**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]. glucose (i.e. 60 g) was needed to facilitate memory, whereas the lower dose (25 g) enhanced

Figure 1. Comprehensive model of glucose memory facilitation The mechanisms responsible for memory formation and retrieval are in constant perturbations of **Figure 1.** Comprehensive model of glucose memory facilitation

working memory performance following a 2 hour fast [9].

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 research‐ ers 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 fragili‐ ty 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

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

**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

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

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].

neurons in relation to cerebral glucose metabolism.

affect both memory formation and retrieval [9, 29].

[9, 11, 12, 14, 21, 29, 30].

114 Glucose Homeostasis

has other peculiarities [21].

**3. Factors that affect memory: Scanning for glucose's role**

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 The mechanisms responsible for memory formation and retrieval are in constant perturba‐ tions 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

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 neuroendocrine 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

3

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 gastrointesti‐ nal 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 regulato‐ ry 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 endoge‐ nous 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 concentra‐ tion 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].

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

Glycemia and Memory

117

http://dx.doi.org/10.5772/58241

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

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

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

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

astroglial linkages [68, 69].

**5. Mechanisms of glucose effect on memory**

model of glucose memory facilitation effect (Figure 1).

**5.1. Conceptual model of glucose memory facilitation**

facilitation effect. The domain is episodic memory [41].

a comprehensive model of glucose memory facilitation.

*5.2.1. Neurotransmitter systems*

**5.2. Comprehensive model of glucose memory facilitation**

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 synthe‐ sized 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].
