basis. We also quantified two transporters involved in metabolism through the astrocyte-neuron lactate shuttle, excitatory amino acid transporter 2 (EAAT2) and glucose transporter 1 (GLUT1). We expected these transporters would be increased in human brains due to their high rate of metabolic consumption and associated gene activity. While humans have higher EAAT2 cell density, GLUT1 vessel volume, and GLUT1 area fraction compared to baboons and chimpanzees, they did not differ from macaques. Therefore, EAAT2 and GLUT1 are not related to increased energetic demands of the human brain. Taken together, these data provide evidence that astrocytes play a unique role in both brain expansion and evolution among primates, with an emphasis on layer I astrocytes having a potentially significant role in human-specific metabolic processing and cognition.

(Phospho)creatine: the reserve and merry-go-round of brain energetics.

(Phospho)creatine: the reserve and merry-go-round of brain energetics.

Social Brain Energetics: Ergonomic Efficiency, Neurometabolic Scaling, and Metabolic Polyphenism in Ants.

Metabolism, a metric of the energy cost of behavior, plays a significant role in social evolution. Body size and metabolic scaling are coupled, and a socioecological pattern of increased body size is associated with dietary change and the formation of larger and more complex groups. These consequences of the adaptive radiation of animal societies beg questions concerning energy expenses, a substantial portion of which may involve the metabolic rates of brains that process social information. Brain size scales with body size, but little is understood about brain metabolic scaling. Social insects such as ants show wide variation in worker body size and morphology that correlates with brain size, structure, and worker task performance, which is dependent on sensory inputs and information-processing ability to generate behavior. Elevated production and maintenance costs in workers may impose energetic constraints on body size and brain size that are reflected in patterns of metabolic scaling. Models of brain evolution do not clearly predict patterns of brain metabolic scaling, nor do they specify its relationship to task performance and worker ergonomic efficiency, two key elements of social evolution in ants. Brain metabolic rate is rarely recorded and therefore the conditions under which brain metabolism influences the evolution of brain size are unclear. We propose that studies of morphological evolution, colony social organization, and worker ergonomic efficiency should be integrated with analyses of species-specific patterns of brain metabolic scaling to advance our understanding of brain evolution in ants.

P-105 - Brain energetics by biomedical modalities

P-105 - Brain energetics by biomedical modalities

Why do humans undergo an adiposity rebound? Exploring links with the energetic costs of brain development in childhood using MRI-based 4D measures of total cerebral blood flow

BackgroundIndividuals typically show a childhood nadir in adiposity termed the adiposity rebound (AR). The AR serves as an early predictor of obesity risk, with early rebounders often at increased risk; however, it is unclear why this phenomenon occurs, which could impede understandings of weight gain trajectories. The brain’s energy requirements account for a lifetime peak of 66% of the body’s resting metabolic expenditure during childhood, around the age of the AR, and relates inversely to weight gain, pointing to a potential energy trade-off between brain development and adiposity. However, no study has compared developmental trajectories of brain metabolism and adiposity in the same individuals, which would allow a preliminary test of a brain-AR link.MethodsWe used cubic splines and generalized additive models to compare age trajectories of previously collected MRI-based 4D flow measures of total cerebral blood flow (TCBF), a proxy for cerebral energy use, to the body mass index (BMI) in a cross-sectional sample of 82 healthy individuals (0–60 years). We restricted our AR analysis to pre-pubertal individuals (0–12 years, n = 42), predicting that peak TCBF would occur slightly after the BMI nadir, consistent with evidence that lowest BMI typically precedes the nadir in adiposity.ResultsTCBF and the BMI showed inverse trajectories throughout childhood, while the estimated age at peak TCBF (5.6 years) was close but slightly later than the estimated age of the BMI nadir (4.9 years).ConclusionsThe timing of peak TCBF in this sample points to a likely concordance between peak brain energetics and the nadir in adiposity. Inverse age trajectories between TCBF and BMI support the hypothesis that brain metabolism is a potentially important influence on early life adiposity. These findings also suggest that experiences influencing the pattern of childhood brain energy use could be important predictors of body composition trajectories.

Dietary factors and brain health.

Nutrition is a complex exposure (i.e., the food exposome) that influences brain function and health through multiple pathways. We review recent epidemiological studies that have improved the characterization of the food exposome and brain health in humans and have revealed promising nutrition-based strategies to prevent cognitive aging. A selection of epidemiological research from the past 18 months of both observational and clinical studies is presented, with a focus on novel findings, including novel nutrient and diet patterns, diet-related approaches to rescue brain energetics defects in aging, and biomarker-based studies to decipher specific neurobiological pathways of nutrition and brain health. Although healthy diets such as the Mediterranean diet promote brain health throughout life, specific diets, such as the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay diet, or specific nutrients (LC n-3 polyunsaturated fatty acids, carotenoids, vitamin D, B vitamins, polyphenols) alone or in combination, may prevent cognitive aging. Diet management approaches to rescue brain energetics defects such as the Modified Mediterranean-ketogenic diet may be promising to prevent neurodegenerative diseases. Expanding research also suggests that promotion of a healthy gut microbiome through prebiotic foods may preserve the diet-gut-brain axis with aging. Future studies should explore more individualized preventive approaches through a 'precision nutrition' framework.

Transforming a neural circuit to function without oxygen and glucose delivery

Disruptions in the delivery of oxygen and glucose impair the function of neural circuits, with lethal consequences commonly observed in stroke and cardiac arrest. Intense focus has been placed on understanding how to overcome neuronal failure during energy stress. Important insights into neuroprotective strategies have come from studies of evolutionary adaptations for survival in hypoxic environments, such as those seen in turtles, naked mole-rats, and several other animals1. Amphibians are not usually numbered among 'champion' hypoxia-tolerant vertebrates, yet here we demonstrate a massive increase in the capacity of a neural circuit to produce activity following oxygen and glucose deprivation in adult bullfrogs. Rhythmic output from a brainstem circuit failed following minutes of severe hypoxia and simulated ischemia; however, after hibernation this network produced patterned activity for ∼3.5 hours during severe hypoxia and ∼2 hours in ischemia. This remarkable improvement was supported by a switch to brain glycogen to fuel anaerobic glycolysis, a pathway thought to support neuronal homeostasis for only a few minutes during ischemia2. These results reveal that circuit activity can exhibit dramatic metabolic plasticity that minimizes the need for ATP synthesis, and these findings represent the greatest range in hypoxia tolerance within a vertebrate neural network. Uncovering the rules that allow the brain to flexibly run only on endogenous fuel reserves will reveal new insights into brain energetics, circuit evolution, and neuroprotection.

Creatine transporter deficiency impairs stress adaptation and brain energetics homeostasis.

The creatine transporter (CrT) maintains brain creatine (Cr) levels, but the effects of its deficiency on energetics adaptation under stress remain unclear. There are also no effective treatments for CrT deficiency, the second most common cause of X-linked intellectual disabilities. Herein, we examined the consequences of CrT deficiency in brain energetics and stress-adaptation responses plus the effects of intranasal Cr supplementation. We found that CrT-deficient (CrT–/y) mice harbored dendritic spine and synaptic dysgenesis. Nurtured newborn CrT–/y mice maintained baseline brain ATP levels, with a trend toward signaling imbalance between the p-AMPK/autophagy and mTOR pathways. Starvation elevated the signaling imbalance and reduced brain ATP levels in P3 CrT–/y mice. Similarly, CrT–/y neurons and P10 CrT–/y mice showed an imbalance between autophagy and mTOR signaling pathways and greater susceptibility to cerebral hypoxia-ischemia and ischemic insults. Notably, intranasal administration of Cr after cerebral ischemia increased the brain Cr/N-acetylaspartate ratio, partially averted the signaling imbalance, and reduced infarct size more potently than intraperitoneal Cr injection. These findings suggest important functions for CrT and Cr in preserving the homeostasis of brain energetics in stress conditions. Moreover, intranasal Cr supplementation may be an effective treatment for congenital CrT deficiency and acute brain injury.