Brain foods: the effects of nutrients on brain function...

Brain foods: the effects of nutrients on brain function

It has long been suspected that the relative abundance of specific nutrients can affect cognitive processes and emotions. Newly described influences of dietary factors on neuronal function and synaptic plasticity have revealed some of the vital mechanisms that are responsible for the action of diet on brain health and mental function. Several gut hormones that can enter the brain, or that are produced in the brain itself, influence cognitive ability. In addition, well-established regulators of synaptic plasticity, such as brain-derived neurotrophic factor, can function as metabolic modulators, responding to peripheral signals such as food intake. Understanding the molecular basis of the effects of food on cognition will help us to determine how best to manipulate diet in order to increase the resistance of neurons to insults and promote mental fitness.


Gómez-Pinilla F. Brain foods: the effects of nutrients on brain function. Nat Rev Neurosci. 2008 Jul;9(7):568-78.

Department of Neurosurgery, University of California at Los Angeles School of Medicine, Los Angeles 90095, California, USA. fgomezpi@mednet.ucla.edu


Although food has classically been perceived
as a means to provide energy and building
material to the body, its ability to prevent
and protect against diseases is starting to be
recognized. In particular, research over the
past 5 years has provided exciting evidence
for the influence of dietary factors on
specific molecular systems and mechanisms
that maintain mental function. For instance,
a diet that is rich in omega‑3 fatty acids is
garnering appreciation for supporting cogni‑
tive processes in humans [1] and upregulating
genes that are important for maintaining
synaptic function and plasticity in rodents [2].
In turn, diets that are high in saturated
fat are becoming notorious for reducing
molecular substrates that support cognitive
processing and increasing the risk of neuro‑
logical dysfunction in both humans [3] and
animals [4]. Although these studies emphasize
an important effect of food on the brain,
further work is necessary to determine the
mechanisms of action and the conditions for
therapeutic applications in humans.

Over thousands of years, diet, in conjunc‑
tion with other aspects of daily living, such
as exercise, has had a crucial role in shaping
cognitive capacity and brain evolution (BOX 1).
Advances in molecular biology have revealed
the ability of food‑derived signals to influence
energy metabolism and synaptic plasticity
and, thus, mediate the effects of food on
cognitive function, which is likely to have
been crucial for the evolution of the modern
brain. Feeding habits have been intrinsically
associated with the development of human
civilization, as people’s choice of what to eat
is influenced by culture, religion and society.
The newly discovered effects of food on cog‑
nition are intriguing for the general public,
as they might challenge preconceptions,
and they attract substantial interest from the
media. The fact that feeding is an intrinsic
human routine emphasizes the power of
dietary factors to modulate mental health not
only at the individual level, but also at the
collective, population‑wide level. Here I
discuss the effects of both internal signals
that are associated with feeding and dietary
factors on cell metabolism, synaptic plasticity
and mental function (FIG. 1). Throughout I
use the term cognition from a neurobiological
perspective, to refer to the mental processes
that are involved in acquiring knowledge
and to the integration of these processes into
the conscious aspect of emotions, which
influences mood and has psychiatric
manifestations [5].


INTERNAL SIGNALS AND COGNITION

The influence of visceral signals on mental
function has been appreciated since ancient
times, and to this day lifestyle factors, such
as diet and exercise, are used as part of thera‑
pies to reduce depression, schizophrenia and
bipolar disorders. In this section I discuss
the influence of vagal nerve stimulation
(VNS) and gut hormones on cognition and
emotion (FIG. 1).


Effects of vagal nerve stimulation on cognition.

Vagal afferents from the gastrointestinal tract
are critical for monitoring various aspects
of digestion, such as the release of enzymes
and food absorption. The use of vNS has
become a routinely approved procedure
for the treatment of refractory partial‑onset
seizures. Based on observations that the
application of VNS to patients with epilepsy
was associated with improved mood, VNS
was perceived as a potential treatment for
depression. In humans, VNS failed to pro‑
duce improvements in depression patients
who participated in a short‑term open trial
(lasting 10 weeks) [6]; however, in a longer‑term
study (lasting 12 months), VNS produced
beneficial effects that were sustained after
2 years [7]. Specifically, patients treated with
VNS doubled their improvement per month
in the Inventory of Depressive Symptoms
self report relative to patients receiving
treatment as usual (TAu) by itself. TAu
consisted of managing treatment‑resistant
depression with medication or with another
therapy that was deemed appropriate by
the treating physician. Based on the results
of the long‑term studies, the uS Food and
Drug Administration recently approved the
use of VNS for the treatment of chronic (not
acute) resistant depression (see
REF. 8
for
a review). Although the mechanisms that
underlie the effects of VNS on depression
are not well‑understood, a recent study
demonstrated that VNS increases the levels
of the mrNAs for brain‑derived neuro‑
trophic factor (BDNF) and fibroblast growth
factor 2 (FGF2) in the rat hippocampus
and cerebral cortex, as well as the level of
noradrenaline in the prefrontal cortex [9]. As
elevations of BDNF [10]
and noradrenaline
have been associated with the effects of
antidepressant treatments, these findings
provide insights into how signals derived
from the gut can affect mood. Furthermore,
on the basis that neurons of the dorsal motor
nucleus of the vagus nerve retrogradely
transport BDNF and other neurotrophins [11],
it is likely that neurotrophins are involved
in sensory and motor signalling from the
viscera. Interestingly, a separate line of
investigations indicated that the application
of VNS to humans [12]
or rodents [12]
enhanced
memory performance, suggesting that the
information that is signalled to the brain
by the vagus nerve might serve to influence
higher‑order cognitive processing.

________
Box 1 | Feeding as an adaptive mechanism for the development of cognitive skills
Adaptations that facilitated food acquisition
and energy efficiency exerted strong
evolutionary pressures on the formation of
the modern brain and the energy-
demanding development of cognitive skills.
For example, the wildebeest annually travels
hundreds of miles to find feeding grounds in
the savannah, a behaviour that requires fully
operational and complex navigational,
defensive and cognitive conducts for
survival. The function of brain centres that
control eating behaviour is integrated with
those of centres that control cognition (FIG. 1).
For instance, animals that eat a potentially
poisonous meal develop a perpetual
aversion to its flavour through complex
mechanisms of learning and memory that
involve the hypothalamus, the hippocampus
and the amygdala [133]. In turn, pleasant
memories of foods have been related to
brain pathways that are associated with
reward [134].
Abundant paleontological evidence
suggests that there is a direct relationship
between access to food and brain size, and
that even small differences in diet can have
large effects on survival and reproductive
success [135]. Larger brains in humanoids are
associated with the development of
cooking skills, access to food, energy
savings and upright walking and running [136];
all of these features require coordination
with cognitive strategies that are centred
in successful feeding. Dietary consumption
of omega-3 fatty acids is one of the best-
studied interactions between food and brain evolution. Docosahexaenoic acid (DHA) is the
most abundant omega-3 fatty acid in cell membranes in the brain [137]; however, the human body
is not efficient at synthesizing DHA, so we are largely dependent on dietary DHA [138]. It has been
proposed that access to DHA during hominid evolution had a key role in increasing the brain/
body-mass ratio (also known as encephalization) [138] (see figure, part
a
). The fact that DHA is an
important brain constituent supports the hypothesis that a shore-based diet high in DHA was
indispensable for hominid encephalization. Indeed, archeological evidence shows that early
hominids adapted to consuming fish and thus gained access to DHA before extensive
encephalization occurred. The interplay between brain and environment is ongoing. Over the
past 100 years, the intake of saturated fatty acids, linoleic acid and trans fatty acids has
increased dramatically in Western civilizations, whereas the consumption of omega-3 fatty
acids has decreased. This might explain the elevated incidence of major depression in countries
such as the United States and Germany (see figure, part
b
) [78]. Both photographs in part
a
© Jeffrey H. Schwartz. Part
b
of the figure reproduced, with permission, from
REF. 78 (1998)
Lancet Publishing Group.
________



Gut hormones associated with cognition.

In addition to the capacity of the gut to
directly stimulate molecular systems that are
associated with synaptic plasticity and learn‑
ing, several gut hormones or peptides, such
as leptin, ghrelin, glucagon‑like peptide 1
(GlP1) and insulin have been found to influ‑
ence emotions and cognitive processes
(FIG. 1).

Leptin is synthesized in adipose tissue
and sends signals to the brain to reduce
appetite (see REF. 13 for a review). leptin
receptors have been identified in several
brain areas, including the hypothalamus, the
cerebral cortex and the hippocampus. The
fact that leptin elevates BDNF expression
in the hypothalamus suggests that BDNF
might mediate the effects of leptin on food
intake and energy homeostasis [14]. like BDNF,
leptin facilitates synaptic plasticity in the
hippocampus [15]. Genetically obese rodents
with dysfunctional leptin receptors show
impairments in long‑term potentiation
(lTP) and long‑term depression and dif‑
ficulties in spatial learning [16]. These effects
were rescued by administrating leptin into
the hippocampus [15,17]. New studies showing
that leptin promotes rapid changes in hippo‑
campal dendritic morphology suggest that
leptin exerts a direct action on hippocampal
plasticity [18].

Ghrelin is an adipogenic hormone that
is secreted by an empty stomach (see REF. 19
for a review); it acts as an appetite stimulant
in mice [20] and humans [21]. Ghrelin is the
endogenous ligand of the growth hormone
secretagogue receptor, which is expressed in
the arcuate nucleus in the hypothalamus [22]
and in the hippocampus [23]. Peripheral
administration of ghrelin increases food
intake in normal rodents [24,25] and humans [26,27],
whereas chronic administration can lead to
adiposity [24,25]. Ghrelin also promotes rapid
reorganization of synaptic terminals in the
hypothalamus [28], and in the hippocampus
it promotes synapse formation in dendritic
spines and lTP, which are paralleled by
enhanced spatial learning and memory
formation [29].


________
Figure 1. Effects of feeding on cognition. Neural circuits that are involved in feeding behaviour
show precise coordination with brain centres that modulate energy homeostasis and cognitive func-
tion. 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 and
glucagon-like peptide 1 (GLP1) [31], into the circulation (see REF. 31 for a review); these substances can
then reach centres such as the hypothalamus and the hippocampus and activate 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. The positive actions of leptin on hippocampus-dependent synaptic plasticity — that is,
its actions on NMDA (N-methyl-d-aspartate) receptor function and long-term potentiation facilitation
— are well characterized (see REF. 13 for a review). Insulin-like growth factor 1 (IGF1) is produced by
the liver and by skeletal muscle in response to signals derived from metabolism and exercise. 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 amyg-
dala and the cerebral cortex. Visceral signals can also modulate cognition and body physiology
through the hypothalamic–pituitary axis (HPA). The effects of the hypothalamus can also involve the
immune system, as it heavily innervates the thymus and several immune-system molecules can affect
synaptic plasticity and cognition. The parasympathetic innervation of the gut by the vagus nerve
provides sensory information to the brain, enabling gut activity to influence emotions. In turn, emo-
tions can also influence the viscera through parasympathetic efferents in the vagus nerve. Vagal nerve
stimulation is being used therapeutically to treat chronic depression.
________


GlP1, which is synthesized by intestinal
cells, regulates energy metabolism by
stimulating pancreatic insulin secretion and
subsequent glucose uptake by muscle cells,
and by suppressing food intake through
actions on the hypothalamus. GlP1 recep‑
tors are expressed in neurons, and infusion
of GlP1 into the brain has been shown to
improve associative and spatial memory in
rats [30]. Owing to their multiple actions on
somatic and neural targets, ghrelin, leptin
and GlP1 can integrate processes that
influence cognition and emotion.

Finally, insulin, which has classically been
regarded as a gut hormone that is produced
in the pancreas, has also been found to alter
synaptic activity and cognitive processing
(see REF. 31 for a review). Insulin secretion is
normally stimulated by the mental anticipa‑
tion to meals and continues during digestion
and the absorption of foods into the
bloodstream. Insulin can enter the brain and
interact with specific signal‑transduction
receptors located in discrete brain regions,
such as the hippocampus. overall, the
evidence seems to indicate that the act of
feeding can itself modulate cognitive pro‑
cesses on two levels, through neural circuits
that connect the gut and the brain and
through the release of gut peptides into the
bloodstream (FIG. 1).

Thus, as predicted from an evolutionary
perspective, the gut does influence the
molecular mechanisms that determine
the capacity for acquiring new memories
and that control emotions, as well as overall
mental function. It is not surprising that
visceral signals are now recognized as essen‑
tial factors for the treatment of psychiatric
disorders. The challenge now is to better our
understanding of the molecular mechanisms
by which peripheral signals can modulate
mental processes.


FROM ENERGY METABOLISM TO COGNITION

The brain consumes an immense amount
of energy relative to the rest of the body.
Thus, the mechanisms that are involved in
the transfer of energy from foods to neurons
are likely to be fundamental to the control of
brain function. Processes that are associated
with the management of energy in neurons
can affect synaptic plasticity [32] (FIG. 2), which
could explain how metabolic disorders can
affect cognitive processes. Interestingly,
synaptic function can, in turn, alter meta‑
bolic energy, allowing mental processes to
influence somatic function at the molecular
level. BDNF is an excellent example of a
signalling molecule that is intimately related
to both energy metabolism and synaptic
plasticity: it can engage metabolic signals to
affect cognitive function [32]. BDNF is most
abundant in brain areas that are associated
with cognitive and metabolic regulation:
the hippocampus and the hypothalamus,
respectively [33]. Learning to carry out a task
increases BDNF‑mediated synaptic plasticity
in the hippocampus [34,35], and genetic deletion
of the BDNF gene impairs memory for‑
mation [36,37]. The met variant of the val66met
BDNF polymorphism, a common genotype
in humans that is related to abnormal traf‑
ficking and secretion of BDNF in neuronal
cells [38], is associated with abnormal hippo‑
campal functioning and memory process‑
ing [39]. In turn, BDNF has also been shown
to influence multiple parameters of energy
metabolism, such as appetite suppression [40,41],
insulin sensitivity [42,43] and glucose [44] and lipid
metabolism [45]. In addition, the hypothalamic
melanocortin 4 receptor, which is crucial for
the control of energy balance, regulates the
expression of BDNF in the ventral medial
hypothalamus [46], supporting an association
between energy metabolism and synaptic
plasticity. In rodents, a reduction in energy
metabolism caused by infusing a high
dose of vitamin D3 into the brain has been
shown to abolish the effects of exercise on
downstream effectors of BDNF‑mediated
synaptic plasticity, such as calcium/calmod‑
ulin‑dependent protein kinase II (CamKII),
synapsin I and cyclic AmP‑responsive
element (Cre)‑binding protein (CreB) [32].
In humans, a de novo mutation in TrkB,
a BDNF receptor, has been linked with
hyperphagic obesity, as well as impairments
in learning and memory [47]. Although energy
metabolism and BDNF‑mediated synaptic
plasticity seem to be interconnected, further
studies are crucial to determine the confines
of this relationship for the modulation of
cognitive function.


________
Figure 2. Energy homeostasis and cognition. Diet and exercise can affect mitochondrial energy
production, which is important for maintaining neuronal excitability and synaptic function.The com-
bination of certain diets and exercise can have additive effects on synaptic plasticity and cognitive
function. ATP produced by mitochondria might activate brain-derived neurotrophic factor (BDNF) and
insulin-like growth factor 1 (IGF1), which support synaptic plasticity and cognitive function. Energy-
balancing molecules, such as ubiquitous mitochondrial creatine kinase (uMtCK), AMP-activated
protein kinase (AMPK) and uncoupling protein 2 (UCP2) [141,146],interact with BDNF to modulate synaptic
plasticity and cognition. Excess energy production caused by high caloric intake o rstrenuous exercise
results in the formation of reactive oxygen species (ROS). When ROS levels exceed the buffering
capacity of the cell, synaptic plasticity and cognitive function are compromised, probably owing to a
reduction in the actions of signal-transduction modulators such as BDNF. Energy metabolism can also
affect molecules such as silent information regulator 1 (SIRT1), a histone deacetylase that contributes
to the reduction of ROS and promotes chromatin modifications that underlie epigenetic alterations
that might affect cognition [146]. On the basis of its demonstrated susceptibility for epigenetic modifica-
tion [73], another potential target for the effects of diet on epigenetics is the BDNF gene. Two main
findings support a mechanism whereby exercise, similar to diet, enhances cognitive processes through
effects on energy metabolism and synaptic plasticity. First, the combination of exercise and certain
diets elevates the expression of uMtCK, AMPK and UCP2, which might affect energy homeostasis and
brain plasticity. Second, disruption of energy homeostasis during voluntary wheel-running abolished
the effects of exercise on the actions of BDNF and BDNF endproducts that are important for learning
and memory, suggesting that energy metabolism influences BDNF function [147].
________



The mechanism whereby BDNF affects
metabolism and synaptic plasticity seems to
involve insulin‑like growth factor 1 (IGF1) [48].
IGF1 is synthesized in the liver, in skeletal
muscle and throughout the brain, whereas
brain IGF1 receptors are expressed mainly in
the hippocampus [49]. A reduction of IGF1 sig‑
nalling in rodents results in hyperglycaemia
and insulin resistance, and infusion of IGF1
into the brain decreases plasma insulin levels
and increases insulin sensitivity [50]. IGF1 also
supports nerve growth and differentiation,
neurotransmitter synthesis and release [51] and
synaptic plasticity [52], and might contribute
to sustaining cognitive function after brain
insults [53,54], diabetes [55] and aging [56]. IGF1 has
been shown in rodents to entrain similar
downstream pathways to BDNF, such
as the Akt signalling system [57]. Interestingly,
the omega‑3 fatty acid docosahexaenoic
acid (DHA) stimulates neuronal plasticity
through the Akt pathway [58], suggesting
that Akt activation might be crucial for
integrating the effects of food‑derived
signals on brain plasticity. The phosphatidyl‑
inositol 3‑kinase (PI3K)/Akt/mammalian
target of rapamycin (mTor) signalling path‑
way seems to integrate the effects of BDNF
and IGF1 on energy metabolism, synaptic
plasticity, and learning and memory (FIG. 3).

Disturbances in energy homeostasis
have been linked to the pathobiology of
several mental diseases, and so dietary
management is becoming a realistic strategy
to treat psychiatric disorders. Numerous
studies have found that there might be an
association between abnormal metabolism
(diabetes type II, obesity and metabolic
syndrome) and psychiatric disorders [59].
In a large study of patients with manic
depression [60] or schizophrenia [61,62], the rate
of diabetes was found to be higher than
in the general population (1.2% of people
aged 18–44 years and 6.3% of people aged
45–64 years [163]). The overall prevalence
of diabetes in a group of 95 patients with
schizophrenia was 15.8%, and this increased
to 18.9% with age [61], whereas diabetes in 203
patients with manic depression ranged from
2.9% in patients of approximately 30 years
of age to 25% in patients of 75–79 years of
age [60]. However, it is difficult to ascertain a
cause–effect relationship between diabetes
and psychiatric disorders in these studies
given that schizophrenia, manic depression
and other psychiatric disorders are associ‑
ated with poor quality of life and the side
effects of anti‑psychotic medication. on
the basis of its effects on synaptic plasticity
and energy metabolism, BDNF has been the
focus of research into current hypotheses of
schizophrenia and depression [63–66]. Low levels
of BDNF in the plasma are associated with
impaired glucose metabolism and type II
diabetes [67], and BDNF is reduced in the hippo‑
campus, in various cortical areas [68]
and in the serum [69] of patients with schizophrenia. In
mice, genetic deletion of the TrkB receptor
in the forebrain produces schizophrenic‑like
behaviour [70]. Furthermore, BDNF levels are
reduced in the plasma of patients with major
depression [71], and chronic administration of
antidepressants elevates hippocampal BDNF
levels [72]. A recent study in rodents demon‑
strated that defeat stress, an animal model
of depression, induced a lasting repression
of BDNF transcripts, whereas antidepres‑
sant treatment reversed this repression by
ind]ucing histone acetylation [73]. Although
the evidence is not conclusive to argue that
BDNF has a role in mediating depression or
schizophrenia, it is becoming clear that most
treatments for depression or schizophrenia
— that is, exercise and drugs — involve the
action of BDNF.


________
Figure3. Dietary omega‑3 fatty acids can affect synaptic plasticity and cognition. Theomega-3
fatty acid docosahexaenoic acid (DHA), which humans mostly attain from dietary fish, can affect
synaptic function and cognitive abilities by providing plasma membrane fluidity at synaptic regions.
DHA constitutes more than 30% of the total phospholipid composition of plasma membranes in the
brain, and thus it is crucial for maintaining membrane integrity and, consequently, neuronal excitability
and synaptic function. Dietary DHA is indispensable for maintaining membrane ionic permeability and
the function of transmembrane receptors that support synaptic transmission and cognitive abilities.
Omega-3 fatty acids also activate energy-generating metabolic pathways that subsequently affect
molecules such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor1 (IGF1). IGF1
can be produced in the liver and in skeletal muscle, as well as in the brain, and so it can convey peripheral
messages to the brain in the context of diet and exercise. BDNF and IGF1 acting at presynaptic and
postsynaptic receptors can activate signalling systems, such as the mitogen-activated protein kinase
(MAPK) and calcium/calmodulin-dependent protein kinase II (CaMKII) systems, which facilitate synaptic
transmission and support long-term potentiation that is associated with learning and memory. BDNF
has also been shown to be involved in modulating synaptic plasticity and cognitive function through
the phosphatidyl inositol3-kinase(PI3K)/Akt/mammalian target o frapamycin (mTOR) signalling path-
way. The activities of the mTOR and Akt signalling pathways are also modulated by metabolic signals
such as insulin and leptin (not shown). 4EBP, eukaryotic translation-initiation factor 4E binding protein;
CREB, cyclic AMP-responsive element (CRE)-binding protein; IGFR, insulin-like growth factor receptor;
IRS1, insulin receptor substrate1; p70S6K, p70S6 kinase.
________



EFFECTS OF NUTRIENTS ON COGNITION

Several dietary components have been iden‑
tified as having effects on cognitive abilities
(TABLE 1). Dietary factors can affect multiple
brain processes by regulating neurotrans‑
mitter pathways, synaptic transmission,
membrane fluidity and signal‑transduction
pathways. This section focuses on recent
evidence that shows the capacity of nutrients
to affect neural pathways that are associated
with synaptic plasticity.

Dietary lipids, which were originally
thought to affect the brain through their
effects on cardiovascular physiology, are
garnering recognition for their direct actions
on the brain. omega‑3 polyunsaturated
fatty acids are normal constituents of cell
membranes and are essential for normal
brain function (FIG. 3). In spite of the large
variability in the design of experiments to
evaluate the action of different dietary
elements on cognitive abilities, there is a gen‑
eral consensus that a deficiency of omega‑3
fatty acids in rodents results in impaired
learning and memory [74,75]. Dietary deficiency
of omega‑3 fatty acids in humans has been
associated with increased risk of several
mental disorders, including attention‑deficit
disorder, dyslexia, dementia, depression,
bipolar disorder and schizophrenia [76–80]. As
the omega‑3 fatty acid DHA is a prominent
component of neuronal membranes, and as
the human body is inefficient in synthesizing
DHA, we are reliant on dietary DHA. Some
of the mechanisms by which DHA affects
brain plasticity and cognition are starting
to be elucidated. For example, DHA dietary
supplementation has been found to elevate
levels of hippocampal BDNF and enhance
cognitive function in rodent models of brain
trauma [81]. DHA might enhance cognitive
abilities by facilitating synaptic plasticity
and/or enhancing synaptic membrane
fluidity; it might also act through its effects
on metabolism, as DHA stimulates glucose
utilization [82] and mitochondrial function [83],
reducing oxidative stress (OS) [81].

Most of the studies in humans have been
directed at evaluating the effects of omega‑3
fatty acids on reducing the cognitive deficit
that is associated with psychiatric disorders.
Several other, widely publicized, attempts
to determine the effects of omega‑3 fatty
acid supplementation on the performance
of school children have been carried out. A
randomized double‑blind controlled trial in
which half of the children received omega‑3
fatty acids and the other half received
placebos is being conducted across several
schools in Durham, UK [84]. Previous studies
from the same investigators showed that
omega‑3 fatty acid supplementation was
associated with reduced cognitive deficits
(in reading and spelling, and teaching‑
rated behaviour) in children affected with
developmental coordination disorder — that
is, in children with specific impairments
of motor function that are independent of
their motor ability [85]. In the new studies,
children were selected on the basis that
“they were not fulfilling their potential at
school” but their general ability was deemed
“normal”, and they were subjected to regular
tests to measure their coordination, concen‑
tration and academic ability. According to
preliminary results [84], some level of improve‑
ment in school performance was observed
in the group receiving omega‑3 fatty acids,
unleashing a flurry of speculations from
the media. Although the results of the
Durham study require scientific scrutiny for
validation, they seem to agree with those of
another study [86] in which omega‑3 fatty acids
(DHA 88 mg per day and eicosapentaenoic
acid (ePA) 22 mg per day) and micro‑
nutrients (iron, zinc, folate and vitamins A,
B6, B12 and C) were provided in a drink
mix to 396 children (6–12 years of age) in
Australia and 394 children in Indonesia. The
results showed higher scores on tests that
measured verbal intelligence and learning
and memory after 6 and 12 months in both
boys and girls in Australia, but in only girls
in Indonesia. Although these results are con‑
sistent with described roles of omega‑3 fatty
acids during brain development and cogni‑
tion [87], it is plausible that the other dietary
supplements that were present in the cocktail
could have contributed to the behavioural
effects. This would suggest that select dietary
components might act in an additive fashion.

In contrast to the healthy effects of
diets that are rich in omega‑3 fatty acids,
epidemiological studies indicate that diets
with high contents of trans and saturated fats
adversely affect cognition [3]. Rodent studies
that evaluated the effects of “junk food”,
characterized by high contents of saturated
fat and sucrose, have shown a decline in
cognitive performance and reduced hippo‑
campal levels of BDNF‑related synaptic plas‑
ticity after only 3 weeks of dietary treatment [4].
These findings suggest that the diet had a
direct effect on neurons that was independent
of insulin resistance or obesity. More alarming
is the fact that this diet elevated the neurologi‑
cal burden that was associated with experi‑
mental brain injury, as evidenced by worse
performance in learning tasks and a reduc‑
tion of BDNF‑mediated synaptic plasticity [88].
Evidence that the antioxidants curcumin and
vitamin e counteracted the effects of the diet
suggests that increased oS might mediate the
effects of the diet on plasticity [89,90].

Flavonols are part of the flavonoid family
that is found in various fruits, cocoa, beans
and the Ginkgo biloba tree. Although the
antioxidant effects of flavonols are well
established in vitro, there is general agreement
that flavonols have more complex actions
in vivo that require further investigation.
The flavonol quercetin, a major component
of G. biloba extracts, has been shown to
reduce learning and memory impairment in
cerebral ischaemic rodents [91]. Dietary sup‑
plementation with the plant‑derived flavanol
(–)epicathechin, which has been shown to
cross the blood–brain barrier, elevated indices
of synaptic spine density and angiogenesis
and increased hippocampus‑dependent
memory in mice [92]. More interestingly, the
positive effects of (–)epicathechin dietary
supplementation on memory formation in
this study were found to be further enhanced
by concomitant exercise (see BOX 2).

Folate or folic acid is found in various
foods, including spinach, orange juice and
yeast. The liver generates several forms
of folate after the intestine has absorbed
vitamin B. Folate deficiency, which is mostly
caused by low dietary intake, has been
associated with a number of physiological
abnormalities during development and
adulthood [93]. Adequate levels of folate are
essential for brain function, and folate
deficiency can lead to neurological dis‑
orders, such as depression [94] and cognitive
impairment. Folate supplementation either
by itself [95,96] or in conjunction with other B
vitamins [97,98] has been shown to be effective
at preventing cognitive decline and dementia
during aging, and at potentiating the effects
of antidepressants [99]. The results of a recent
randomized clinical trial indicated that a
3‑year folic acid supplementation can help
to reduce the age‑related decline in cognitive
function [100]. These studies, however, have
sparked further debate in the scientific
community that age, vitamin B12 status,
genetic makeup, the presence of existing
medical conditions and the current drug
programme of patients receiving folic
acid are important factors to be taken
into consideration to reduce undesirable
secondary effects, such as anaemia, low
immune function and cancer [101]. The
effects of other nutrients on cognition
are summarized in TABLE 1.


CALORIC INTAKE AND COGNITION

>> Caloric restriction. Altering the caloric
content of the diet is a potential means by
which to affect cognitive capacity. New
research indicates that metabolic processes
that are initiated by the burning of fuels in
mitochondria can modulate select aspects of
synaptic plasticity and hence have the
potential to affect cognitive function (FIG. 2).
Certain mechanisms that regulate cell
metabolism are integrated with mechanisms
that modulate synaptic function. For
example, excess calories can reduce synaptic
plasticity [32,102] and increase the vulnerability of
cells to damage [103] by causing free‑radical for‑
mation that surpasses the buffering capacity
of the cell. moderate caloric restriction could
thus protect the brain by reducing oxida‑
tive damage to cellular proteins, lipids and
nucleic acids [104]. Studies in rodents indicate
that elevated oS decreases BDNF‑mediated
synaptic plasticity and cognitive function [32,102].
Caloric restriction also elevates levels of
BDNF [105,106], suggesting that BDNF might
mediate the effects of low caloric intake on
synaptic plasticity. reducing caloric intake to
approximately 40% of control nominal values
in mice from weaning to 35 months of age
decreases the deficits in motor and cognitive
function that are associated with aging [107].
Alternate‑day feeding ameliorates age‑related
deficits in cognitive function in a mouse
model of Alzheimer’s disease when the feed‑
ing programme is maintained between 3 and
17 months of age [108].

According to the ‘thrifty‑gene’ hypothesis,
our genome has adapted through thousands
of years of evolution to profit from nominal
amounts of calories in order to cope with
limited food resources [109]. A standing concern
in the field has been how caloric intake or
meal frequency affects energy metabolism
and health in humans. recent studies in
middle‑aged men and women have estab‑
lished that alterations in meal frequency,
without a reduction in energy intake, result in
unchanged levels of several metabolic param‑
eters, such as glucose, insulin, leptin and
BDNF [110]. However, another study in which
subjects were maintained on an alternate‑day
caloric‑restriction diet over a 2‑month period
resulted in weight loss and improved cardio‑
vascular‑disease and diabetes‑risk profiles [111].
The apparent discrepancy between these two
studies suggests that the number of calories
seems to be a crucial factor for the physiologi‑
cal effects, such that controlled meal skipping
or intermittent caloric restriction might have
health benefits in humans. However, further
preclinical information is required for the
design of therapeutic applications, so caution
should be exerted in the interpretation of
these studies to avoid misconceptions such
as the belief that a low‑calorie diet might
be sufficient to promote health. This view
disregards the fact that the nutritional bal‑
ance of the diet is a vital requirement for
the potential health benefits of low‑calorie
diets. It will be of considerable interest to
determine how these dietary manipulations
can affect other physiological parameters,
such as hormonal profiles and immune‑
system status, which are crucial for assessing
the benefits of restricted caloric intake for
therapeutic purposes.


________
Table 1. Select nutrients that affect cognitive function

Omega-3fatty acids (for example, docosahexaenoic acid. DHA)
- Effects on cognition and emotion: Amelioration of cognitive decline in the elderly [148]; basis for treatment in patients with mood disorders [80]; improvement of cognition in traumatic brain injury in rodents [81]; amelioration of cognitive decay in mouse model of Alzheimer’s disease [149,150]
- Food sources: Fish (salmon), flaxseeds, krill, chia, kiwi fruit, butternuts, walnuts

Curcumin
- Effects on cognition and emotion: Amelioration of cognitive decay in mouse model of Alzheimer’s disease [123]; amelioration of cognitive decay in traumatic brain injury in rodents [89]
- Food sources: Turmeric (curry spice)


Flavonoids
- Effects on cognition and emotion: Cognitive enhancement in combination with exercise in rodents [92]; improvement of cognitive function in the elderly [151]
- Food sources: Cocoa, green tea, Ginkgo tree, citrus fruits, wine (higher in red wine), dark chocolate

Saturated fat
- Effects on cognition and emotion: Promotion of cognitive decline in adult rodents [4]; aggravation of cognitive
impairment after brain trauma in rodents [88]; exacerbation of cognitive decline in aging humans [3]
- Food sources: Butter, ghee, suet, lard, coconut oil, cottonseed oil, palm kernel oil, dairy products (cream, cheese), meat

B vitamins
- Effects on cognition and emotion: Supplementation with vitamin B6, vitamin B12 or folate has positive effects
on memory performance in women of various ages [152]; vitamin B12 improves cognitive impairment in rats fed a choline-deficient diet [153]
- Food sources: Various natural sources. Vitamin B12 is not available from plant products

Vitamin D
- Effects on cognition and emotion: Important for preserving cognition in the elderly [154]
- Food sources: Fish liver, fattyfish, mushrooms, fortified products, milk, soy milk, cereal grains

Vitamin E
- Effects on cognition and emotion: Amelioration of cognitive impairment after brain trauma in rodents [102];
reduces cognitive decay in the elderly [119]
- Food sources: Asparagus, avocado, nuts, peanuts, olives, red palm oil, seeds, spinach, vegetable oils, wheat germ

Choline
- Effects on cognition and emotion: Reduction of seizure-induced memory impairment in rodents [155]; a review
of the literature reveals evidence for a causal relationship between dietary choline and cognition in humans and rats [156]
- Food sources: Egg yolks, soy beef, chicken, veal, turkey liver, lettuce

Combination of vitamins (C, E, carotene)
- Effects on cognition and emotion: Antioxidant vitamin intake delays cognitive decline in the elderly [157]
- Food sources: Vitamin C: citrus fruits, several plants and vegetables, calf and beef liver. Vitamin E: see above

Calcium, zinc, selenium
- Effects on cognition and emotion: High serum calcium is associated with faster cognitive decline in the elderly [158];
reduction of zinc in diet helps to reduce cognitive decay in the elderly [159]; lifelong low selenium level associated with lower cognitive function in humans [160]
- Food sources: Calcium: milk, coral. Zinc: oysters, a small amount in beans, nuts, almonds, whole grains, sunflower seeds. Selenium: nuts, cereals, meat, fish, eggs

Copper
- Effects on cognition and emotion: Cognitive decline in patients with Alzheimer’s disease correlates with low plasma concentrations of copper [161]
- Food sources: Oysters, beef/lamb liver, Brazil nuts, blackstrap molasses, cocoa, black pepper

Iron
- Effects on cognition and emotion: Iron treatment normalizes cognitive function in young women [162]
- Food sources: Red meat, fish, poultry, lentils, beans
________



>> Antioxidant foods. The brain is highly sus‑
ceptible to oxidative damage because of its
high metabolic load and its abundance
of oxidizable material, such as the poly‑
unsaturated fatty acids that form the plasma
membranes of neural cells. Several ‘anti‑
oxidant diets’ have become popular for their
publicized positive effects on neural func‑
tion. Berries, for example, have been shown
to have strong antioxidant capacity, but only
a limited number of their many components
have been evaluated separately: two tan‑
nins (procyanidin and prodelphinidin),
anthocyanins and phenolics (see REF. 112
for a review). In rats, polyphenols have been
shown to increase hippocampal plastic‑
ity (as measured by increases in HSP70
(REF. 113) and IGF1 (REF. 114), to provide
protection against kainate‑induced dam‑
age [115] and to benefit learning and memory
performance [114]. It is not clear how berry
extracts can benefit plasticity and cognition,
but their effects are probably associated with
their ability to maintain metabolic homeo‑
stasis, as this would protect membranes
from lipid peroxidation and affect synaptic
plasticity.

Various micronutrients with an anti‑
oxidant capacity that has been associated
with mitochodrial activity have been shown
to influence cognitive function. Alpha lipoic
acid, which is found in meats such as kidney,
heart and liver, and vegetables such as spinach,
broccoli and potatoes, is a coenzyme that is
important for maintaining energy homeostasis
in mitochondria [116]. Alpha lipoic acid has been
shown to improve memory deficits in animal
models of Alzheimer’s disease [117] and to reduce
cognitive decay in a small group of patients
with Alzheimer’s disease [118]. Vitamin E, or
α‑tocopherol, has also been implicated in
cognitive performance, as decreasing serum
levels of vitamin e were associated with poor
memory performance in older individuals [119].
Vitamin E is abundant in vegetable oils, nuts,
green leafy vegetables and fortified cere‑
als, and has been shown to extend lifespan
and improve mitochondrial function and
neurological performance in aging mice [120].
The mechanisms by which vitamin e can
affect cognition are not well‑understood, but
they are likely to be related to the putative
capacity of antioxidants to support synaptic
plasticity [102] by protecting synaptic mem‑
branes from oxidation. Finally, the curry spice
curcumin, a traditional food preservative and
medicinal herb in India [121,122], has been shown
to reduce memory deficits in animal models
of Alzheimer’s disease [123] and brain trauma [89].
Curcumin is relatively non‑toxic and has few
side effects at doses greater than the low dose
that has been tested in mice [122]. Given the high
consumption of curcumin in India, it is pos‑
sible that it might contribute to the low preva‑
lence of Alzheimer’s disease in that country [124].
Curcumin is a strong antioxidant that seems
to protect the brain from lipid peroxidation [125]
and nitric‑oxide‑based radicals [126].



________
Box 2. Additive effects of diet and exercise on synaptic plasticity and cognition

Recent studies have shown a cooperative action of diet and exercise at the molecular level, which could influence cognitive abilities. In addition to its capacity to benefit overall health, numerous studies have shown that exercise enhances learning and memory under a variety of conditions (for reviews see REFS 139,140). In humans, exercise has been shown to counteract the mental decline that is associated with aging [141], enhance the mental capacity of young adults [142] and facilitate functional recovery after brain injury or disease [131]. Studies that showed that exercise promotes neurogenesis in the brain of adult rodents [143] and humans [144] have introduced the possibility that new proliferating neurons might contribute to the effects of exercise on enhancing learning and memory. In rodents, exercise (Exc) and docosahexaenoic acid (DHA) dietary supplementation combined (DHA+Exc) had a greater effect on brain-derived neurotrophic factor (BDNF)-mediated synaptic plasticity (see figure, part a, blue bars) and cognition (spatial learning ability, yellow bars) than either factor alone [132], highlighting the potential of this approach for treating brain injuries. Similarly, the combination of a flavonoid-enriched diet and exercise increased the expression of genes that have a positive effect on neuronal plasticity and decreased the expression of genes that are involved in deleterious processes, such as inflammation and cell death [92]. Exercise has also been proven to be effective at reducing the deleterious effects of unhealthy diets, such as those that are high in saturated fat and sucrose(HF) (see figure, part b) [4]. Molecules that could explain the synergistic effects of diet and exercise include BDNF, which has emerged as an important factor for translating the effects of exercise on synaptic plasticity and cognitive function [132,145], and several molecules that are associated with the action of BDNF on synaptic function, such as synapsin I, calcium/calmodulin-
dependent protein kinase II (CaMKII) and cyclic AMP-responsive element (CRE)-binding protein (CREB). A comprehensive evaluation of how diet interacts with other lifestyle factors is important for determining the best way to enhance brain function and mental health.
______



DIET AND EPIGENETICS

A number of innovative studies are pointing
to the exciting possibility that the effects of
diet on mental health can be transmitted
across generations. The results of these
studies indicate the importance of dietary
components in influencing epigenetic events
— that is, non‑genetic events, such as DNA
methylation, transcriptional activation,
translational control and post‑translational
modifications that cause a potentially
heritable phenotypic change — and, thus,
their potential for disease modulation. The
results of a longitudinal study that included
more than 100 years of birth, death, health
and genealogical records of 300 Swedish
families in an isolated village showed that an
individual’s risk for diabetes and early death
was increased if their paternal grandparents
grew up in times of food abundance rather
than times of food shortage [164]. Although
the molecular mechanisms for the influence
of diet on epigenetics are unknown, it is
known that the BDNF system is particularly
susceptible to epigenetic modifications that
influence cognitive function [127]. Chromatin
modifications at specific BDNF promoters
determine the differential expression of
discrete BDNF splice variants. Such modi‑
fications have been observed in Alzheimer’s
disease [128] and can also be elicited by particu‑
lar antidepressant drugs [73]. Accordingly, it is
likely that the various BDNF splice variants
have differential effects on neuronal plasticity
and cognition (see REF. 65 for a review).
Neural activity dissociates methyl‑CpG‑
binding protein 2 (meCP2) from its latent
location at BDNF promoter III, enabling
transcription of BDNF [129]. A recent study in
a rodent model of depression demonstrated
that depressive manifestations and subse‑
quent antidepressant treatment are associated
with sustained changes in histone acetylation
and methylation at BDNF promoter III [73].

These studies represent a starting point
for understanding how intracellular signal‑
ling that is triggered by lifestyle factors can
promote lasting changes in DNA function
in the brain and in cognitive capacity. Silent
information regulator 2 (SIRT2), a member
of the sirtuin protein family, has emerged as
an important modulator of genomic stability
and cellular homeostasis that seems to act
by silencing the function of specific genes. A
diet that is high in saturated fat reduces the
expression of SIrT2 in the rat hippocampus [90],
whereas a diet that is high in omega‑3 fatty
acids has the opposite effect [2]. Although
the mechanisms that are involved in the
regulation of SIrT2 by dietary factors require
further investigation, the fact that energy
metabolism is involved in the modulation of
SIrT2 (as with BDNF) can provide a link for
the influence of dietary factors on long‑term
genomic stability. Interestingly, a recent
study in humans examined the association
between SIRT1 (homologous to the rat Sirt2
gene) gene polymorphisms and cognition [130].
In this study, 1,245 inhabitants of leiden
(in the Netherlands) who were at least
85 years old were genotyped for 5 SIRT1
polymorphisms during a period of 4.4 years.
Those who were homozygous for one of
the polymorphisms that affected the SIRT1
promoter region showed better preservation
on all measurements of cognitive function
than the others. Findings that SIrT2 protein
is present in rodent hippocampal tissue [2]
and that SIrT2 function is involved in the
maintenance of energy homeostasis could
provide clues to how SIRT1 might relate to
cognitive function.


CONCLUSIONS AND FUTURE DIRECTIONS

Diet, exercise and other aspects of our daily
interaction with the environment have the
potential to alter our brain health and mental
function. we now know that particular
nutrients influence cognition by acting on
molecular systems or cellular processes that
are vital for maintaining cognitive func‑
tion. This raises the exciting possibility that
dietary manipulations are a viable strategy
for enhancing cognitive abilities and pro‑
tecting the brain from damage, promoting
repair and counteracting the effects of aging.
emerging research indicates that the effects
of diet on the brain are integrated with the
actions of other lifestyle modalities, such as
exercise (see BOX 2) and sleep [131,132]. The com‑
bined action of particular diets and exercise
on the activation of molecular systems that
are involved in synaptic plasticity has strong
implications for public health and the design
of therapeutic interventions. owing to the
encouraging results of clinical and preclinical
studies that showed the beneficial effects of
foods on the brain, the topic has attracted
substantial media attention. Some of the
information that has been conveyed has been
hazy or exaggerated, and has contributed to
people’s apprehension of taking advantage
of scientific advances. As discussed, several
dietary components have been found to have
positive effects on cognition; however, cau‑
tion is required, as a balanced diet is still the
stepping‑stone for any dietary supplementa‑
tion. By the same token, popular dietary
prescriptions that might help to reduce weight
do not necessarily benefit the physiology of
the body or the mind.

Brain networks that are associated
with the control of feeding are intimately
associated with those that are involved in
processing emotions, reward and cogni‑
tion. A better understanding of how these
networks interact will probably produce fun‑
damental information for the development
of strategies to reduce food addiction and
obesity, a major social and economic burden
in western society. It is encouraging that
modern psychiatry has started to appraise
the implementation of some of these con‑
cepts for the treatment of various mental
disorders. For example, a consensus report
from the American Psychiatric Association’s
Committee on research on Psychiatric
Treatments has provided general guiding
principles for the use of omega‑3 fatty acids
for the treatment of mood disorders [80].

The fact that dietary factors and other
aspects of lifestyle have an effect on a
long‑term timescale contributes to an under‑
estimation of their importance for public
health. Accordingly, the slow and imper‑
ceptible cognitive decay that characterizes
normal aging is within the range‑of‑action
of brain foods, such that successful aging
is an achievable goal for dietary therapies.
The capacity of diet to modulate cognitive
abilities might have even longer‑term impli‑
cations in light of recent studies that imply
that nutritional effects might be transmitted
over generations by influencing epigenetic
events. research indicating that an excessive
intake of calories might negate the positive
effects of certain diets suggests that there
is an undefined line between abundance of
foods and neural health. Ironically, judging
by the increasing rate of obesity in western
countries, which affects individual’s health
and the economy as a whole, the excessive
food intake in these wealthy nations seems to
be almost as harmful as the lack of it in poor
countries. It is intriguing that several coun‑
tries with limited resources, such as India,
have a reduced prevalence of neurological
disorders that have been associated with diet,
such as Alzheimer’s disease. This raises the
concern of whether industrialized societies
are consuming a balanced diet that takes
into consideration appropriate numbers of
calories as well as appropriate nutrients and
adequate levels of exercise. many practical
questions regarding the design of diets to
specifically improve brain function, such as
type, frequency and amount of nutrients that
constitute healthy brain food, remain to be
answered, but we are beginning to uncover
the basic principles that are involved in the
actions of foods on the brain. Incorporating
this knowledge into the design of novel treat‑
ments could be vital to combating mental
diseases and neurological weaknesses.

___
Fernando Gómez-Pinilla is at the Departments of
Neurosurgery and Physiological Science, University of
California at Los Angeles School of Medicine,
Los Angeles 90095, California, USA.
e-mail: fgomezpi@mednet.ucla.edu

doi:10.1038/nrn2421
___

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