Open access
1. Introduction
One of the major functions of brain cells (neurons) is to receive, store, and participate in information retrieval – an important process for the successful daily activities of humans [1-3]. This function of neurons is termed ‘memory’ [1, 4, 5]. The present understanding of memory function is the product of the pioneering work of the German scientist Hermann Ebbinghaus [5]. Research suggests that many factors (both endogenous and exogenous) could affect memory function [6-8]. However, the effect of glucose on memory function remains extremely significant for the following reasons [9-12]. First, glucose is the vital energy substrate for neuronal functions [13, 14]. Second, inadequate level of glucose in the blood has been associated with a decrease in memory function [15]. Third, disorders in glucose metabolism have been related to various aspects of memory disorders [8, 16]. Furthermore, metabolic products of glucose in neurons themselves participate in one or more stages of memory formation [17-20]. Notwithstanding the significant accumulation of research data in last decades on the relationship between glycemiа and neuronal functions [11, 12, 21], the mechanisms of how glucose affect memory functions remains entirely not understood. In this chapter, we shall examine the possible mechanisms and processes involved in the glucose regulation of memory function. We shall elaborate on the effect of glucose on the major processes of memory functions, precisely on the formation and retrieval of “neural data” – memory.
2. Memory as an integral function of neurons
More than 90% of human activities are dependent on higher integrative brain functions – a major subdivision, which is the topic of our discussion in the chapter. The higher integrative brain functions are the driving force during physical work. This is because the brain is the “chief” that directs resources for the successful completion of the task. Successful activities of humans are largely dependent on memory function [22]. This function of neurons becomes vividly indispensable in situations involving its disorder. Memory is that function of neurons that involve storage and retrieval of information [22]. Some researchers have argued “forgetting” as an important aspect of memory function [23, 24]. This is partly because without forgetting, some new information might hardly go into storage. Hence, there are theories of forgetting – the most known ones are the single-trace fragility theory, decay theory, retrieval failure, interference theory, repression, consolidation theory [22]. Generally, several concepts/theories/models/hypotheses have been used to explain memory function of neurons [22, 25-27]. However, with steady scientific progress it is becoming clearer that none of these gives a complete, and precise definition of memory. In this regard, we shall also discuss briefly on the modern concepts of memory function of neurons in relation to cerebral glucose metabolism.
3. Factors that affect memory: Scanning for glucose’s role
Several factors affect memory functions, and they can either be endogenous or exogenous. Generally, the widely known substances/factors include narcotics, some prescription drugs, alcohol, some biomolecules (most notably glucose, fatty acids, amino acids), environmental factors, genetic and epigenetic factors [6-8, 21, 28]. Among the biomolecules that affect memory formation and retrieval, glucose is widely known and well-studied molecule. Glucose is the main substrate for memory formation and retrieval. Glucose not only provides the energy for memory formation and retrieval, but also, is involved in providing the necessary subunits or components for the formation of various neural components of the “neural data” – memory [9, 11, 12, 14, 21, 29, 30].
4. Glycemia: A key regulating factor for memory formation and retrieval
Decades of research have shown that a change in the glycemic level leads to a corresponding change in memory function of the brain [21, 29-41]. For example, decrease in blood glucose below the set point is reported to negatively affect memory function [9, 21, 29, 30]. Glycemia affect both memory formation and retrieval [9, 29].
Results of several studies have observed an inverted-U shaped dose-response relationship between glucose load and memory [31-34]. Recent study has shown that the optimum dose of glucose memory enhancement may differ under conditions of depleted glucose resources, and has other peculiarities [21].
Several controversies in the glucose memory facilitation effect remain. While some previous studies reported a “no effect relationship” between glucose and memory function [35, 36], others confirm this dose-response relationship [9, 31, 37, 38]. Researchers have suggested that this relationship is extremely dependent on the type of cognitive/memory task [39, 40]. Modulating factors of the glucose memory facilitation effect include physiological state (body mass index etc.), glucose dose, types of cognitive tasks used and cognitive demand [9, 39]. These factors are the possible sources of variance in the glucose facilitation of memory. Owen and colleagues (2008) investigated the dose response relationship of the glucose memory facilitation effect at glucose dosages of 0, 15, 25, 50 and 60 g [9]. They also examined the interactions between length of fasting interval (2 hours versus 12 hours) and the optimum dose of glucose. Their results revealed glucose facilitation of spatial working memory and verbal declarative memory following 25 g glucose. Furthermore, they observed that glucose memory facilitation effect is dependent on the following: the greater the length of fasting, the greater the glucose dose needed to facilitate memory [9]. So, at overnight fast (approximately 12 hours) the higher dose of glucose (i.e. 60 g) was needed to facilitate memory, whereas the lower dose (25 g) enhanced working memory performance following a 2 hour fast [9].
Figure 1.
Comprehensive model of glucose memory facilitation
The mechanisms responsible for memory formation and retrieval are in constant perturbations of several factors (which might be competing factors, endogenous or exogenous in nature). The processes and mechanisms that ensure memory formation are the synthesis and activity of neurotransmitters (dopamine, d-serine, glutamate, acetylcholine etc), and receptor subunit systems; metabolic signaling pathways; LTP/LTD (long-term potentiation/long-term depression); genetic and epigenetic modifications. (Memory retrieval might involve the same systems and processes, but with different mechanisms). Both memory formation and retrieval involve other brain functions, including attention. The systems and processes earlier stated are affected by cerebral glucose, which can serve as a substrate or produce intermediate substrates for some stages of their syntheses. The cerebral glucose content is dependent on the plasma glucose, both of which are under constant regulation by the brain (hypothalamus), some internal organs (liver, kidney). The blood glucose is constantly regulated, also by the effect of the neuro-endocrine control on the gastrointestinal tract, organs (such as the liver and kidney), as well as the effect of the hypothalamus on these organs. The processes that are regulated in these organs by the higher regulatory centres (e.g. hypothalamus) are food intake, gluconeogenesis, glycogenolysis, glucose cycling – to ensure normal glycemic allostasis. These higher control centres, and the memory function are under constant pressure from modulating factors such as exogenous (e.g. environmental, ethanol), endogenous (ethanol, some physiological indices) – might affect the resultant effect of glucose on memory function. Alcohol actions [42-45] as represented on the model are one of a bi-directional effect of summation, meaning that alcohol affects memory, as well as glucose regulatory systems. The receptor systems of the brain could be modulated by both alcohol and glucose [46, 47]. Alcohol is a psychotic substance in widespread usage in the world. Importantly, this substance is also produced in vivo during biochemical reactions in an organism (including humans). In certain circumstances (varying physiological state, for instance during pregnancy, disease states), the level of endogenous ethanol produced significantly increases. This increase might have a protective effect, but the reason or mechanism on the general role of the increase in endogenous concentration ethanol is not fully known. Ethanol affects some neurotransmitters and receptor systems. Ethanol acts on ionotropic, metabotropic G-protein receptor, potassium ion channels [48-50]. Ethanol acts on metabotropic receptors of mGluR5, mGluR2/3, mGluR1 [51-53]. These metabotropic receptors (mGluR3 of the prefrontal cortex) have been also implicated in cognitive disorders in especially alcoholics [54]. mGluR5 and mGluR1 receptors have been recently implicated in cognition [53]. Ethanol causes hypoglycemia [43, 55]. Besides, it is reported that alcohol causes disorders in the expression of several genes, although the mechanisms remain not quite clear [56].
Glucose plays a pivotal role in memory and might enhance LTP/LTD [57] as hypoglycemia is associated with deficits in memory, and learning [58, 59]. Apart from producing ATP for neural energy, other substances may be synthesized from glucose that affects neuronal activity and functions (including memory) [60-62]. For example, it is known that d-serine (maybe synthesized from glucose molecule) affects LTP, synaptic plasticity, enhance information retrieval [60-64]. Hypoglycemia is associated with both d-serine and NO release aimed at enhancing LTP [58]. These substances can also regulate neuronal transcription factors [65]. A vast number of these signaling pathways, neurotransmitter and receptor systems, and are dependent on the activity level of neurons, and activity dependent transcriptions – activators and suppressor [66, 67]. Other brain cells (especially astrocytes) can modulate neuronal activity through various mechanisms, involving NMDA, d-serine, Ca2+, ATP, glutamate. Hence, these brain cells, which are affected by ethanol, might exert their resultant effect on neurons through astroglial linkages [68, 69].
5. Mechanisms of glucose effect on memory
While several studies have noted that glucose is a critical factor for memory function, what is not exactly clear is whether the effect is a direct or indirect one. In this section, we shall be mainly concerned with the mechanisms and processes of how glucose affects memory. Pertinent literature and latest developments in the field will be reviewed. It will be necessary to have in mind that memory function (formation and retrieval of neural data) is overlapped or is connected with other brain functions such as perception, attention etc. Therefore, glucose is a vital regulating factor for other brain functions. We shall consider the various views, concepts and models of how glucose affects memory function, and provide a comprehensive model of glucose memory facilitation effect (Figure 1).
5.1. Conceptual model of glucose memory facilitation
Smith and colleagues (2011) suggested a conceptual model of glucose facilitation of memory. Their neurocognitive model stipulates that glucose or acute stress/emotional arousal increases the concentration of circulating glucose in the periphery, and subsequently, the central nervous system. This increase in glucose exerts its effects on insulin, acetylcholine (Ach) synthesis and/or KATP channel function which subsequently leads to memory enhancement. Research has confirmed that there is specific cognitive domain that is most amenable to the glucose memory facilitation effect. The domain is episodic memory [41].
5.2. Comprehensive model of glucose memory facilitation
Memory formation or retrieval involves the synthesis of many biomolecules related to glucose metabolism [41, 70-73]. Glucose memory facilitation effect is a complex phenomenon comprising of several players including organs/systems of glucose metabolism, several competing factors, both genetic and epigenetic [42, 46, 72, 74]. Based on available data, here we propose a comprehensive model of glucose memory facilitation.
5.2.1. Neurotransmitter systems
Several neurotransmitter systems have been implicated in memory function. Here, we shall briefly consider a few of the principal neurotransmitter systems involved in memory function. The literatures report significant role of dopaminergic, glutamatergic, serotonergic, cholinergic, and noradrenergic systems in memory function [75-78]. We shall consider d-serine involvement in memory formation owing to the fact that its main receptor – the NMDA receptor is one of the key receptors involved in long-term memory formation (as a result of its long-term potentiation effect). Long-term potentiation, as opposed to long-term depression is an integral process necessary for memory formation (especially long-term memory) [68, 69]. In fact, the NMDA receptor itself is implicated as one of the “alcohol receptors” [79]. Therefore, bi-directional effect of summation might occur through alcohol effect on neurotransmitter receptor systems, and glucose metabolism. The resultant effect is aggravation of memory dysfunction.
5.2.2. Metabolic signaling pathways
Since glucose is a metabolic product or must be involved in the cell’s metabolic pathways before its usefulness is realized; therefore, it is necessary to assume that metabolic pathways, involving glucose molecule are those pathways crucial for memory formation or retrieval. Unfortunately, research in this aspect is scanty. A number of signaling pathways are involved in glucose metabolism, but there is no sufficient evidence on how they are associated with memory function [80]. The widely studied signaling pathways that have a relationship between glucose metabolism and memory functions [81, 82] include CREB pathway [83, 84], AMPK [85, 86], Notch signaling [87], mTOR pathway [88] etc. The mTOR pathway has been majorly implicated in both glucose and memory function. Importantly, it was reported that glucose specifically affects memory through this pathway [84, 88, 89].
5.2.3. Genetic and epigenetic regulation (activity dependent genes and epigenetic factors)
The enhancement of memory by glucose might be related partly to the functions of activity dependent genes [90, 91], as well as epigenetic modifications (DNA methylation and histone modifications) by glucose or its metabolites [10, 91-94].
Since epigenetic profile of the cells play crucial role in glucose metabolism and neuronal cell functions, here, we would suggest that the initial epigenetic data (program) of the involved cells responsible for glucose memory facilitation are partly important for the differences reported in the literature. Epigenetic mechanisms of glucose metabolism and memory functions are regulated by the activity of transcription factors [10, 95]. Due to the importance of glucose in the functioning of the CNS [96], this regulation may be modulated by glucose molecule itself. For example, the data of Li et al. (2010) indicate that glucose regulates gene transcription in the liver by increasing the level of ATP, hence inhibiting AMP-activated protein kinase and inducing hepatocyte nuclear factor 4alpha to stimulate cytochrome P450 7A1 gene transcription. Glucose also increases histone acetylation and decreases H3K9 methylation in the cytochrome P450 7A1 chromatin [97].
Recent experiments show that glucose is involved in the regulation of functions even at the progenitor cell level. Metabolism-sensing factors have recently been implicated in the regulation of neural stem cell fate through epigenetics modification [92, 98]. Hayakawa et al. (2013) reported that in embryonic stem cell population, glucose metabolite induces switching from the inactive state by Ogt-Sirt1 to the active state by Mgea5, p300, and CBP at the Hcrt gene locus [92]. The many pathways of glucose metabolism allows for the inclusion of its metabolic products into numerous cellular activities. For example, substrates of glucose metabolic pathways (acetyl-CoA, ATP, NAD+, glutamine, UDP-N-acetyl-glucosamine, N-acetyl-D-mannosamine etc.) are candidates of epigenetic modifications. Acetyl-CoA is a donor of histone acetylation. NAD+regulates Sirt1, a member of the sirtuin family, which functions as histone deacetylase and is also a metabolic sensor [92] (for review see Hayakawa et al. 2013). Epigenetic regulation by glucose or its metabolites affects memory functions and glucose metabolism itself through a shift in the cellular concentrations of critical metabolites implicated in higher integrative brain functions and metabolism.
A key mechanism for this epigenetic regulation is executed by the peripheral circadian oscillation [99]. However, importantly the peripheral clock and the central one could have some kind of metabolic associations. The concentration of NAD+/NADH plays critical link between metabolism and circadian rhythm [99]. Glucose and other metabolic substances may modulate the circadian rhythm by fluctuations in NAD+/NADH ratio. Compelling evidences now indicate that circadian misalignment could cause serious metabolic problems. In fact, transgenerational inheritance in metabolic alterations could be related to some mechanisms of epigenetic origin modulated by circadian clocks. Methylation of the leptin gene is associated with impaired glucose tolerance in the period of gestation [100]. This and many other discoveries on transgenerational inheritance represent substantial contribution to understanding the pathogenesis of diabetes, obesity in children [100-102].
Epigenetic regulations are not only affected by metabolites, but also body mass index, intrauterine environment, exercise, and other environmental factors [101].
It might be possible that epigenetic dysregulation of cerebral glucose metabolism is the result of cognitive impairment since glucose metabolism is controlled by epigenetic mechanisms and is also associated with cognition. Emerging evidences indicate that metabolic regulation (through epigenetic mechanisms) might be involved in memory function disorders. Reports show that a major pathogenesis of the CNS disorder such as Alzheimer's disease involves metabolic alterations, especially in glucose metabolism and associated hormonal or peptide signaling. Metabolic disorders in CNS pathologies are associated with brain insulin signaling. For example, a substantial quantity of insulin receptors is located in the hippocampus (a brain region which is basically concerned with the acquisition, consolidation and recall of new information) [103]. Impaired brain insulin signaling is implicated in cognitive impairment. Moreover, cognitive impairment is associated with diabetes and obesity, which are metabolic disorders [104]. De la Monte (2009) reported that in the initial stage of Alzheimer's disease, cerebral glucose metabolism is reduced by 45% and cerebral blood flow approximately by 18% [104]. Earlier, Arnáiz et al. (2001) reported that among twenty patients with mild cognitive impairment, impaired cerebral glucose metabolism and cognitive functioning were able to predict deterioration in mild cognitive impairment [105]. Mild cognitive impairment is an important indicator of the development of Alzheimer's disease. Notably, impairment in cerebral glucose metabolism was even a better predictor (75%) compared to neurospcyhological tests (65%) widely used in the assessment of cognitive impairment [105]. The authors further concluded that measures of temporoparietal cerebral metabolism and visuospatial function may aid in predicting the evolution to Alzheimer's disease for patients with mild cognitive impairment [105].
These data are very important especially when we consider the increasing prevalence of cognitive disorders. For instance, it is estimated that in 2030 years, the cases of Alzheimer's disease in relation to 2012 will double (35.6 million). No doubts, research in this direction is exceedingly necessary [106]. Previously other authors have also reported that impairment in cerebral glucose metabolism is associated with decline in cognition and memory functions. Schapiro et al (1988) studied the rate of cerebral metabolism for glucose with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose in a 47 year-old man with trisomy 21 Down's syndrome and Alzheimer related dementia, and reported poorer general intelligence, visuospatial ability, language, and memory function compared with younger (19-33 years) patients with Down's syndrome [107]. Cerebral metabolism for glucose in the older patient was 28% less than in the younger patients. Besides, hypometabolism was reported in the parietal and temporal lobes of the brain cortices. Importantly, the study of Schapiro et al (1988) was probably one of the most comprehensive investigations to show the association between different diseases involving CNS disorder and their relationship with cerebral glucose metabolism [107]. Approximately a decade after Schapiro et al.'s (1988) work [107], Pietrini et al. (1997) reported another predictor method for Alzheimer's disease risk prior to dementia in patients with Down's syndrome who were above 40 years (mean of 50 years) of age [108]. Pietrini, et al. (1997) confirmed their hypothesis that despite normal cerebral glucose metabolism at rest, an audiovisual stimulation (was used as a stress test) revealed abnormalities in cerebral glucose metabolism before the development of dementia in the parietal and temporal cortices which represent most vulnerable regions to Alzheimer's disease [108].
These CNS pathologies are now believed to be regulated by epigenetic mechanisms [109] and could have pretty good correlations with epigenetic mechanisms of cerebral glucose metabolism. Other CNS pathologies involving cognitive impairments such as epilepsy [110], schizophrenia [111, 112], Parkinson's disease [113], multiple sclerosis [114] had been associated with disturbances in glucose metabolism.
Figure 2.
Interacting system (comprising of memory function, error monitoring and processing system, and modulators) of the reciprocability of neural systems of memory and the error monitoring and processing system. The modulators between the two reciprocals are glucose, other endogenous and exogenous substances/factors. N/B: Glucose can be an endogenous, as well as an exogenous factor; exogenous sources include per os administration of glucose, etc.; endogenous sources include gluconeogenetic production of glucose molecules, etc.
6. Glucose error commission depression effect: Cue to an overlapping bridge of neural error systems, memory and glucose metabolism?
Our data and those of other authors show strong negative relations between glycemia and error commission. Whether this is due to the effect of glucose on memory or neural systems of error commission, is what is not exactly clear (see figure 2). There are no precise borders between the brain regions responsible for memory and error commission. Therefore, it is possible that the effect of glucose on error commission could be the resultant effect on the chief brain regions for memory function. Neural systems (or regions) of memory implicated in error commission have been linked to brain regions also involved in some aspects of memory function [115-117]. The brain systems concerned with error commission are referred to the error monitoring and processing system. The major regions of the brain concerned with error commission are the anterior cingulate cortex, basal ganglia, prefrontal cortex. These brain regions (especially the prefrontal cortex) are also implicated in memory function [45, 115, 117].
7. Effect of alcohol on glycemia and memory: More than just a bi-directional modulating effect
Alcohol is the most prevalent psychotic substance in the world. While alcohol affects glucose metabolism, memory also remains one of the most vulnerable functions of the brain that suffers from the negative effect of alcohol use [15, 16, 29, 30, 44, 45, 118]. Hence, there is the need to examine its effect on memory function and glucose regulatory mechanisms. Here, we view alcohol as a positive modulating factor for memory (especially at endogenous concentration), and as a psychopathological substance at blood concentrations higher than the normal physiological level.
8. Conclusion
Glucose is the foremost energy substrate for neuronal functions (memory). It provides the energy bonds needed for the formation of memory and takes part in information retrieval from neural stores. Both glucose and its metabolites are involved in different stages of memory formation and retrieval. Several factors such as ethanol, some physiological indices, and other competing factors modulate the effect of glucose on memory function.
References
- 1.
Sokolov EN. Brain Functions: Neuronal Mechanisms of Learning and Memory. Annu Rev Psychol 1977; 28: 85-112. - 2.
Funahashi S. Neuronal mechanisms of executive control by the prefrontal cortex. Neurosci Res 2001; 39: 147 – 165. - 3.
Parker BA, Polk DM, Rabdiya V, Meda SA, Anderson K, Hawkins KA, Pearlson GD, Thompson PD. Changes in Memory Function and Neuronal Activation Associated with Atorvastatin Therapy. Pharmacotherapy 2010;30(6):236e–240e. - 4.
Endel T. Ebbinghaus's memory: What did he learn and remember? J Exp Psychol Learn Mem Cogn 1985; 11(3): 485-490. - 5.
Ebbinghaus H. Memory: A contribution to experimental psychology. New York: Dover; 1964/original work published in 1885. - 6.
Win-Shwe TT, Ohtani S, Ushiyama A, Fujimaki H, Kunugita N. Can intermediate-frequency magnetic fields affect memory function-related gene expressions in hippocampus of C57BL/6J mice? J Toxicol Sci 2013;38(2):169-76. - 7.
Buffardi L. Factors affecting memory span in binary and octal responding. Am J Psychol 1972; 85 (3):377-391. - 8.
Othman Z, Jamaluddin R, Alwi MNM, Ismail HC. Demographic And Clinical Factors Associated With Verbal Memory Performance In Patients With Schizophrenia In Hospital Universiti Sains Malaysia (HUSM), Malaysia. Asean J Psychiatr 2011;12 (2). - 9.
Owen L, Sünram-Lea SI. Glucose facilitation of cognition: Factors responsible for variability in behavioural response. Appetite 2008; 50 (2-3): 564. - 10.
Owen L, Sunram-Lea SI. Metabolic Agents that Enhance ATP can Improve Cognitive Functioning: A Review of the Evidence for Glucose, Oxygen, Pyruvate, Creatine, and L-Carnitine. Nutrients 2011; 3: 735-755. - 11.
Sünram-Lea SI, Dewhurst SA, Foster JK. The effect of glucose administration on the recollection and familiarity components of recognition memory. Biol Psychol 2008;77(1):69-75. - 12.
Korol DL, Gold PE. Glucose, memory, and aging. Am J Clin Nutr 1998;67(suppl):764S–71S. - 13.
Hoyland A, Dye L, Lawton CL. A systematic review of the effect of breakfast on the cognitive performance of children and adolescents. Nutr Res Rev 2009; 22:220-243. - 14.
Owen L, Finnegan Y, Hu H, Scholey AB, Sünram-Lea SI. Glucose effects on long-term memory performance: duration and domain specificity. Psychopharmacology (Berl) 2010;211(2):131-40. - 15.
Welcome MO, Pereverzeva EV, Pereverzev VA. Long-term disorders of cognitive functions in sober people who episodically use alcohol, role of functional hypoglycemia and insufficiency of gluconeogenesis. Vestnik Smolensk Med Acad 2011; 3: 2-20. - 16.
Welcome MO, Razvodovsky YE, Pereverzeva EV, Pereverzev VA. State of cognitive functions of students-medics with different relationship to alcohol use. Minsk: Belarusian State Medical University Press; 2013. - 17.
Hoyer S. memory function and brain glucose metabolism. Pharmacopsychiatry 2003; 36 (1):S62-S67. - 18.
Riege WH, Metter EJ, Kuhl de, Phelps ME. Brain Glucose Metabolism and Memory Functions: Age Decrease in Factor Scores. J Gerontol 1985; 40(4): 459-467. - 19.
Newcomer JW, Craft S, Fucetola R, Moldin SO, Selke Q, Paras L-U, Miller R. Glucose-Induced Increase in Memory Performance in Patients With Schizophrenia. Schizophrenia Bulletin 1999; 25(2):321-335. - 20.
Qin M, Smith BC. Regionally selective decreases in cerebral glucose metabolism in a mouse model of phenylketonuria. J Inherit Metab Dis 2007;30(3):318-25. - 21.
Owen L, Scholey A, Finnegan Y, Sünram-Lea SI. Response variability to glucose facilitation of cognitive enhancement. Br J Nutr 2013, In press. - 22.
Baddeley A. Working Memory: Theories, Models, and Controversies. Annu Rev Psychol 2012;63:1–29. - 23.
Wickelgren WA. Single-trace fragility theory of memory dynamics. Mem Cogn 1974; 2 (4): 775-780. - 24.
Wixted JT. Analyzing the Empirical Course of Forgetting. J Exp Psychol Learn Mem Cogn 1990; 16 (5): 927-935. - 25.
Chechile RA. Memory Hazard Functions: A Vehicle for Theory Development and Test. Psychol Rev 2006;113(1):31–56. - 26.
Loflus GR. Consistency and Confoundings: Reply to Slamecka. J Exp Psychol Learn Mem Cogn 1985; 11 (4): 817-820. - 27.
Saraswat V, Jagadeesan R, Michael M, von Praun C. A Theory of Memory Models. Proceedings of the 12th ACM SIGPLAN symposium on Principles and practice of parallel programming, ACM New York, NY, USA; 2007. p. 161 – 172. - 28.
Bazan NG, Packard MG, Teather L, Allan G. Bioactive lipids in excitatory neurotransmission and neuronal plasticity. Neurochem Int 1997;30(2):225-31. - 29.
Welcome MO, Razvodovsky YE, Pereverzeva EV, Pereverzev VA. The effect of blood glucose concentration on the error monitoring and processing system in alcohol users during intensive mental activities. Port Harcourt Med J 2011; 5 (3) 293-306. - 30.
Welcome MO, Razvodovsky YE, Pereverzeva EV, Pereverzev VA. The error monitoring and processing system in alcohol use. IJCRIMPH. 2010; 2 (10): 318-336. - 31.
Rodriguez WA, Horne CA, Padilla JL. Effects of glucose and fructose on recently reactivated and recently acquired memories. Prog Neuropsychopharmacol Biol Psychiatry 1999;23(7):1285-317. - 32.
Baldi E, Bucherelli C. The inverted “U-shaped” dose-effect relationships in learning and memory: modulation of arousal and consolidation. Nonlinear Biol Toxicol Med 2005;3: 9–21. - 33.
McEwen BS, Sapolsky RM. Stress and cognitive function. Curr Opin Neurobiol 1995; 5(2):205-216. - 34.
Flint Jr W. Emotional Arousal, Blood Glucose Levels, and Memory Modulation: Three Laboratory Exercises in Cognitive Neuroscience. J Undergrad Neurosci Educ 2004, 3(1):A16 – A23. - 35.
Azari NP. Effects of glucose on memory processes in young adults. Psychopharmacology (Berl) 1991;105(4):521-4. - 36.
Gold PE, Vogt J, Hall JL. Glucose effects on memory: behavioral and pharmacological characteristics. Behav Neural Biol 1986;46(2):145-55. - 37.
Rodriguez WA, Horne CA, Mondragon AN, Phelps DD. Comparable dose-response functions for the effects of glucose and fructose on memory. Behav Neural Biol 1994;61(2):162-9. - 38.
Sünram-Lea SI, Owen L, Finnegan Y, Hu H. Dose-response investigation into glucose facilitation of memory performance and mood in healthy young adults. J Psychopharmacol 2011;25(8):1076-87. - 39.
Sünram-Lea SI, Foster JK, Durlach P, Perez C. Investigation into the significance of task difficulty and divided allocation of resources on the glucose memory facilitation effect. Psychopharmacology (Berl) 2002;160(4):387-97. - 40.
Foster JK, Lidder PG, Sünram SI. Glucose and memory: fractionation of enhancement effects? Psychopharmacology (Berl) 1998;137(3):259-70. - 41.
Smith MA, Riby LM, van Eekelen JAM, Foster JK. Glucose enhancement of human memory: A comprehensive research review of the glucose memory facilitation effect. Neuroscience & Biobehavioral Rev 2011; 35(3): 770–783. - 42.
Wickelgren WA. Alcoholic intoxication and memory storage dynamics. Mem Cognit 1975 ;3(4):385-9. - 43.
De Galan BE, Schouwenberg BJ, Tack CJ, Smits P. Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes. Neth J Med 2006; 64:269-279. - 44.
Welcome MO. The state of higher integrative functions of the brain and level of glycemia in young adults who use alcoholic beverages. PhD thesis. Belarusian State Medical University; 2013. - 45.
Welcome MO, Pereverzev VA. Basal Ganglia and the Error Monitoring and Processing System: How Alcohol Modulates the Error Monitoring and Processing Capacity of the Basal Ganglia (P). In: Barrios FA, Bauer C (ed.) Basal Ganglia – An Integrative View. Croatia: InTech; 2013. p. 65-86. - 46.
Ungerer A, Mathis C, Mélan C. Are glutamate receptors specifically implicated in some forms of memory processes? Exp Brain Res 1998;123(1-2):45-51. - 47.
Haltia LT, Rinne JO, Merisaari H, Maguire RP, Savontaus E, Helin S, Någren K, et al. Effects of intravenous glucose on dopaminergic function in the human brain in vivo. Synapse 2007; 61: 748 – 756. - 48.
Cowen MS, Djouma E, Lawrence AJ. The Metabotropic Glutamate 5 Receptor Antagonist 3-[(2-Methyl-1, 3-thiazol-4-yl)ethynyl]-pyridine Reduces Ethanol Self-Administration in Multiple Strains of Alcohol-Preferring Rats and Regulates Olfactory Glutamatergic Systems. JPET 2005; 315:590–600. - 49.
Bird MK, Lawrence AJ. Group I Metabotropic Glutamate Receptors: Involvement in Drug-Seeking and Drug-Induced Plasticity. Curr Mol Pharmacol 2009; 2: 83-94. - 50.
Luscher C, Ungless MA. The mechanistic classification of addictive drugs. PLoS Med 2006; 3(11): e437. doi:10.1371/journal.pmed.0030437. - 51.
Hodge CW, Miles MF, Sharko AC, Stevenson RA, Hillman JR, Lepoutre V, Besheer J, Schroeder JP. The mGluR5 antagonist MPEP selectivity inhibits the onset and maintenance of ethanol self-administration in mice. Psychopharmacology 2006;183: 429-438. - 52.
Carta M, Mameli M, Valenzuela CF. Alcohol Potently Modulates Climbing Fiber3Purkinje Neuron Synapses: Role of Metabotropic Glutamate Receptors. J Neurosci 2006; 26(7):1906 –1912. - 53.
Olive MF. Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Curr Drug Abuse Rev 2009; 2(1): 83–989. - 54.
Xia Y, Ma D, Hu J, Tang C, Wu Z, Liu L, Xin F. Effect of metabotropic glutamate receptor 3 genotype on N-acetylaspartate levels and neurocognition in non-smoking, active alcoholics. Behav Brain Functions 2012; 8:42. - 55.
Krebs, H. A. and Perkins, J. R. The physiological role of liver alcohol dehydrogenase. Biochem J 1970; 118: 635–644. - 56.
Pignataro L, Miller AN, Ma L, Midha S, Protiva P, Herrera DG, Harrison NL. Alcohol Regulates Gene Expression in Neurons via Activation of Heat Shock Factor 1. J Neurosci 2007; 27(47):12957–12966. - 57.
Gault VA, Holscher C. Protease-resistant glucose-dependent insulinotropic polypeptide agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloid. J Neurophysiol 2008; 99:1590-1595. - 58.
Zorumski CF, Izumi Y. Modulation of LTP induction by NMDA receptor activation and nitric oxide release. Prog Brain Res 1998;118:173-82. - 59.
Godfraind JM, Xu YZ. Two-deoxyglucose-induced long-term potentiation in slices of rat dentrate gyrus. Crit Rev Neurobiol 2006;18(1-2):37-48. - 60.
Cui C, Grandison L, Noronha A. Neural-Immune Interactions in Brain Function and Alcohol Related Disorders. New York: Springer-Verlag; 2012. - 61.
Wolosker H. D-serine regulation of NMDA receptor activity. Sci STKE 2006;2006(356):pe41. - 62.
Rosenberg D, Kartvelishvily E, Shleper M, Klinker CMC, Bowser MT, Wolosker H. Neuronal release of D-serine: a physiological pathway controlling extracellular D-serine concentration. FASEB J 2010; 24: 2951–2961. - 63.
Zhang Z, Gong N, Wang W, Xu L, Xu T-L. Bell-Shaped D-Serine Actions on Hippocampal Long-Term Depression and Spatial Memory Retrieval. Cerebral Cortex 2008;18:2391-2401. - 64.
Zhuang Z, Yang B, Theus MH, Sick JT, Bethea JR, Sick TJ, Liebl DJ. EphrinBs regulate D-serine synthesis and release in astrocytes. J Neurosci 2010; 30(47): 16015–16024. - 65.
Contestabile A. Regulation of transcription factors by nitric oxide in neurons and in neural-derived tumor cells. Prog Neurobiol 2008;84(4):317-28. - 66.
West AE, Griffith EC, Greenberg ME. Regulation of transcription factors by neuronal activity. Nature Rev Neurosci 2002; 3: 921-931. - 67.
Zhang J, Shapiro MS. Activity-Dependent Transcriptional Regulation of M-Type (Kv7) K+Channels by AKAP79/150-Mediated NFAT Actions. Neuron 2012; 76 (6):1133-1146. - 68.
Yang Y, Ge W, Chen Y, Zhang Z, Shen W, Wu C, Poo M, Duan S. Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. PNAS 2003; 100 (25):15194–15199. - 69.
Henneberger C, Papouin T, Oliet SHR, Rusakov DA. Long-term potentiation depends on release of D-serine from astrocytes. Nature 2010; 463: 232-234. - 70.
Herculano-Houzel S. Scaling of Brain Metabolism with a Fixed Energy Budget per Neuron: Implications for Neuronal Activity, Plasticity and Evolution. PLoS One 2011; 6(3): e17514. doi:10.1371/journal.pone.0017514. - 71.
Nehlig A, Coles JA. Cellular pathways of energy metabolism in the brain: is glucose used by neurons or astrocytes? Glia 2007;55(12):1238-50. - 72.
Jakoby P, Schmidt E, Ruminot I, Gutiérrez R, Barros LF, Deitmer JW. Higher Transport and Metabolism of Glucose in Astrocytes Compared with Neurons: A Multiphoton Study of Hippocampal and Cerebellar Tissue Slices. Cereb Cortex 2014;24(1):222-31. - 73.
Sibson NR. Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. Proc Natl Acad Sci USA 1998; 95: 316 –321. - 74.
Tsacopoulos M, Magistretti PJ. Metabolic Coupling between Glia and Neurons. J Neurosci 1996;76(3):877-885. - 75.
Wenk G, Hughey D, Boundy V, Kim A, Walker L, Olton D. Neurotransmitters and memory: role of cholinergic, serotonergic, and noradrenergic systems. Behav Neurosci 1987;101(3):325-32. - 76.
Shetty DN, Pathak SS. Correlation between plasma neurotransmitters and memory loss in pregnancy. J Reprod Med 2002;47(6):494-6. - 77.
Dash PK, Moore AN, Kobori N, Runvan JD. Molecular activity underlying working memory. Learn Mem 2007; 14: 554-563. - 78.
Berry JA, Cervantes-Sandoval I, Nicholas EP, Davis RL. Dopamine Is Required for Learning and Forgetting in Drosophila. Neuron 2012; 74 (3):530-542. - 79.
Feyder M, Camp MC, Holmes A, Chen Y-C. Ethanol and NMDA Receptor Interactions: Implications for Pharmacotherapeutic Treatments. J Med Sci 2010;30(1):003-010. - 80.
Teperino R, Amann S, Bayer M, McGee SL, Loipetzberger A, Connor T, et al. Hedgehog Partial Agonism Drives Warburg-like Metabolism in Muscle and Brown Fat. Cell 2012; 151 (2): 414. doi: 10.1016/j.cell.2012.09.021. - 81.
Graham NA, Tahmasian M, Koshli B, et al. Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death. Mol Syst Biol 2012;8:589. doi: 10.1038/msb.2012.20. - 82.
Summers SA, Yin VP, Whiteman EL, Garza LA, Cho H, Tuttle RL, Birnbaum MJ. Signaling Pathways Mediating Insulin-Stimulated Glucose Transport. Ann NY Acad Sci 1999; 892:169-186. - 83.
Aonurm-Helm A, Zharkovsky T, Jürgenson M, Kalda A, Zharkovsky A. Dysregulated CREB signaling pathway in the brain of neural cell adhesion molecule (NCAM)-deficient mice. Brain Res 2008 3;1243:104-12. - 84.
Simons AL, Orcutt KP, Madsen JM, Scarbrough PM, Spitz DR. The Role of Akt Pathway Signaling in Glucose Metabolism and Metabolic Oxidative Stress. In: Spitz DR et al. (eds.) Oxidative Stress in Cancer Biology and Therapy, Oxidative Stress in Applied Basic Research and Clinical Practice. LLC: Springer; 2012. p. 21-46. - 85.
Potter WB, O'Riordan KJ, Barnett D, Osting SMK, Wagoner M, et al. Metabolic Regulation of Neuronal Plasticity by the Energy Sensor AMPK. PLoS One 2010; 5(2): e8996. doi:10.1371/journal.pone.0008996. - 86.
Felipe BL. Metabolic signaling by lactate in the brain. Trends Neurosci 2013. 10.1016/j.tins.2013.04.002. - 87.
Lasky JL, Wu H. Notch Signaling, Brain Development, and Human Disease. Pediatr Res 2005; 57: 104R–109R. - 88.
Hoeffer CA, Klann E. mTOR Signaling: At the Crossroads of Plasticity, Memory, and Disease. Trends Neurosci 2010; 33(2): 67. doi:10.1016/j.tins.2009.11.003. - 89.
Dash PK, Orsi SA, Moore AN. Spatial Memory Formation and Memory-Enhancing Effect of Glucose Involves Activation of the Tuberous Sclerosis Complex–Mammalian Target of Rapamycin Pathway. J Neurosci 2006; 26(31):8048–8056. - 90.
Melzer P, Steiner H. Stimulus-Dependent Expression of Immediate-Early Genes in Rat Somatosensory Cortex. J Comp Neurol 1997;380:145–153. - 91.
Masri S, Sassone-Corsi P. The circadian clock: a framework linking metabolism, epigenetics and neuronal function. Nature Rev Neurosci 2013;14: 69-75. - 92.
Hayakawa K, Hirosawa M, Tabei Y, Arai D, Tanaka S, Murakami N, Yagi S, Shiota K. Epigenetic switching by the metabolism-sensing factors in the generation of orexin neurons from mouse embryonic stem cells. J Biol Chem 2013;288(24):17099-110. - 93.
Duarte AI, Moreira PI, Oliveira CR. Insulin in Central Nervous System: More than Just a Peripheral Hormone. J Aging Res 2012, Article ID 384017. doi:10.1155/2012/384017. - 94.
Stone WS, Seidman LJ. Toward a Model of Memory Enhancement in Schizophrenia: Glucose Administration and Hippocampal Function. Schizophr Bull 2008; 34 (1): 93–108. - 95.
Choi S-W, Friso S. Epigenetics: A New Bridge between Nutrition and Health. Adv Nutr 2010; 1: 8–16. - 96.
Benton D, Parker PY. Breakfast, blood glucose, and cognition. Am J Clin Nutr 1998;67(suppl):772S–8S. - 97.
Li T, Chanda D, Zhang Y, Choi HS, Chiang JY. Glucose stimulates cholesterol 7 β-hydroxylase gene transcription in human hepatocytes. J Lipid Res 2010. 51: 832–842. - 98.
Kaelin Jr. WG, McKnight SL. Influence of Metabolism on Epigenetics and Disease. Cell 2013;153: 56-69. - 99.
Lu C, Thompson CB. Metabolic regulation of epigenetics. Cell Metab 2012; 16(1): 9–17. - 100.
Bouchard L, Thibault S, Guay S-P, Santure M, Monpetit A, St-Pierre J, Perron P, Brisson D. Leptin Gene Epigenetic Adaptation to Impaired Glucose Metabolism During Pregnancy. Diabetes Care 2010;33:2436–2441. - 101.
Jufvas Ås, Sjödin S, Lundqvist K, Amin R, Vener AV, Strålfors P. Global differences in specific histone H3 methylation are associated with overweight and type 2 diabetes. Clin Epigen 2013, 5:15. - 102.
Jayaraman S. Epigenetic Mechanisms of Metabolic Memory in Diabetes. Circ Res 2012;110:1039-1041. - 103.
Schiöth HB, Craft S, Brooks SJ, Frey II WH, Benedict C. Brain Insulin Signaling and Alzheimer's Disease: Current Evidence and Future Directions. Mol Neurobiol 2012; 46:4–10. - 104.
de la Monte SM. Insulin resistance and Alzheimer’s disease. BMB reports 2009;42(8): 475-481. - 105.
Arnáiz E, Jelic V, Almkvist O, Wahlund L-O, Winblad B, Valind S, Nordberg A. Impaired cerebral glucose metabolism and cognitive functioning predict deterioration in mild cognitive impairment. Neuroreport 2001; 12 (4):851-855. - 106.
Freiherr J, Hallschmid M, Frey WH 2nd, Brünner YF, Chapman CD, Hölscher C, Craft S, De Felice FG, Benedict C. Intranasal Insulin as a Treatment for Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence. CNS Drugs 2013; 27:505–514. - 107.
Schapiro MB, Ball MJ, Grady CL, Haxby JV, Kaye JA, Rapoport SI. Dementia in Down's syndrome: cerebral glucose utilization, neuropsychological assessment, and neuropathology. Neurology 1988;38(6):938-42. - 108.
Pietrini P, Dani A, Furey ML, Alexander GE, Freo U, Grady CL, Mentis MJ, Mangot D, Simon EW, Horwitz B, Haxby JV, Schapiro MB. Low glucose metabolism during brain stimulation in older Down's syndrome subjects at risk for Alzheimer's disease prior to dementia. Am J Psychiatry 1997;154(8):1063-9. - 109.
Roffman JL, Nitenson AZ, Agam Y, Isom M, Friedman JS, Dyckman KA, Brohawn DG, Smoller JW, Goff DC, Manoach DS. A hypomethylating variant of MTHFR, 677C>T, blunts the neural response to errors in patients with schizophrenia and healthy individuals. PLoS One. 2011;6(9):e25253. doi: 10.1371/journal.pone.0025253. - 110.
Jokeit H, Seitz RJ, Markowitsch HJ, Neumann N, Witte OW, Ebner A. Prefrontal asymmetric interictal glucose hypometabolism and cognitive impairment in patients with temporal lobe epilepsy. BRAIN 1997; 120: 2283–2294. - 111.
Siegel BV Jr, Buchsbaum MS, Bunney WE Jr, Gottschalk LA, Haier RJ, Lohr JB, Lottenberg S, Najafi A, Nuechterlein KH, Potkin SG, et al. Cortical-striatal-thalamic circuits and brain glucose metabolic activity in 70 unmedicated male schizophrenic patients. Am J Psychiatry 1993;150(9):1325-36. - 112.
Buchsbaum MS, Haier RJ, Potkin SG, Nuechterlein K, Bracha HS, Katz M, et al. Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics. Arch Gen Psychiatry 1992;49(12):935-42. - 113.
Peppard RF, Martin WRW, Clark CM, Carr GD, McGeer PL, Calne DB. Cortical glucose metabolism in parkinson's and alzheimer's disease. J Neurosci Res 1990; 27 (4): 561–568. - 114.
Shkil’nyuk GG, Il’ves AG, Kataeva GV, Prakhova LN, Reznikova TN, Seliverstova NA, Stolyarov ID. The Role of Changes in Glucose Metabolism in the Brain in the Formation of Cognitive Impairments in Patients with Remitting and Secondary-Progressive Multiple Sclerosis. Neurosci Behav Physiol 2013; 43 (5):565-570. - 115.
Holroyd CB, Praamstra P, Plat E, Coles MGH. Spared error-related potentials in mild to moderate Parkinson’s disease. Neuropsychologia. 2002; 40: 2116–2124. - 116.
Holroyd CB, Yeung N. Alcohol and error processing. Trends Neurosci 2003; 26: 402-404. - 117.
Hester R, Foxe JJ, Molholm S, Shpaner M, Garavan H. Neural mechanisms involved in error processing: a comparison of errors made with and without awareness. NeuroImage. 2005; 27: 602–608. - 118.
Yazan Alderazi, Francesca Brett. Alcohol and the nervous system. Curr Diagn Pathol 2007; 13: 203–209.