**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 com‐ prising 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, choliner‐ gic, 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.

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

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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 discov‐ eries on transgenerational inheritance represent substantial contribution to understanding the

Epigenetic regulations are not only affected by metabolites, but also body mass index,

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 neurospcyholog‐ ical 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

intrauterine environment, exercise, and other environmental factors [101].

in higher integrative brain functions and metabolism.

pathogenesis of diabetes, obesity in children [100-102].

cognitive impairment [105].
