Author: Francesco Bruno
Date: 12/02/2013


How does food affect our brain?

In the last decades several studies have provided strong evidence for the influence of dietary factors on specific molecular systems and mechanisms that maintain mental functions. Moreover, the importance of having healthy food habits is known to be a protective factor against diseases among most cultures. We can assert that in the scale of the evolution feeding has been an adaptive mechanism for the development of cognitive skills, as demonstrated by the confirmation that changes in nutritional behaviours have been supported by changes in those brain centres that control cognition: in particular, adaptations that facilitated food acquisition and energy efficiency exerted a strong evolutionary pressure on the formation of the modern brain and on the energy-demanding development of cognitive skills (Gómez-Pinilla, Brain foods: the effects of nutrients on brain function. Nature Neurosci. 9, 568 – 578 [2008]).
I will display certain aspects of the relationship between feeding and cognition, as the role of some hormones in modelling neuronal pathways and the effects of some nutrients on cognitive functions.


The gastrointestinal tract products a large variety of hormones which act peripherally and influence the different responses of the tissues to the food intake. Some of these hormones, like insulin, IGF1, leptin and ghrelin, are known to have an effect on the CNS, where they might modulate the nutritional behaviour. Their effect has been evaluated within the hypothalamus at first, but further researches have demonstrated a wider activity elsewhere in the brain, especially in the hippocampus, where they are involved in cognitive functions and in the modulation of synaptic plasticity.

INSULIN. Insulin is best known for its ability to regulate glycaemia by stimulating the glucose assumption in the liver and in the muscles, whereas its effects on the CNS are less noted. However, insulin fulfils an important role in the regulation of food intake, as confirmed by several studies that determined the action of this hormone on the hypothalamic centres which are responsible of the sense of hunger (Niswender K. D., Schwartz M.W., Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities. Frontiers in Neuroendocrinology 24, 1 – 10 [2003]) – we will discuss this point later. Furthermore the traditional view of the brain as being metabolically unresponsive to insulin is incorrect, at least to regard with the hippocampus (McNay E., Insulin and ghrelin: peripheral hormones modulating memory and hippocampal function. Current Opinion in Pharmacoogy 7, 628 – 632 [2007]), whose cells express both the insulin receptor and the insulin-regulated glucose transporter GluT4. Thus, in these neurons the insulin-mediated regulation of the glucose uptake seems to be correlated to an increased local glycolytic metabolism, and there is some evidence that an improvement of spatial memory skills depends thereof. In addition to the metabolic effects, the signalling involves processes of LTD, alterations of the frequency-response range for induction of both LTD and LTP and hyperpolarization of the hippocampal neurons. The underlying pathway provides for the stimulation of phosphatidylinositol 3-kinase (PIK3) and the following activation of PKB/Akt; this kinase is implicated in several reactions, among which the phosphorylation (and hence the inhibition) of Tsc1/2, a GTPase Activating Protein (GAP) that stimulates the inactivation of the monomeric GTPase Rheb, thus activated by the signalling; in turn, Rheb promotes the activation of mTOR, an important intracellular messenger involved in the stimulation of protein biosynthesis. Therefore, one of the most important processes by which ultimately insulin operates its neurotrophic effects is the direct enhancement of the translation, known as an essential condition for the formation of new synaptic contacts, thus, of memories. As well as this, further studies indicate the role of other components of the pathway, as the MAP kinases, which could lead to the LTD through an alteration of the membrane conductance (it is not well understood whether the LTD is NMDA-dependent or independent).

INSULIN-LIKE GROWTH FACTOR 1. Its effects are similar to the ones of insulin, particulary in regard to the neurotrophic actions which enhance the synaptic plasticity. The IGF1 is synthetized in liver, in skeletal muscles and throughout the brain, whereas brain IGF1 receptors are expressed mainly in the hippocampus. The production of IGF1 depends on the energy of the mitochondrial activity, being in proportion to ATP levels in the cell. When diet and exercise increase the metabolic rate, more ATP is produced and consequently more IGF1 is synthetized, and then the function of the cell is supported.
The pathway triggered by the IGF1 is largely overlapping to the one of insulin, consisting of the activation of the tyrosine-kinase receptor and PI3K-Akt-mTOR. Moreover, further researches have suggested a wider action in both presynaptic and postsynaptic cells in association with the Brain-Derived Neurotrophic Factor (BDNF): the most studied pathway includes the activation of the calcium/calmodulin-dependent protein kinase II (CaMKII) and the MAPK system, that are involved in the enhancement of the neurotransmission (by stimulating the function of the synapsin 1 and the release of the glutamate) and in the expression of a pattern of genes CREB-dependent, in the presynaptic and postsynaptic neurons respectively. Disturbances in energy homeostasis have been linked to the pathobiology of several mental diseases and the relationship between the reduction of the mitochondrial activity and the drop of the IGF1 and BDNF levels represents a key to evaluate the problem.
Some foods are known to increase the effects of both IGF1 and BDNF by affecting energy-generating metabolic pathways. In particular, there is strong evidence that omega-3 fatty acids, as the docosahexaenoic acid (DHA), can activate these pathways; furthermore, they have a role in improving the plasma membrane fluidity at synaptic regions, thus maintaining the integrity of the membrane and the ionic excitability of the cell. We are largely dependent on dietary DHA, which is prevalent in some foods like fish: could this be the reason why it is often said that eating fish makes us more intelligent?

LEPTIN. Leptin is produced by the adipose tissue and it acts on the CNS as a “signal of adiposity”, as well as the insulin. The region that is mainly triggered by leptin is the Arcuate Nucleus of the hypothalamus, where it inhibits the activity of a population of neurons which employ neuropeptide Y (NPY) as neurotransmitter, whereas it stimulates the action of another group of cells that produce POMC (cleaved in other peptides, as α-MSH at a later stage). The final effect of this process is the inhibition of the sense of hunger and the enhancement of the satiety. Furthermore, leptin and insulin operate together on the hypothalamus reducing the stimulus leading to food intake. In fact, what has become apparent is that their actions in the CNS are again partially complimentary and partially redundant. Nevertheless, insulin appears to be less effective than leptin and dependent on the integrity of its signalling to be able to affect the mechanism of food intake.

The intracellular cascades of two hormones meet on a common trigger, IRS2, which ultimately phosphorylates the PI3K. An effect of leptin on the hypothalamus seems to be the elevations of levels of BDNF, according to its ability to enhance the metabolic production of energy.
As the insulin, leptin also has a role in improving the activity of the hippocampus, where it can stimulate LTD or LTP and enhance the synaptic plasticity, probably through exerting a direct action on the hippocampal dendritic morphology.

GHRELIN. Ghrelin is secreted from an empty stomach and it plays an important role on the CNS, where it acts as an appetite stimulant, in contrast with insulin and leptin. The antagonism with the “adiposity signals” is largely due to the activation of NPY neurons in the Arcuate Nucleus and the inhibition of the POMC ones. Moreover, several studies have contemplated the action of the ghrelin on other parts of the brain, as the hippocampus (in particular in CA1), the amydgala and dorsal raphe (Carlinia V. P., Varasa M. M., Cragnolinia A. B., Schiöthb H. B., Scimonellia T. N., de Barioglioa S. R., Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochemical and Biophysical Research Communications 313, 635 – 641 [2004]). Injected in these regions ghrelin enhances memory retention by increasing spine density and has an anxiogenic effect (but there is some doubt about the dose which can lead to the manifestation of anxiety; it seems to be about 3 nmol/μl). A possible explication of both the effects is that ghrelin inhibits the serotoninergic neurotransmission within the hypothalamus, responsible of the induction of the hunger stimulus in the ventromedial region and involved in the control and the decrease of the anxiety.

This short inspection aims at highlighting the linkage between the hormonal response to the food and the cognitive processes. The evolutionary reasons of these phenomena seem to be clear: the food plays a fundamental role in the survival of an organism, whence the necessity that the organism itself does not forget if something it has eaten is good or not, so as to choose the best nourishment in the future. Similarly, animals retain a profound memory of a food which damaged them – this phenomenon is called “aversive conditioning” – and the processes of synaptic plasticity triggered by hormones and substances obtained from the diet could be analysed in order to this evolutionist view. Furthermore, it is interesting to note that different hormones may provoke different responses in those centres which regulate food intake (e.g. insulin and leptin versus ghrelin) but the same neurotrophic response within certain structures involved in the formation of new memories, as the hippocampus.


Some nutrients are known to affect the cognitive skills due to their influence on certain centres of the CNS.

OMEGA-3 polyunsaturated fatty acids are normal constituents of cell membranes and are essential for a normal brain function. We have already roughed the importance of the DHA, which might have an effect on the BDNF expression and the enhancement of synaptic plasticity. This molecule has been studied in several trials, among which a randomized double-blind controlled trial occurred in Durham, UK (Portwood M. M., The role of dietary fatty acids in children's behaviour and learning. Nutr. Health 18, 233 - 247 [2006]); several schools partook in this experiment, on the occasion of which half of the children received omega-3 fatty acids and the other half received placebos. The aim of the trial was to evaluate whether the cognitive skills of the two groups were otherwise affected by the treatment. Finally, some level of improvement in school performance was observed in the group receiving omega-3 fatty acids. Nonetheless, other possible supplements that could have contributed to the behavioural effects should be considered.

TRANS and SATURATED FATS adversely affect cognition, in contrast to the healthy effects of omega-3 fatty acids. In particular, their action reduces the hippocampal levels of BDNF-related synaptic plasticity after only three weeks of dietary treatment (Molteni R., Barnard J. R., Ying Z., Roberts C. K., Gomez-Pinilla F., A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience 112, 803 –814 [2002]). To this end some researches have strengthened the idea that overeating represents a risk factor for cognitive processes and the most likely explanation is the increase of oxidative stress due to the rise of glucose levels.

Thus, it is necessary to consider the ROS formation (e.g. superoxide anion radical) as a cause of neuron damage and cognitive dysfunction. Another cause that finally affects the homeostasis of the cell is a process called glycation, a non-enzymatic glycosylation of protein or lipid substrates which also can lead to the formation of oxidising products. This process progresses through multiple steps (Amadori reactions, Schiff base reactions, and Maillard reactions) up to the production of advanced-glycation end products (AGE), like carboxymethyllysine (CML), carboxyethyllysine (CEL), and argpyrimidine, which is the most common. These molecules may be more reactive than sugars they were formed from, enhancing the risk of damaging several cell structures.
For these reasons the integrity of physiological systems controlling and reducing the reactivity of ROS is a strong instrument that the cell has available to prevent degenerative processes depending on them. These systems include a particular isoform of an uncoupling protein (UCP4) (Liu D., Chan S. L., de Souza-Pinto N. C., Slevin Jr. J. R., Wersto R. P., Zhan M., Mustafa K., de Cabo R., Mattson M. P., Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress. NeuroMolecular Medicine 8, 389 – 413 [2006]) expressed in the mitochondrial inner membrane and implicated in the regulation of mitochondrial membrane potential and cellular energy metabolism. UCP4 modulates neuronal energy metabolism by increasing glucose uptake and shifting the mode of ATP production from mitochondrial respiration to glycolysis, thereby maintaining cellular ATP levels. The UCP4-mediated shift in energy metabolism reduces ROS production and increases the resistance of neurons to oxidative and mitochondrial stress. Furthermore, it has been demonstrated (Mattson M. P., The Impact of Dietary Energy Intake on Cognitive Aging. Front. Aging Neurosci. 2:5 [2010]) that decreasing energy intake and increasing its expense might upregulate the expression of BDNF, UCP4 and other neuroprotective proteins as well as reduce ROS levels, therefore some neurobiologists have theorise the healthy effects of a “caloric restriction” on the CNS.

ANTIOXIDANT FOODS represent a protection against the oxidative damage due to the high metabolic load of the brain. Certain products are becoming popular for their antioxidant properties:
- Berries (Joseph J. A., Shukitt-Hale B., Lau, F. C. Fruit polyphenols and their effects on neuronal signaling and behavior in senescence. Ann. NY Acad. Sci. 1100, 470 – 485 [2007]): a limited number of their many components (two tannins – procyanidin and prodelphinidin – anthocyanins and phenolics) seems to affect positively plasticity and cognition, probably because of the ability to maintain metabolic homeostasis and protect membrain from lipid peroxidation.
- Spinach, broccoli and potatoes which contain alpha-lipoic acid, known as a coenzyme that is important for maintaining energy homeostasis in mitochondria. In effect, alpha-lipoic acid plays a fundamental role in mitochondrial metabolism.

Biologically, it exists in proteins where it is linked covalently to a lysyl residue as a lipoamide. The mitochondrial E3 enzyme, dihydrolipoyl dehydrogenase, reduces lipoate to dihydrolipoate at the expense of NADH. Lipoate is also a substrate for the NADPH dependent enzyme GSH reductase. In recent years, LA has gained considerable attention as an antioxidant. The reduced form of LA, dihydrolipoic acid, reacts with oxidants such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by reducing oxidised vitamin C and GSH, which may in turn recycle vitamin E (Liu J., The Effects and Mechanisms of Mitochondrial Nutrient a-Lipoic Acid on Improving Age-Associated Mitochondrial and Cognitive Dysfunction: An Overview. Neurochem. Res. 33, 194 – 203 [2008]).
- Alpha-tocopherol (vit. E) and curcumin (an indian curry spice, known as a traditional food preservative and medicinal herb) are also supposed to protect the nervous system by the oxidative attack to neurons’ membranes (Navarro A. et al., Vitamin E at high doses improves survival, neurological performance, and brain mitochondrial function in aging male mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R1392 R1399 [2005], Ammon H. P., & Wahl M. A., Pharmacology of Curcuma longa. Planta Med. 57, 1 – 7 [1991]).


Neural circuits that are involved in feeding behaviour show precise coordination with brain centres that modulate energy homeostasis and cognitive functions. The effects of food on cognition and emotions can start before the act of feeding itself, as the recollection of foods through olfactory and visual sensory inputs alters the emotional status of the brain. The ingestion of foods triggers the release of hormones or peptides, such as insulin, which activates signal-transduction pathways that promote synaptic activity and contribute to learning and memory. In turn, the lack of food that is signalled by an empty stomach can elicit the release of ghrelin, which can also support synaptic plasticity and cognitive function. Chemical messages derived from adipose tissue through leptin can activate specific receptors in the hippocampus and the hypothalamus and influence learning and memory. Insulin-like growth factor 1 (IGF1) is produced by the liver and by skeletal muscle in response to signals derived from metabolism and exercise, as well as BDNF. IGF1 can signal to neurons in the hypothalamus and the hippocampus, with resulting effects on learning and memory performance. In addition to regulating appetite, the hypothalamus coordinates activity in the gut and integrates visceral function with limbic-system structures such as the hippocampus, the amygdala and the cerebral cortex.
Finally, some foods have a role in affecting cognitive processes, and this evidence increasingly upholds the strong linkage between feeding and brain functioning.

2013-06-28T08:40:03 - Gianpiero Pescarmona

Poco ferro disturba le giovani menti
tags: Elementi di transizione, Metalli pesanti, Ferro, Composti del ferro, Ferro alimentare
bambino pediatra
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Nei bambini e adolescenti l’anemia da carenza di ferro (Ida) aumenta il rischio di disturbi psichiatrici. Lo afferma Ya-Mei Bai, psichiatra della National Yang-Ming University di Taiwan in uno studio pubblicato online su Bmc Psychiatry. «Secondo l'Organizzazione Mondiale della Sanità, la scarsità di ferro è la carenza nutrizionale più diffusa, e l’anemia da carenza di ferro è una condizione frequente nei bambini e adolescenti dei paesi non industrializzati, ma anche nel mondo occidentale» si legge nelle premesse. È caratterizzata da un difetto di sintesi dell'emoglobina per la scarsa disponibilità di ferro, con ridotta capacità dei globuli rossi di trasportare ossigeno ai tessuti. Da qui i sintomi: pallore, dispnea, vertigini e, in certi casi, disturbi cognitivi. «Il ferro svolge un ruolo cruciale nello sviluppo del cervello, in particolare nella mielinizzazione della materia bianca e nel funzionamento di diversi sistemi di neurotrasmettitori, come dopamina, noradrenalina e serotonina» spiega lo psichiatra cinese. Alcuni studi indicano che essa influenza lo sviluppo cognitivo, ma l'associazione tra anemia ferrocarenziale e disturbi psichiatrici in bambini e adolescenti è da dimostrare. «Questo studio, usando un archivio assicurativo nazionale, il Taiwan National Health Insurance Database, ha verificato il rapporto tra le due condizioni in giovane età» sottolinea Bai. I partecipanti sono stati 2.957 ragazzi con diagnosi di anemia da carenza di ferro e 11.828 individui sani abbinati per età e sesso. I risultati, aggiustati per dati demografici e fattori di rischio legati all’anemia, dimostrano che bambini e adolescenti con anemia avevano un rischio più elevato dei soggetti di controllo di sviluppare disturbi psichiatrici come ansia, depressione, disturbo bipolare e autismo. I ricercatori fanno opportunamente notare che le associazioni osservate non indicano se la carenza di ferro è responsabile dei problemi psichiatrici o viceversa. Per esempio, i disturbi alimentari osservati nei bambini con sintomi psichiatrici potrebbero contribuire alla carenza di ferro.

Bmc Psychiatry 2013, 13:161

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