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1.  Diet and cognition: interplay between cell metabolism and neuronal plasticity 
Purpose of Study
To discuss studies in humans and animals revealing the ability of foods to benefit the brain: new information with regards to mechanisms of action and the treatment of neurological and psychiatric disorders.
Recent Findings
Dietary factors exert their effects on the brain by affecting molecular events related to the management of energy metabolism and synaptic plasticity. Energy metabolism influences neuronal function, neuronal signaling, and synaptic plasticity, ultimately affecting mental health. Epigenetic regulation of neuronal plasticity appears as an important mechanism by which foods can prolong their effects on long term neuronal plasticity.
The prime focus of the discussion is to emphasize the role of cell metabolism as a mediator for the action of foods on the brain. Oxidative stress promotes damage to phospholipids present in the plasma membrane such as the omega-3 fatty acid DHA, disrupting neuronal signaling. Thus, dietary DHA seems crucial for supporting plasma membrane function, interneuronal signaling, and cognition. The dual action of brain-derived neurotrophic factor (BDNF) in neuronal metabolism and synaptic plasticity is crucial for activating signaling cascades under the action of diet and other environmental factors, using mechanisms of epigenetic regulation.
PMCID: PMC4005410  PMID: 24071781
Epigenetics; Membrane Fluidity; Omega-3 fatty acids; Polyphenols; Metabolic Syndrome; Exercise
2.  Exercise facilitates the action of dietary DHA on functional recovery after brain trauma 
Neuroscience  2013;248:655-663.
The abilities of docosahexaenoic acid (DHA) and exercise to counteract cognitive decay after TBI is getting increasing recognition; however, the possibility that these actions can be complementary remains just as an intriguing possibility. Here we have examined the likelihood that the combination of diet and exercise has the added potential to facilitate functional recovery following TBI. Rats received mild fluid percussion injury (mFPI) or sham injury and then were maintained on a diet high in DHA (1.2% DHA) with or without voluntary exercise for 12 days. We found that FPI reduced DHA content in the brain, which was accompanied by increased levels of lipid peroxidation assessed using 4-HHE. FPI reduced the enzymes Acox1 and 17 -HSD4, and the calcium-independent phospholipases A2 (iPLA2), which are involved in metabolism of membrane phospholipids. FPI reduced levels of syntaxin-3 (STX-3), involved in the action of membrane DHA on synaptic membrane expansion, and also reduced BDNF signaling through its TrkB receptor. These effects of FPI were optimally counteracted by the combination of DHA and exercise. Our results support the possibility that the complementary action of exercise is exerted on restoring membrane homeostasis after TBI, which is necessary for supporting synaptic plasticity and cognition. It is our contention that strategies that take advantage of the combined applications of diet and exercise may have additional effects to the injured brain.
PMCID: PMC3951948  PMID: 23811071
DHA; exercise; BDNF; omega-3 fatty acids; cognition
3.  Dietary therapy to promote neuroprotection in chronic spinal cord injury 
Journal of neurosurgery. Spine  2012;17(2):134-140.
The pathogenesis of cervical spondylotic myelopathy (CSM) is related to both primary mechanical and secondary biological injury. The authors of this study explored a novel, noninvasive method of promoting neuroprotection in myelopathy by using curcumin to minimize oxidative cellular injury and the capacity of omega-3 fatty acids to support membrane structure and improve neurotransmission.
An animal model of CSM was created using a nonresorbable expandable polymer placed in the thoracic epidural space, which induced delayed myelopathy. Animals that underwent placement of the expandable polymer were exposed to either a diet rich in docosahexaenoic acid and curcumin (DHA-Cur) or a standard Western diet (WD). Twenty-seven animals underwent serial gait testing, and spinal cord molecular assessments were performed after the 6-week study period.
At the conclusion of the study period, gait analysis revealed significantly worse function in the WD group than in the DHA-Cur group. Levels of brain-derived neurotrophic factor (BDNF), syntaxin-3, and 4-hydroxynonenal (4-HNE) were measured in the thoracic region affected by compression and lumbar enlargement. Results showed that BDNF levels in the DHA-Cur group were not significantly different from those in the intact animals but were significantly greater than in the WD group. Significantly higher lumbar enlargement syntaxin-3 in the DHA-Cur animals combined with a reduction in lipid peroxidation (4-HNE) indicated a possible healing effect on the plasma membrane.
Data in this study demonstrated that DHA-Cur can promote spinal cord neuroprotection and neutralize the clinical and biochemical effects of myelopathy.
PMCID: PMC3951955  PMID: 22735048
myelopathy; docosahexaenoic acid; curcumin; membrane; spinal cord injury; rat
4.  The Influence of Exercise on Cognitive Abilities 
Comprehensive Physiology  2013;3(1):403-428.
Scientific evidence based on neuroimaging approaches over the last decade has demonstrated the efficacy of physical activity improving cognitive health across the human lifespan. Aerobic fitness spares age-related loss of brain tissue during aging, and enhances functional aspects of higher order regions involved in the control of cognition. More active or higher fit individuals are capable of allocating greater attentional resources toward the environment and are able to process information more quickly. These data are suggestive that aerobic fitness enhances cognitive strategies enabling to respond effectively to an imposed challenge with a better yield in task performance. In turn, animal studies have shown that exercise has a benevolent action on health and plasticity of the nervous system. New evidence indicates that exercise exerts its effects on cognition by affecting molecular events related to the management of energy metabolism and synaptic plasticity. An important instigator in the molecular machinery stimulated by exercise is brain-derived neurotrophic factor, which acts at the interface of metabolism and plasticity. Recent studies show that exercise collaborates with other aspects of lifestyle to influence the molecular substrates of cognition. In particular, select dietary factors share similar mechanisms with exercise, and in some cases they can complement the action of exercise. Therefore, exercise and dietary management appear as a noninvasive and effective strategy to counteract neurological and cognitive disorders.
PMCID: PMC3951958  PMID: 23720292
5.  Hypothalamic stimulation enhances hippocampal BDNF plasticity in proportion to metabolic rate 
Brain stimulation  2012;5(4):642-646.
Energy metabolism is emerging as a driving force for cellular events underlying cognitive processing. The hypothalamus integrates metabolic signals with the function of centers related to cognitive processing such as the hippocampus.
Hypothalamic activity can influence molecular systems important for processing synaptic plasticity underlying cognition in the hippocampus. The neurotrophin BDNF may act as a mediator for the effects of energy metabolism on synaptic plasticity and cognitive function.
The hypothalamus of rats confined to a respiratory chamber was electrically stimulated, and energy expenditure (EE) was assessed via indirect calorimetry. MRNA levels for BDNF and molecules related to synaptic plasticity and control of cellular energy metabolism were assessed in the hippocampus.
Electrical stimulation of the rat hypothalamus elevates mRNA levels of hippocampal BDNF. BDNF mRNA levels increased according to the metabolic rate of the animals, and in proportion to the mRNA of molecules involved in control of cellular energy metabolism such as ubiquitous mitochondrial creatine kinase (uMtCK).
Results show a potential mechanism by which cellular energy metabolism impacts the substrates of cognitive processing, and may provide molecular basis for therapeutic treatments based on stimulation of deep brain structures.
PMCID: PMC3383390  PMID: 22441161
Energy metabolism; cognition; diabetes; hippocampus; trophic factors
6.  Vulnerability Imposed by Diet and Brain Trauma for Anxiety-Like Phenotype: Implications for Post-Traumatic Stress Disorders 
PLoS ONE  2013;8(3):e57945.
Mild traumatic brain injury (mTBI, cerebral concussion) is a risk factor for the development of psychiatric illness such as posttraumatic stress disorder (PTSD). We sought to evaluate how omega-3 fatty acids during brain maturation can influence challenges incurred during adulthood (transitioning to unhealthy diet and mTBI) and predispose the brain to a PTSD-like pathobiology. Rats exposed to diets enriched or deficient in omega-3 fatty acids (n-3) during their brain maturation period, were transitioned to a western diet (WD) when becoming adult and then subjected to mTBI. TBI resulted in an increase in anxiety-like behavior and its molecular counterpart NPY1R, a hallmark of PTSD, but these effects were more pronounced in the animals exposed to n-3 deficient diet and switched to WD. The n-3 deficiency followed by WD disrupted BDNF signaling and the activation of elements of BDNF signaling pathway (TrkB, CaMKII, Akt and CREB) in frontal cortex. TBI worsened these effects and more prominently in combination with the n-3 deficiency condition. Moreover, the n-3 deficiency primed the immune system to the challenges imposed by the WD and brain trauma as evidenced by results showing that the WD or mTBI affected brain IL1β levels and peripheral Th17 and Treg subsets only in animals previously conditioned to the n-3 deficient diet. These results provide novel evidence for the capacity of maladaptive dietary habits to lower the threshold for neurological disorders in response to challenges.
PMCID: PMC3590222  PMID: 23483949
7.  Dietary Omega-3 Deficiency from Gestation Increases Spinal Cord Vulnerability to Traumatic Brain Injury-Induced Damage 
PLoS ONE  2012;7(12):e52998.
Although traumatic brain injury (TBI) is often associated with gait deficits, the effects of TBI on spinal cord centers are poorly understood. We seek to determine the influence of TBI on the spinal cord and the potential of dietary omega-3 (n-3) fatty acids to counteract these effects. Male rodents exposed to diets containing adequate or deficient levels of n-3 since gestation received a moderate fluid percussion injury when becoming 14 weeks old. TBI reduced levels of molecular systems important for synaptic plasticity (BDNF, TrkB, and CREB) and plasma membrane homeostasis (4-HNE, iPLA2, syntaxin-3) in the lumbar spinal cord. These effects of TBI were more dramatic in the animals exposed to the n-3 deficient diet. Results emphasize the comprehensive action of TBI across the neuroaxis, and the critical role of dietary n-3 as a means to build resistance against the effects of TBI.
PMCID: PMC3532480  PMID: 23300842
8.  The Salutary Effects of DHA Dietary Supplementation on Cognition, Neuroplasticity, and Membrane Homeostasis after Brain Trauma 
Journal of Neurotrauma  2011;28(10):2113-2122.
The pathology of traumatic brain injury (TBI) is characterized by the decreased capacity of neurons to metabolize energy and sustain synaptic function, likely resulting in cognitive and emotional disorders. Based on the broad nature of the pathology, we have assessed the potential of the omega-3 fatty acid docosahexaenoic acid (DHA) to counteract the effects of concussive injury on important aspects of neuronal function and cognition. Fluid percussion injury (FPI) or sham injury was performed, and rats were then maintained on a diet high in DHA (1.2% DHA) for 12 days. We found that DHA supplementation, which elevates brain DHA content, normalized levels of brain-derived neurotrophic factor (BDNF), synapsin I (Syn-1), cAMP-responsive element-binding protein (CREB), and calcium/calmodulin-dependent kinase II (CaMKII), and improved learning ability in FPI rats. It is known that BDNF facilitates synaptic transmission and learning ability by modulating Syn-I, CREB, and CaMKII signaling. The DHA diet also counteracted the FPI-reduced manganese superoxide dismutase (SOD) and Sir2 (a NAD+-dependent deacetylase). Given the involvement of SOD and Sir2 in promoting metabolic homeostasis, DHA may help the injured brain by providing resistance to oxidative stress. Furthermore, DHA normalized levels of calcium-independent phospholipase A2 (iPLA2) and syntaxin-3, which may help preserve membrane homeostasis and function after FPI. The overall results emphasize the potential of dietary DHA to counteract broad and fundamental aspects of TBI pathology that may translate into preserved cognitive capacity.
PMCID: PMC3191367  PMID: 21851229
brain-derived neurotrophic factor; plasticity; Sir2; superoxide dismutase; traumatic brain injury
9.  Effects of Diet and/or Exercise in Enhancing Spinal Cord Sensorimotor Learning 
PLoS ONE  2012;7(7):e41288.
Given that the spinal cord is capable of learning sensorimotor tasks and that dietary interventions can influence learning involving supraspinal centers, we asked whether the presence of omega-3 fatty acid docosahexaenoic acid (DHA) and the curry spice curcumin (Cur) by themselves or in combination with voluntary exercise could affect spinal cord learning in adult spinal mice. Using an instrumental learning paradigm to assess spinal learning we observed that mice fed a diet containing DHA/Cur performed better in the spinal learning paradigm than mice fed a diet deficient in DHA/Cur. The enhanced performance was accompanied by increases in the mRNA levels of molecular markers of learning, i.e., BDNF, CREB, CaMKII, and syntaxin 3. Concurrent exposure to exercise was complementary to the dietary treatment effects on spinal learning. The diet containing DHA/Cur resulted in higher levels of DHA and lower levels of omega-6 fatty acid arachidonic acid (AA) in the spinal cord than the diet deficient in DHA/Cur. The level of spinal learning was inversely related to the ratio of AA∶DHA. These results emphasize the capacity of select dietary factors and exercise to foster spinal cord learning. Given the non-invasiveness and safety of the modulation of diet and exercise, these interventions should be considered in light of their potential to enhance relearning of sensorimotor tasks during rehabilitative training paradigms after a spinal cord injury.
PMCID: PMC3401098  PMID: 22911773
10.  Natural mood foods: The actions of polyphenols against psychiatric and cognitive disorders 
Nutritional Neuroscience  2012;15(3):127-133.
Polyphenols, natural compounds found in plant-based foods, possess special properties that can battle oxidative stress and stimulate the activation of molecules that aid in synaptic plasticity, a process that underlies cognitive function. Unlike many traditional treatments, polyphenols affect a broad range of mechanisms in the brain that can assist in the maintenance of cognitive and mental health, as well as the recovery from neurodegenerative diseases. Examining the molecular basis underlying the link between food intake and brain function has presented the exciting possibility of using diet as a viable method to battle cognitive and psychiatric disorders.
We will discuss the molecular systems that link polyphenols, the gut, and the brain, as well as introduce published human and animal studies demonstrating the effects of polyphenol consumption on brain plasticity and cognition.
By influencing cellular energy metabolism and modulating the signaling pathways of molecules involved with brain plasticity, dietary factors – formerly recognized for just their effects on bodily systems – have emerged as affecters of the brain.
Thus, the consumption of diets enriched with polyphenols may present the potential of dietary manipulation as a non-invasive, natural, and inexpensive therapeutic means to support a healthy brain.
PMCID: PMC3355196  PMID: 22334236
BDNF; Cognition; Metabolism; Polyphenol; Psychiatric disorder; Synaptic plasticity
11.  High-fat diet transition reduces brain DHA levels associated with altered brain plasticity and behaviour 
Scientific Reports  2012;2:431.
To assess how the shift from a healthy diet rich in omega-3 fatty acids to a diet rich in saturated fatty acid affects the substrates for brain plasticity and function, we used pregnant rats fed with omega-3 supplemented diet from their 2nd day of gestation period as well as their male pups for 12 weeks. Afterwards, the animals were randomly assigned to either a group fed on the same diet or a group fed on a high-fat diet (HFD) rich in saturated fats for 3 weeks. We found that the HFD increased vulnerability for anxiety-like behavior, and that these modifications harmonized with changes in the anxiety-related NPY1 receptor and the reduced levels of BDNF, and its signalling receptor pTrkB, as well as the CREB protein. Brain DHA contents were significantly associated with the levels of anxiety-like behavior in these rats.
PMCID: PMC3362800  PMID: 22666534
12.  The influence of naturalistic experience on plasticity markers in somatosensory cortex and hippocampus: effects of whisker use 
Brain research  2011;1388:39-47.
We have previously demonstrated that exposure of adult rat to a type of enriched environment, known as ‘naturalistic habitat’ (NH), induces extensive functional plasticity in the whiskers’ representations within the primary somatosensory cortex. Here we have investigated the molecular basis for such functional plasticity involved in this model. Based on the role of BDNF on synaptic plasticity and neuronal growth, the focus of this study is on BDNF and its downstream effectors CREB, synapsin I, and GAP-43. In particular, we determined the effects of natural whiskers use during 2, 7 or 28 days exposure to a NH on barrel cortex and hippocampus, as compared to standard cage controls. Naturalistic whiskers use resulted in increased levels of mRNAs and proteins for BDNF and its downstream effectors. Level changes for these markers were already detected after 2 days in the naturalistic habitat and grew larger over longer exposures (7 and 28 days). The cerebral cortex was found to be sensitive to the naturalistic habitat exposure at all time points, and more sensitive than the hippocampus to the trimming of the whiskers. Trimming of the whiskers decreased the level of most of the markers under study suggesting that whiskers exert a tonic influence on plasticity markers that can be further enhanced by naturalistic use. These results implicate BDNF and its downstream effectors in the plasticity induced by the naturalistic habitat. The critical action of experience on molecular substrates of plasticity seems to provide molecular basis for the design of experienced-based rehabilitative strategies to enhance brain function.
PMCID: PMC3225184  PMID: 21385568
Rat; somatosensory cortex; hippocampus; environmental enrichment; cortical plasticity
13.  Exercise can increase small heat shock proteins (sHSP) and pre- and post-synaptic proteins in the hippocampus 
Brain Research  2008;1249:191-201.
The molecular events mediating the complex interaction between exercise and cognition are not well-understood. Although many aspects of the signal transduction pathways mediate exercise induced improvement in cognition are understood, little is known about the molecular events interrelating physiological stress with synaptic proteins, following physical exercise. Small heat shock proteins (sHSP), HSP27 and α-B-crystallin are co-localized to synapses and astrocytes, but their role in the brain is not well-undersood. We investigated whether their levels in the hippocampus were modulated by exercise, using a well characterized voluntary exercise paradigm. Since sHSP are known to be regulated by many intracellular signaling molecules in other cells types outside the brain, we investigated whether similar regulation may be playing a role in the brain by measuring protein kinase B (PKB/Akt), pGSK3 and the mitogen activated protein (MAP) kinases, p38, phospho-extracellular signal-regulated kinase (pERK) and phospho-c-Jun kinase (pJNK). Results demonstrated exercise-dependent increases in HSP27 and α-B-crystallin levels. We observed that increases in sHSP coincided with robust elevations in the presynaptic protein, SNAP25 and the post-synaptic proteins NR2b and PSD95. Exercise had a differential impact on kinases, significantly reducing pAkt and pERK, while increasing p38 MAPK. In conclusion, we demonstrate four early novel hippocampal responses to exercise that have not been identified previously: the induction of (1) sHSPs (2) the synaptic proteins SNAP-25, NR2b, and PSD-95, (3) the MAP kinase p38 and (4) the immediate early gene product MKP1. We speculate that sHSP may play a role in synaptic plasticity in response to exercise.
PMCID: PMC3307371  PMID: 19014914
Western; HSP27; MAP kinases; Akt; MKP1; p38; exercise; post-synaptic protein
14.  Brain and Spinal Cord Interaction: Protective Effects of Exercise Prior to Spinal Cord Injury 
PLoS ONE  2012;7(2):e32298.
We have investigated the effects of a spinal cord injury on the brain and spinal cord, and whether exercise provided before the injury could organize a protective reaction across the neuroaxis. Animals were exposed to 21 days of voluntary exercise, followed by a full spinal transection (T7–T9) and sacrificed two days later. Here we show that the effects of spinal cord injury go beyond the spinal cord itself and influence the molecular substrates of synaptic plasticity and learning in the brain. The injury reduced BDNF levels in the hippocampus in conjunction with the activated forms of p-synapsin I, p-CREB and p-CaMK II, while exercise prior to injury prevented these reductions. Similar effects of the injury were observed in the lumbar enlargement region of the spinal cord, where exercise prevented the reductions in BDNF, and p-CREB. Furthermore, the response of the hippocampus to the spinal lesion appeared to be coordinated to that of the spinal cord, as evidenced by corresponding injury-related changes in BDNF levels in the brain and spinal cord. These results provide an indication for the increased vulnerability of brain centers after spinal cord injury. These findings also imply that the level of chronic activity prior to a spinal cord injury could determine the level of sensory-motor and cognitive recovery following the injury. In particular, exercise prior to the injury onset appears to foster protective mechanisms in the brain and spinal cord.
PMCID: PMC3284558  PMID: 22384207
15.  The combined effects of exercise and foods in preventing neurological and cognitive disorders 
Preventive Medicine  2011;52(Suppl 1):S75-S80.
Exercise and select diets have important influences on health and plasticity of the nervous system, and the molecular mechanisms involved with these actions are starting to be elucidated. New evidence indicates that exercise, in combination with dietary factors, exerts its effects by affecting molecular events related to the management of energy metabolism and synaptic plasticity.
Published studies in animals and humans describing the effects of exercise and diets in brain plasticity and cognitive abilities are discussed.
New evidence indicates that exercise and select diets exert their effects by affecting molecular events related to the management of energy metabolism and synaptic plasticity. An important instigator in the molecular machinery stimulated by exercise is brain-derived neurotrophic factor (BDNF), which acts at the interface of metabolism and plasticity.
Recent studies show that selected dietary factors share similar mechanisms with exercise, and in some cases they can complement the action of exercise. Therefore, exercise and dietary management appear as a non-invasive and effective strategy to counteract neurological and cognitive disorders.
PMCID: PMC3258093  PMID: 21281667
Neurotrophin; Synaptic plasticity; Brain trauma; Diet; Omega-3-fatty acids
16.  The Influence of Dietary Factors in Central Nervous System Plasticity and Injury Recovery 
Although feeding is an essential component of life, it is only recently that the actions of foods on brain plasticity and function have been scrutinized. There is evidence that select dietary factors are important modifiers of brain plasticity and can have an impact on central nervous system health and disease. Results of new research indicate that dietary factors exert their effects by affecting molecular events related to the management of energy metabolism and synaptic plasticity. Recent study results show that select dietary factors have mechanisms similar to those of exercise, and that, in some cases, dietary factors can complement the action of exercise. Abundant research findings in animal models of central nervous system injury support the idea that nutrients can be taken in through whole foods and dietary supplements to reduce the consequences of neural damage. Therefore, exercise and dietary management appear as a noninvasive and effective strategy to help counteract neurologic and cognitive disorders.
PMCID: PMC3258094  PMID: 21703566
18.  Brain and Spinal Cord Interaction: A Dietary Curcumin Derivative Counteracts Locomotor and Cognitive Deficits After Brain Trauma 
In addition to cognitive dysfunction, locomotor deficits are prevalent in traumatic brain injured (TBI) patients; however, it is unclear how a concussive injury can affect spinal cord centers. Moreover, there are no current efficient treatments that can counteract the broad pathology associated with TBI.
The authors have investigated potential molecular basis for the disruptive effects of TBI on spinal cord and hippocampus and the neuroprotection of a curcumin derivative to reduce the effects of experimental TBI.
The authors performed fluid percussion injury (FPI) and then rats were exposed to dietary supplementation of the curcumin derivative (CNB-001; 500 ppm). The curry spice curcumin has protective capacity in animal models of neurodegenerative diseases, and the curcumin derivative has enhanced brain absorption and biological activity.
The results show that FPI in rats, in addition to reducing learning ability, reduced locomotor performance. Behavioral deficits were accompanied by reductions in molecular systems important for synaptic plasticity underlying behavioral plasticity in the brain and spinal cord. The post-TBI dietary supplementation of the curcumin derivative normalized levels of BDNF, and its downstream effectors on synaptic plasticity (CREB, synapsin I) and neuronal signaling (CaMKII), as well as levels of oxidative stress–related molecules (SOD, Sir2).
These studies define a mechanism by which TBI can compromise centers related to cognitive processing and locomotion. The findings also show the influence of the curcumin derivative on synaptic plasticity events in the brain and spinal cord and emphasize the therapeutic potential of this noninvasive dietary intervention for TBI.
PMCID: PMC3258099  PMID: 21343524
traumatic brain injury; hippocampus; learning; BDNF; curcumin derivative
19.  Omega-3 Fatty Acid Deficiency during Brain Maturation Reduces Neuronal and Behavioral Plasticity in Adulthood 
PLoS ONE  2011;6(12):e28451.
Omega-3-fatty acid DHA is a structural component of brain plasma membranes, thereby crucial for neuronal signaling; however, the brain is inefficient at synthesizing DHA. We have asked how levels of dietary n-3 fatty acids during brain growth would affect brain function and plasticity during adult life. Pregnant rats and their male offspring were fed an n-3 adequate diet or n-3 deficient diets for 15 weeks. Results showed that the n-3 deficiency increased parameters of anxiety-like behavior using open field and elevated plus maze tests in the male offspring. Behavioral changes were accompanied by a level reduction in the anxiolytic-related neuropeptide Y-1 receptor, and an increase in the anxiogenic-related glucocorticoid receptor in the cognitive related frontal cortex, hypothalamus and hippocampus. The n-3 deficiency reduced brain levels of docosahexaenoic acid (DHA) and increased the ratio n-6/n-3 assessed by gas chromatography. The n-3 deficiency reduced the levels of BDNF and signaling through the BDNF receptor TrkB, in proportion to brain DHA levels, and reduced the activation of the BDNF-related signaling molecule CREB in selected brain regions. The n-3 deficiency also disrupted the insulin signaling pathways as evidenced by changes in insulin receptor (IR) and insulin receptor substrate (IRS). DHA deficiency during brain maturation reduces plasticity and compromises brain function in adulthood. Adequate levels of dietary DHA seem crucial for building long-term neuronal resilience for optimal brain performance and aiding in the battle against neurological disorders.
PMCID: PMC3233581  PMID: 22163304
20.  The Influence of Diet and Physical Activity on Brain Repair and Neurosurgical Outcome 
Surgical neurology  2008;70(4):333-336.
PMCID: PMC3225186  PMID: 18793906
Omega-3 fatty acids; curcumin; exercise; neural regeneration; neurotrophin; cognition; synaptic plasticity
21.  Differential effects of exercise and dietary docosahexaenoic acid (DHA) on molecular systems associated with control of allostasis in the hypothalamus and hippocampus 
Neuroscience  2010;168(1):130-137.
Given the robust influence of diet and exercise on brain plasticity and disease, we conducted studies to determine their effects on molecular systems important for control of brain homeostasis. Studies were centered on a battery of proteins implicated in metabolic homeostasis that have the potential to modulate brain plasticity and cognitive function, in rat hypothalamus and hippocampus. Adult male rats were exposed to a docosahexaenoic acid (DHA) enriched diet (1.25% DHA) with or without voluntary exercise for 14 days. Here we report that the DHA diet and exercise influence protein levels of molecular systems important for the control of energy metabolism (primarily phospho - AMPK, silent information regulator type 1), food intake (primarily leptin and ghrelin receptors), stress (primarily glucocorticoid receptors, and 11beta-hydroxysteroid dehydrogenase 1 (11βHSD1). Exercise or DHA dietary supplementation had differential effects on several of these class proteins, and the concurrent application of both altered the pattern of response elicited by the single applications of diet or exercise. For example, exercise elevated levels of glucocorticoids receptors in the hypothalamus and the DHA diet had opposite effects, while the concurrent application of diet and exercise counteracted the single effects of diet or exercise. In most of the cases, the hypothalamus and the hippocampus had a distinctive pattern of response to the diet or exercise. The results harmonize with the concept that exercise and dietary DHA exert specific actions on the hypothalamus and hippocampus, with implications for the regulations of brain plasticity and cognitive function.
PMCID: PMC3225187  PMID: 20303394
Stress; metabolism; synaptic plasticity; homeostasis; mood; depression; anxiety
22.  The Influences of Diet and Exercise on Mental Health Through Hormesis 
Ageing research reviews  2007;7(1):49-62.
It is likely that the capacity of the brain to remain healthy during ageing depends upon its ability to adapt and nurture in response to environmental challenges. In these terms, main principles involved in hormesis can be also applied to understand relationships at a higher level of complexity such as those existing between the CNS and the environment. This review emphasizes the ability of diet, exercise, and other lifestyle adaptations to modulate brain function. Exercise and diet are discussed in relationship to their aptitude to impact systems that sustain synaptic plasticity and mental health, and are therefore important for combating the effects of aging. Mechanisms that interface energy metabolism and synaptic plasticity are discussed, as these are the frameworks for the actions of cellular stress on cognitive function. In particular, neurotrophins are emerging as main factors in the equation that may connect lifestyle factors and mental health.
PMCID: PMC3225189  PMID: 17604236
23.  A pyrazole curcumin derivative restores membrane homeostasis disrupted after brain trauma 
Experimental neurology  2010;226(1):191-199.
We have assessed potential mechanisms associated with the deleterious effects of TBI on the integrity of plasma membranes in the hippocampus, together with consequences for behavioral function. In addition, we have investigated the efficacy of a dietary intervention based on a pyrazole curcumin derivative with demonstrated bioactivity and brain absorption, to re-establish membrane integrity. We report that moderate fluid percussion injury (FPI) increases levels of 4-Hydroxynonenal (HNE), an intermediary for the harmful effects of lipid peroxidation on neurons. A more direct action of FPI on membrane homeostasis was evidenced by a reduction in calcium-independent phospholipase A2 (iPLA2) important for metabolism of membrane phospholipids such as DHA, and an increase in the fatty acid transport protein (FATP) involved in translocation of long-chain fatty acids across the membrane. A potential association between membrane disruption and neuronal function was suggested by reduced levels of the NR2B subunit of the transmembrane NMDA receptor, in association with changes in iPLA2 and syntaxin-3 (STX-3, involved in the action of membrane DHA on synaptic membrane expansion). In addition, changes in iPLA2, 4-HNE, and STX-3 were proportional to reduced performance in a spatial learning task. In turn, the dietary supplementation with the curcumin derivative counteracted all the effects of FPI, effectively restoring parameters of membrane homeostasis. Results show the potential of the curcumin derivative to promote membrane homeostasis following TBI, which may foster a new line of non-invasive therapeutic treatments for TBI patients by endogenous up-regulation of molecules important for neural repair and plasticity.
PMCID: PMC3225197  PMID: 20816821
rat; membrane damage; curcumin; 4-hydoxynonenal; cognition
24.  DHA dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition 
Neuroscience  2008;155(3):751-759.
Omega-3 fatty acids (i.e., docosahexaenoic acid; DHA), similar to exercise, improve cognitive function, promote neuroplasticity, and protect against neurological lesion. In this study, we investigated a possible synergistic action between DHA dietary supplementation and voluntary exercise on modulating synaptic plasticity and cognition. Rats received DHA dietary supplementation (1.25% DHA) with or without voluntary exercise for 12 days. We found that the DHA-enriched diet significantly increased spatial learning ability, and these effects were enhanced by exercise. The DHA-enriched diet increased levels of pro-BDNF and mature BDNF, whereas the additional application of exercise boosted the levels of both. Furthermore, the levels of the activated forms of CREB and synapsin I were incremented by the DHA-enriched diet with greater elevation by the concurrent application of exercise. While the DHA diet reduced hippocampal oxidized protein levels, a combination of a DHA diet and exercise resulted in a greater reduction rate. The levels of activated forms of hippocampal Akt and CaMKII were increased by the DHA-enriched diet, and with even greater elevation by a combination of diet and exercise. Akt and CaMKII signaling are crucial step by which BDNF exerts its action on synaptic plasticity and learning and memory. These results indicate that the DHA diet enhance the effects of exercise on cognition and BDNF-related synaptic plasticity, a capacity that may be used to promote mental health and reduce risk of neurological disorders.
PMCID: PMC3208643  PMID: 18620024
DHA; exercise; BDNF; omega-3 fatty acids; cognition
25.  Exercise-induced improvement in cognitive performance after traumatic brain-injury in rats is dependent on BDNF Activation 
Brain research  2009;1288:105-115.
We have previously shown that voluntary exercise upregulates brain-derived neurotrophic factor (BDNF) within the hippocampus and is associated with an enhancement of cognitive recovery after a lateral fluid-percussion injury (FPI). In order to determine if BDNF is critical to this effect we used an immunoadhesin chimera (TrkB-IgG) that inactivates free BDNF. This BDNF inhibitor was administered to adult male rats two weeks after they had received a mild fluid percussion injury (FPI) or sham surgery. These animals were then housed with or without access to a running wheel (RW) from post-injury-day (PID) 14 to 20. On PID 21, rats were tested for spatial learning in a Morris Water Maze. Results showed that exercise counteracted the cognitive deficits associated with the injury. However this exercise-induced cognitive improvement was attenuated in the FPI-RW rats that were treated with TrkB-IgG. Molecules important for synaptic plasticity and learning were measured in a separate group of rats that were sacrificed immediately after exercise (PID 21). Western blot analyses showed that exercise increased the mature form of BDNF, synapsin I and cyclic-AMP response-element-binding protein (CREB) in the vehicle treated Sham-RW group. However, only the mature form of BDNF and CREB were increased in the vehicle treated FPI-RW group. Blocking BDNF (pre administration of TrkB-IgG) greatly reduced the molecular effects of exercise in that exercise-induced increases of BDNF, synapsin I and CREB were not observed. These studies provide evidence that BDNF has a major role in exercise's cognitive effects in traumatically injured brain.
PMCID: PMC2735616  PMID: 19555673
TBI; hippocampus; fluid-percussion-injury; Synapsin I and CREB

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