Aerobic glycolysis in the human brain is associated with development and neotenous gene expression

“The 116 AGassociated genes were analyzed with three gene ontology methods, including GeneMANIA (Warde-Farley et al., 2010), DAVID (Huang da et al., 2009), and userListEnrichmentR (Miller et al., 2011) (Table 1, see also Tables S3 and S4).”

“Interestingly, in the adult brain, the highest levels of resting state AG are found in the default mode network (DMN), a constellation of brain regions originally identified as most active in the absence of attention-demanding, goal-directed task performance (Raichle et al., 2001).”

“More recently, the DMN has emerged as among the most functionally robust networks in the brain, as evidenced by its correlated intrinsic activity (Fox and Raichle, 2007), a property now widely referred to as functional connectivity (Bullmore and Sporns, 2012).”

“Similar results are obtained with other gene ontology tools, including GeneMANIA and userListEnrichment (Table S4) (Miller et al., 2011; Warde-Farley et al., 2010).”

“Most of this glucose is oxidized in order to supply the large amounts of ATP required to maintain membrane ion gradients and other cellular processes related to synaptic transmission (Attwell and Laughlin, 2001; Lennie, 2003; Raichle and Mintun, 2006; Sibson et al., 1997, 1998).”

“The DMN also constitutes a central hub of structural (axonal) connectivity (Bullmore and Sporns, 2012; Vaishnavi et al., 2010).”

“The AHBA data were corrected for batch C effects and normalized to the 75%quantile as previously described (Hawrylycz et al., 2012).”

“Accordingly, it may not be coincidental that neuronal bursting plays a role in shaping synaptic connections during development (Katz and Shatz, 1996).”

“Regions are named according to the BSS (Kang et al., 2011): CBC, cerebellum; MD, thalamus; AMY, amygdala; HIP, hippocampus; ITC, inferior temporal cortex; STR, striatum; V1C, primary visual cortex; STC, superior temporal cortex; A1C, auditory cortex; IPC, inferior parietal cortex; M1C, primary motor cortex; S1C, prima…”

“Uncoupling of glucose metabolism from oxygen consumption is characteristic of the brain’s response to imposed tasks (‘‘activation’’) (Fox et al., 1988).”

“It also stimulates gene expression related to long-term memory (Barros, 2013; Suzuki et al., 2011).”

“Other top 116 associations with aerobic glycolysis included potassium ion channels, genes implicated in synaptic transmission and plasticity, neuropeptides and neuropeptide receptors, and NRGN (neurogranin), a gene implicated in schizophrenia (Stefansson et al., 2009).”

“Most of this glucose is oxidized in order to supply the large amounts of ATP required to maintain membrane ion gradients and other cellular processes related to synaptic transmission (Attwell and Laughlin, 2001; Lennie, 2003; Raichle and Mintun, 2006; Sibson et al., 1997, 1998).”

“…stages of life, including premature neonates, growing normal children, young adults, and the elderly (Altman et al., 1993; Burns and Tyrrell, 1992; Chugani et al., 1987; Frewen et al., 1991; Himwich et al., 1959; Kennedy and Sokoloff, 1957; Kinnala et al., 1996; Kuhl et al., 1982; Leenders et…”

“More recently, the concept has been broadened to encompass within-species delayed maturation of specific features (Petanjek et al., 2011).”

“Bacteria evolve according to this tradeoff to occupy niches on the basis of either high ATP yield or rapid growth (Pfeiffer et al., 2001; Schuetz et al., 2012).”

“More specifically, we hypothesize that AG supports synaptic and neurite formation as well as turnover, which most likely persists throughout the lifespan (Goyal and Raichle, 2013; Marder and Goaillard, 2006).”

“Most of this glucose is oxidized in order to supply the large amounts of ATP required to maintain membrane ion gradients and other cellular processes related to synaptic transmission (Attwell and Laughlin, 2001; Lennie, 2003; Raichle and Mintun, 2006; Sibson et al., 1997, 1998).”

“…Tyrrell, 1992; Chugani et al., 1987; Frewen et al., 1991; Himwich et al., 1959; Kennedy and Sokoloff, 1957; Kinnala et al., 1996; Kuhl et al., 1982; Leenders et al., 1990; Pantano et al., 1984; Perlmutter et al., 1987; Petit-Taboué et al., 1998; 50 Cell Metabolism 19, 49–57, January 7, 2014 ª2014…”

“Most of this glucose is oxidized in order to supply the large amounts of ATP required to maintain membrane ion gradients and other cellular processes related to synaptic transmission (Attwell and Laughlin, 2001; Lennie, 2003; Raichle and Mintun, 2006; Sibson et al., 1997, 1998).”

“Some fraction of the resulting lactate may be taken up by neurons; this process is known as the ‘‘astrocyte-neuron lactate shuttle’’ (Kasischke et al., 2004).”

“AG correlates with centrality as defined by large-scale, structural, and resting state functional connectivity studies of the human brain (Bullmore and Sporns, 2012; Vaishnavi et al., 2010).”

“AG is a prominent feature of cancer cell metabolism; its main role is thought to be the support of biosynthetic pathways required for cellular proliferation (Locasale and Cantley, 2011; Lunt and Vander Heiden, 2011).”

“Bacteria evolve according to this tradeoff to occupy niches on the basis of either high ATP yield or rapid growth (Pfeiffer et al., 2001; Schuetz et al., 2012).”

“Ephrins and ephrin receptors are known to support a variety of development and remodeling functions, including the regulation of axon guidance and development of dendritic filopodia (Klein, 2009).”

“The regional neoteny index was calculated as the number of genes (effectively, the percentage of genes) demonstrating significant neoteny on the basis of themethod of Somel et al. (2009).”

“Furthermore, AG identifies regions most vulnerable to amyloid-beta deposition in Alzheimer’s disease (Vlassenko et al., 2010).”

“…et al., 1987; Frewen et al., 1991; Himwich et al., 1959; Kennedy and Sokoloff, 1957; Kinnala et al., 1996; Kuhl et al., 1982; Leenders et al., 1990; Pantano et al., 1984; Perlmutter et al., 1987; Petit-Taboué et al., 1998; 50 Cell Metabolism 19, 49–57, January 7, 2014 ª2014 Elsevier…”

“…1993; Burns and Tyrrell, 1992; Chugani et al., 1987; Frewen et al., 1991; Himwich et al., 1959; Kennedy and Sokoloff, 1957; Kinnala et al., 1996; Kuhl et al., 1982; Leenders et al., 1990; Pantano et al., 1984; Perlmutter et al., 1987; Petit-Taboué et al., 1998; 50 Cell Metabolism 19, 49–57,…”

“Indeed, the upregulation of PDK3 acts as a switch for aerobic glycolysis in certain cancer cell lines (Lu et al., 2008).”

“Lactate has metabolic signaling functions (Barros, 2013).”

“Most of this glucose is oxidized in order to supply the large amounts of ATP required to maintain membrane ion gradients and other cellular processes related to synaptic transmission (Attwell and Laughlin, 2001; Lennie, 2003; Raichle and Mintun, 2006; Sibson et al., 1997, 1998).”

“The 116 AGassociated genes were analyzed with three gene ontology methods, including GeneMANIA (Warde-Farley et al., 2010), DAVID (Huang da et al., 2009), and userListEnrichmentR (Miller et al., 2011) (Table 1, see also Tables S3 and S4).”

“…young adults, and the elderly (Altman et al., 1993; Burns and Tyrrell, 1992; Chugani et al., 1987; Frewen et al., 1991; Himwich et al., 1959; Kennedy and Sokoloff, 1957; Kinnala et al., 1996; Kuhl et al., 1982; Leenders et al., 1990; Pantano et al., 1984; Perlmutter et al., 1987;…”

“Measured AG may also represent lactate efflux generated by glycolysis or a glycogen shunt in order to rapidly supply ATP at intensely active synapses (Shulman et al., 2001).”

“In normal, awake, resting adult humans, lactate efflux most likely accounts for 20% of this excess glucose consumption (Madsen et al., 1995; Raichle et al., 1970), though estimates vary (Dalsgaard et al., 2004).”

“In normal, awake, resting adult humans, lactate efflux most likely accounts for 20% of this excess glucose consumption (Madsen et al., 1995; Raichle et al., 1970), though estimates vary (Dalsgaard et al.”

“…1959; Kennedy and Sokoloff, 1957; Kinnala et al., 1996; Kuhl et al., 1982; Leenders et al., 1990; Pantano et al., 1984; Perlmutter et al., 1987; Petit-Taboué et al., 1998; 50 Cell Metabolism 19, 49–57, January 7, 2014 ª2014 Elsevier Inc. Scheinberg et al., 1953; Takahashi et al., 1999; Yoxall…”

“(B) CMRglc (blue), CMRO2 (red), and CBF (orange) were plotted across the lifespan as normalized proportions of average adult values.”

“In normal, awake, resting adult humans, lactate efflux most likely accounts for 20% of this excess glucose consumption (Madsen et al., 1995; Raichle et al., 1970), though estimates vary (Dalsgaard et al., 2004).”

“…quantitative measurements of brain metabolism reveal that approximately 10%–12% of the total glucose consumed by a normal adult brain (CMRglc) is in excess of oxygen consumption C (CMRO2) (Boyle et al., 1994; Madsen et al., 1995; Powers et al., 2007; Raichle et al., 1970; Vaishnavi et al., 2010).”

“…glucose and oxygen consumption during various stages of life, including premature neonates, growing normal children, young adults, and the elderly (Altman et al., 1993; Burns and Tyrrell, 1992; Chugani et al., 1987; Frewen et al., 1991; Himwich et al., 1959; Kennedy and Sokoloff, 1957; Kinnala et…”

“Lactate affects the redox state of neurons, thereby directing glycolytic intermediates toward biosynthetic pathways as well as increasing neuronal excitability (Cerdán et al., 2006; Ido et al., 2004; Mintun et al., 2004).”

“In neurons, lactatemay spare some glucose from oxidative phosphorylation; this glucose then may contribute three-carbon fragments to anabolic pathways used for creating or turning over synapses (Pavlides et al., 2010; Vaishnavi et al., 2010).”

“Lactate affects the redox state of neurons, thereby directing glycolytic intermediates toward biosynthetic pathways as well as increasing neuronal excitability (Cerdán et al., 2006; Ido et al., 2004; Mintun et al., 2004).”

“The decrease in AG from young adulthood to a C mean age in the 70s has been described previously (Dastur, 1985); in that study, the whole-brain OGI was 4.7 in normal subjects with mean age 21 in comparison to an OGI of 5.9 in older subjects with mean age of 71.”

“Given the present findings, it is intriguing to consider the possibility that amyloid deposition is linked to high rates of synaptic turnover (Bufill et al., 2011; Nikolaev et al., 2009).”

“…al., 1991; Himwich et al., 1959; Kennedy and Sokoloff, 1957; Kinnala et al., 1996; Kuhl et al., 1982; Leenders et al., 1990; Pantano et al., 1984; Perlmutter et al., 1987; Petit-Taboué et al., 1998; 50 Cell Metabolism 19, 49–57, January 7, 2014 ª2014 Elsevier Inc. Scheinberg et al., 1953;…”

“…elderly (Altman et al., 1993; Burns and Tyrrell, 1992; Chugani et al., 1987; Frewen et al., 1991; Himwich et al., 1959; Kennedy and Sokoloff, 1957; Kinnala et al., 1996; Kuhl et al., 1982; Leenders et al., 1990; Pantano et al., 1984; Perlmutter et al., 1987; Petit-Taboué et al., 1998; 50 Cell…”

“A recent meta-analysis of studies on human brain oxygen and glucose consumption identified a similar regional variance of AG (Hyder et al., 2013).”

“…Sokoloff, 1957; Kinnala et al., 1996; Kuhl et al., 1982; Leenders et al., 1990; Pantano et al., 1984; Perlmutter et al., 1987; Petit-Taboué et al., 1998; 50 Cell Metabolism 19, 49–57, January 7, 2014 ª2014 Elsevier Inc. Scheinberg et al., 1953; Takahashi et al., 1999; Yoxall and Weindling, 1998).”

“…Sokoloff, 1957; Kinnala et al., 1996; Kuhl et al., 1982; Leenders et al., 1990; Pantano et al., 1984; Perlmutter et al., 1987; Petit-Taboué et al., 1998; 50 Cell Metabolism 19, 49–57, January 7, 2014 ª2014 Elsevier Inc. Scheinberg et al., 1953; Takahashi et al., 1999; Yoxall and Weindling, 1998).”

“Neoteny traditionally has been assessed in terms of cross-species comparisons (Gould, 2000).”

“Lactate affects the redox state of neurons, thereby directing glycolytic intermediates toward biosynthetic pathways as well as increasing neuronal excitability (Cerdán et al., 2006; Ido et al., 2004; Mintun et al., 2004).”

“Similarity among rank-ordered gene lists was computed with OrderedListR (Lottaz et al., 2006).”

“More specifically, we hypothesize that AG supports synaptic and neurite formation as well as turnover, which most likely persists throughout the lifespan (Goyal and Raichle, 2013; Marder and Goaillard, 2006).”

“…premature neonates, growing normal children, young adults, and the elderly (Altman et al., 1993; Burns and Tyrrell, 1992; Chugani et al., 1987; Frewen et al., 1991; Himwich et al., 1959; Kennedy and Sokoloff, 1957; Kinnala et al., 1996; Kuhl et al., 1982; Leenders et al., 1990; Pantano et…”

“…during various stages of life, including premature neonates, growing normal children, young adults, and the elderly (Altman et al., 1993; Burns and Tyrrell, 1992; Chugani et al., 1987; Frewen et al., 1991; Himwich et al., 1959; Kennedy and Sokoloff, 1957; Kinnala et al., 1996; Kuhl et…”

“There was also gene enrichment for proteins found in the human postsynaptic density but no significant enrichment of genes related to glycolysis or genes regulated by agonal stress (Langfelder and Horvath, 2008; Li et al., 2007).”

“…growing normal children, young adults, and the elderly (Altman et al., 1993; Burns and Tyrrell, 1992; Chugani et al., 1987; Frewen et al., 1991; Himwich et al., 1959; Kennedy and Sokoloff, 1957; Kinnala et al., 1996; Kuhl et al., 1982; Leenders et al., 1990; Pantano et al., 1984; Perlmutter et…”

“…dorsolateral prefrontal cortex, the superior andmedial frontal gyrus, or the precuneus and posterior cingulate cortex, where it accounts for up to 25% of glucose utilization, whereas in other areas, such as the cerebellum, it is virtually nonexistent (Bauernfeind et al., 2014; Goyal et al., 2014).”

“An alternative approach is to use the MNI (or voxel) coordinates of each sample (Goyal et al., 2014; Cioli et al., 2014; French and Paus, 2015; Richiardi et al., 2015; Komorowski et al., 2016; Krienen et al., 2016; Rizzo et al., 2016; Burt et al., 2018; Parkes et al., 2017; Romme et al., 2017; Shin…”

“These ratios do not indicate the percent of RMR or DER used by the brain because some brain glucose uptake (the numerator) is not used in energy production (28).”

“Recent studies have shown that the regions of the brain with the highest level of aerobic glycolysis also express increased levels of genes relating to synapse formation and growth, suggesting aerobic glycolysis could be used in brain development to support the biosynthesis required for growth, similarly to cancer cel…”

“Overlooked by most neuroscientists is one of the important functions performed by glycolysis which is to provide substrate for biosynthesis [21,103,122].”

“Changes in brain energetics, neuronal phosphate, and ATP metabolism occur with age (Forester et al., 2010), and elderly individuals have virtually absent global neuronal aerobic glycolysis (Goyal et al., 2014), which creates a pseudohypoxic state.”

“Differences in species-specificmetabolic properties of cortical neurons may influence human brain neoteny, which is consistent with previous reports of years-long periods of aerobic glycolysis in the developing human cortex (41).”

“In the brain, glycolysis is prominent, accounting for 10 –12% of glucose consumption (56).”

“The brain is the central organ in living organisms and is a major consumer of oxygen to provide uninterrupted supply of energy to approximately 86 billion neurons for their daily activities, it has been estimated it uses almost 20% of the basal oxygen (O2) from the total oxygen supplied to the human body [91,92].”

“Approximately 20% of the basal O2 is consumed by brain to support the ATP driven activity of 86 billion neurons connected by trillions of synapses, supported by 250–300 billion glia [62].”

“All brain regions utilize a mixture of aerobic glycolysis and oxidative phosphorylation, but the highest resting rates of aerobic glycolysis occur in the DLPFC and VLPFC, while the amygdala and hippocampus have relatively low resting rates (Goyal et al., 2014; Vaishnavi et al., 2010).”

“3) Aerobic glycolysis accounts for 2–25% of Glc metabolism in brain (Goyal et al., 2014), but it accounts for 80–96% of glucose consumption in retina (Winkler 1981; Ames et al.”

“This biosynthetic role is reminiscent of the Warburg effect observed in cancer cells and it has also been recently postulated in the rapidly growing human child brain.(53) Moreover, ATP levels are reduced after 2-DG treatment, suggesting that glycolysis may be a major source of ATP early in the differentiation process…”

“, 1981; Attwell and Laughlin, 2001), with even higher metabolic requirements during development (Goyal et al., 2014; Kuzawa et al., 2014).”

“CBF decline in childhood and adolescence has previously been found to be tightly linked to the decline of glucose metabolism (62).”

“Although many aspects of gene expression in the brain show a developmentally persistent profile (35), it is unclear whether the same transcriptional signature of hub connectivity would be apparent throughout development.”

“In particular, a recent meta-analysis by Goyal et al. (2014) showed that aerobic glycolysis is greatly increased during childhood, and that regional increases in glycolysis are associated with expression of genes related to synaptic development.”

“Our recent multitracer PET brain imaging data demonstrate that as the brain ages, its resting metabolism gradually shifts away from a mixture of nonoxidative and oxidative use of glucose to predominantly oxidative metabolism (4, 5).”

“Approximately 30% of the glucose consumed by the infant brain is accounted for by aerobic glycolysis (versus 12% in adults) (Goyal et al., 2014).”

“, 2017) and functional (Goyal et al., 2014; Hawrylycz et al., 2015; Richiardi et al., 2015; Wang et al., 2015; Krienen et al., 2016) brain tissue characteristics, and may thus be”

“It is modulated by arousal (Dienel and Cruz, 2016) and while the function of aerobic glycolysis remains debated, it may be linked to cortical plasticity (Goyal et al., 2014) and the replenishment of glutamate and GABA reserves (Hertz and Chen, 2017).”

“Developmentally, these high glycolytic rates correlate with the highest rates of synaptogenesis and axonal and synaptic growth [77], suggesting that, besides supporting energetic demands, glycolysis is also important to support synaptic growth and formation through biosynthetic pathways [55,77].”

“2C) with 9 independently produced maps of a range of brain functional and developmental parameters, including 1) evolutionary and postnatal surface expansion of the cortex (27); 2) metabolic rates of glucose, oxygen, and aerobic glycolysis (AG) measured by positron emission tomography (PET) (28); 3) microarray measure…”

“However, retina and brain have different functions and structures that influence the nature of the interactions between their neurons and glia: i) Aerobic glycolysis accounts for 2–25% of Glc metabolism in brain (3), but it accounts for 80–96% of it in retina (4–6).”

“In addition, it is interesting that the relatively large glycolytic capacity of brain tissue is most likely attributed to astrocytes [40, 41], and increasing evidence shows that the astrocyte-neuron lactate shuttle is the main way by which lactate transfers to neurons to meet the neuronal energy…”

“Variation in glucose uptake and metabolism in the brain (9, 12) could have a variety of functional outcomes.”

“In the adult brain, regions of transmodal cortex are associated with higher degrees of synapse formation and growth, as measured by aerobic glycolysis 69 .”

“This suggests that neoteny is inherent in the development of human brain regions with high energy demands that are required for cognitive and memory-related functions (24, 52).”

“The astrocytes’ glycolytic capacity is important for brain tissues [27,28] because the increased glycolysis in astrocytes is critical not only for their survival during hypoxia [34] but also in the regulation of brain diseases.”

“CRP was used as the main marker of a peripheral inflammation, consistent with other studies in MDD (Howren et al., 2009; Haapakoski et al., 2015).”

“While many genes show neotenous patterns of expression (30), many others show marked changes in transcriptional”

“Indeed, elevated aerobic glycolysis in the mPFC is closely associated with enhanced expression of genes related to synaptic remodeling and memory formation (45).”

“Interestingly, a meta-analysis of glucose and oxygen consumption across the human lifespan concluded that anaerobic glycolysis appears to decrease dramatically in the elderly, whereas oxygen consumption is slightly higher (Goyal et al., 2014).”

“Throughout human lifespan, the brain glucose utilization peaks at age 4–5 years dominantly in the form of aerobic glycolysis [45].”

“[81] 32 Clin Transl Imaging (2015) 3:27–37”

“Remarkably, these regions correspond to brain areas where the expression of genes related to synapse formation and growth, which is high during the childhood, persists in adults (Goyal et al., 2014).”

“The relatively large glycolytic capacity of brain tissue is most likely attributed to astrocytes [1,10], where glycolysis appears to have a larger enzymatic capacity than oxidative metabolism [11], and neuronal glycolysis is limited [12].”

“Indeed, aerobic glycolysis has been found to account for 10% of the glucose consumed by the adult human brain (Goyal et al., 2014).”

“Comparisons among primates suggest that only a subset of gene expression modules and processes are involved in prolonged human maturation 46,53,54,204 .”

“Stimulation Increases [lactate]i in Astrocytes Genes associated with aerobic glycolysis are mainly expressed in neocortical areas where neuronal cell plasticity is taking place (Goyal et al., 2014).”

“, neotony) that is related to synapse formation and growth (20).”

“Given the high energetic demands for neural function, it is surprising to see this less efficient metabolic state (Goyal et al. 2014).”

“Later, Goyal et al. 15 used nonlinear dimension reduction across whole-genome spatial expression, again from only one of the six AHBA brains, to show that aerobic glycolysis was associated with a second transcriptional component.”

“Goyal et al. (2014) recently demonstrated that periods and regions of the brain where aerobic glycolysis is most active correspond to a high expression of plasticity genes in particular those associated with synaptic remodeling.”

“…here, accounting for prior studies that demonstrate that whole brain glycolysis quantitatively decreases with age and in Alzheimer’s disease (14–15 Increased age was associated with decreases in GI in the superior frontal, superior parietal, caudal middle frontal, medial orbitofrontal, and…”

“In fact, a meta-analysis of gene expression and energy consumption shows a strong correlation between aerobic glycolysis and neuronal development [26].”

“…aerobic glycolysis is observed during early development with the highest synaptic growth rates, while in adults, relatively higher aerobic glycolysis is found in neotenous regions, and during aging, aerobic glycolysis is downregulated, accompanied by decreased plasticity in the brain [81, 82].”

“, in [1–3]) with the topographic organization of gene expressions [4–6].”

“While many genes show ne-otenous expression patterns ( 76 ), many others show highly variable expression patterns through development ( 77 ).”

“Increased utilization of aerobic glycolysis, which predominates in brain regions associated with transcriptional neoteny, may contribute to synapse formation and growth (Goyal et al., 2014).”