Honing in on NMDA’s receptor subunit NR2B …

Fish Oil Boosts
Learning Speed

From a better mouse to a better human

By Will Block

L iving in the Sierra Nevada Mountains can make a person change his (or her) mind about the value of speedy (but accurate) thought. For example, crossing a mountain pass on a two-way road in the middle of a snowstorm can make you appreciate the importance of rapid judgment. So can a confrontation with a 500 lb black bear in the early morning while putting the garbage out. In truth, there are endless varieties of fast-think situations, wherever you live in this world. According to the Centers for Disease Control and Prevention, accidents (unintentional injuries) are the fifth leading cause of death in the United States and an increased learning speed could make all the difference. Recent research indicates that a simple nutritional supplement can give you a significant edge, and help prevent you from becoming a statistic. Read on.

There are two principal dietary omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and these are commonly found in marine (principally fish) oils. But these are not found in plant oils. Instead, plants contain alpha-linolenic acid (ALA), which is essential to us because we cannot produce it in our bodies. However, while ALA may be transformed to EPA and DHA in our bodies, the conversion of ALA to DHA and EPA is too slow and inefficient for optimal health purposes. So it’s therefore important that we get these molecules from fish or, better yet, from distilled and antioxidant protected omega-3 fish-oil supplements, a more reliable and safer source for maintaining optimal levels on a daily basis.

Healthy Brain Function Depends on EPA and DHA

In addition to supporting cardiovascular and immune functions, not to mention improving mood and helping the body in other ways, EPA and DHA are essential for healthy brain function. Importantly, it is in your central nervous system that the highest concentrations of these nutrients appear. EPA is a powerful anti-inflammatory compound. DHA is necessary to prevent excessive excitation of electrically excitable tissues. Both of these factors are relevant to maintaining brain health, and in support, there is epidemiological evidence that people who eat a diet rich in cold water fatty fish (which are rich in DHA and EPA) have a lower age-adjusted incidence of Alzheimer’s disease.

DHA Provides Fluidity for Axonal and Synaptic Growth


EPA and DHA are essential for
healthy brain function.


According to a new study conducted at UCLA’s Department of Neurosurgery in Los Angeles, DHA and exercise complement each other supporting better brain function under both normal and challenging conditions,1 such as when you must figure something out fast or pay a high penalty, possibly one that places your life at risk. DHA is an important component of neuronal membrane phospholipids in the brain, where it may represent up to 17% of the total fatty acids. In these phospholipids, DHA’s flexibility within the lipid bilayer provides cell membranes with the fluidity required for proper functioning during axonal (nerve fiber) and synapse growth. A synapse is the passageway through which a neuron sends an electrical of chemical signal to another cell.

Strategies to Preserve DHA in the Brain

It cannot be stressed enough that although DHA is critical for brain function, the brain and body are inefficient at synthesizing DHA. This suggested to the researchers that the brain might have intrinsic strategies to preserve membrane DHA. Given that exercise is crucial component of daily living, the researchers set out to determine the influence of exercise on molecular mechanisms associated with the metabolism and function of DHA in the hippocampus. The hippocampus is a major component of the brains of humans and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. In other studies, DHA supplementation has been shown to enhance hippocampal-dependent learning and memory in rodents, and to reduce mood disorders in humans.

Exercise Potentiates Hippocampal Activities

Figure 1
LEM1302Fig1DHA_272.gif
(click on thumbnail for full sized image)
With the interrelated hypotheses that DHA may be conserved in the brain and that exercise may collaborate with DHA, the researchers set out to evaluate the possibility that the interaction of DHA and exercise can involve specific elements of the synaptic plasma membrane. What they found is that exercise potentiated the effects of a 12-day DHA dietary supplementation regimen on rats, increasing their levels of syntaxin 3 (STX-3) and the growth-associated protein (GAP-43) in the adult rat hippocampus region. STX-3 is a synaptic membrane-bound protein involved in the effects of DHA on membrane expansion (see Fig. 1 on page 12).

Of added interest, the DHA diet and exercise together also elevated levels of the NMDA (N-methyl-D-aspartate) receptor subunit NR2B, which is important for synaptic function that underlies learning and memory (see subsections below). It has been known for over 60 years that the brain and its functions are enhanced when two (or more) messages arrive in the synapse together and are detected (this is known as Hebb’s rule).2 This detection is a function of the NMDA receptor, which, upon binding with the excitatory neurotransmitter glutamate, controls the formation of learning and memory in most hippocampal pathways. The hippocampus is the part of the brain where much of this activity occurs. NMDA forms a channel that does not open unless two conditions are satisfied simultaneously:

  1. Glutamate binds to the NMDA receptor.
  2. The membrane in which the receptor is embedded is strongly stimulated.


DHA and exercise complement
each other supporting better brain
function under both normal and
challenging conditions.


Other studies have identified the actions of DHA on several neural processes in vitro or in vivo, such as promoting growth of hippocampal neurons, reducing inflammation, and improving signal transduction and neurotransmission. DHA is an important constituent of neuronal membrane phospholipids in the hippocampus.

Exercise Enhances Synaptic Function and Fluidity

As does DHA dietary supplementation, exercise influences synaptic function and plasticity. To be specific, exercise enhances molecular systems that control axonal growth and synaptic plasticity, such GAP-43, which are also modulated by a DHA diet. Additionally, exercise can affect the NR2B subunit of the NMDA receptor, which is implicated in positively modulating synaptic growth and plasticity. Demonstrating the effects of exercise on NMDA function, it has been shown that the application of NR2B subunit antagonists abolishes the effects of exercise on receptor-dependent LTP in the mouse dentate gyrus. The dentate gyrus is part of the hippocampal formation that is thought to contribute to the formation of new memories, as well as possessing other functional roles.

DHA Increases NR2B Levels

Like exercise, a DHA-enriched diet has been shown to increase NR2B levels in tandem with improved cognitive performance in rodents. Consequently, the study of NR2B would seem important to understand how the how a DHA diet and exercise may interact to control cognitive function. STX-3, present in synaptic membranes and in neuronal growth cones, has been found to relate DHA and synaptic membrane function. Moreover, DHA dietary supplementation elevates synaptic STX-3 levels, and the action of DHA on promoting neurite outgrowth and membrane expansion has been shown to rely on STX-3. Neurites are projections from the cell body of a neuron, such as an axon or a dendrite. Proper levels of membrane-bound DHA are crucial to maintaining membrane fluidity and neuronal signaling, with strong implications for mental health. Accordingly, the researchers’ goal was to understand how DHA can support synaptic plasticity and cognitive abilities, and how exercise participates.


It cannot be stressed enough that
although DHA is critical for brain
function, the brain and body are
inefficient at synthesizing DHA.


NR2B and Super-Intelligent Mice

More than a decade ago, NR2B was found to play an important role in creating super-intelligent mice when Dr. Joe Z. Tsien, a Princeton University molecular biologist, led a research effort to alter one minor gene so as to build, not a better mousetrap, but a better mouse.3 The breakthrough of Tsien and colleagues was their realization that NMDA receptor’s most critical element, the protein subunit NR2B, could be enhanced by creating a mouse that overexpressed (and was especially effective at) the production of this protein. When the transgenic mice produced NR2B in abundance, synaptic potentiation was increased, and the exhibition of superior ability in learning and memory in various behavioral tasks followed.

DHA Adds to the Effects of Exercise

Encouraged by in vitro findings that DHA promotes synaptic membrane expansion through activation of STX-3, the researchers sought to determine whether exercise could enhance the action of DHA on hippocampal levels of STX-3. Rats fed a DHA diet or induced to exercise, both produced a significant increase in the levels of STX-3. However, the combination of DHA diet and exercise regimen resulted in the up-regulation of STX-3 levels beyond either the DHA or exercise values.

Also, DHA dietary supplementation enhanced the effects of exercise on the levels of the synaptic plasticity protein NR2B and the growth-associated protein GAP-43. Given the involvement of the NR2B subunit of the NMDA receptor in synaptic plasticity and learning, the researchers assessed the effects of the DHA diet and exercise on hippocampal levels of NR2B. The DHA diet resulted in a significant increase of NR2B levels. Exercise alone also elevated NR2B levels to 123% compared to the controls. The simultaneous application of the DHA diet and exercise regimens produced a greater increase in NR2B levels (169% of control,) compared to either DHA or exercise alone.

Plasticity Markers and Learning Performance after DHA and Exercise

How can the additive effect of a DHA diet and exercise on learning relate to the assessed properties of the membrane? The researchers tested the effects of the DHA diet and exercise on the learning performance by measuring the time taken to locate the hidden platform in the Morris water maze (see sidebar “How Rodents Use their Smarts to Triumph in a Perilous Situation”) using a challenging 2-trial-per-day, 5-day paradigm. What the researchers found was that the latency (delay) to locate the platform was decreased in all three experimental groups (exercise alone, DHA alone, and the two combined) compared to control animals. Upon assessing the learning speed in the Morris water maze by measuring the slope of the escape latency value across the five days of learning (the latency slope has been shown to provide a reliable index of the learning speed), all three experimental groups showed significantly increased rate of learning compared to the control group.

How Rodents Use their Smarts
to Triumph in a Perilous Situation

The Morris water maze is actually just a circular tank with smooth walls that offer no chance of escape. Often the entire tank is painted black, so the water looks black and is therefore opaque. Hidden just below the surface, somewhere in the tank, is a small platform that the rat or mouse can climb up on, if he should stumble upon it while desperately seeking a way out of his predicament. And if he does find it (whew!), he’s going to have to find it again if the researcher puts him in the tank again later on—which the researcher will most certainly do, over and over and over.

But will the rodent have any better chance of finding the platform the next time? Yes, because the tank is not entirely featureless: located around its periphery are several fixed objects or painted-on shapes, such as a square, a circle, a triangle, etc. These visual cues are the only distinctive things the rodent can see in his surroundings. They are, for all practical purposes, the stars in his nighttime sky. With repeated trials in the tank (starting from a different place each time, to make it more challenging), the rodent will soon begin to associate the location of his landfall—that blessed platform—with its position relative to the stars. He will become, in effect, a furry little celestial navigator.

It is important to note that the rats in the UCLA study were not tortured. If the rat failed to find the platform in the allocated time, it was gently placed on the platform. At the end of each trial, the animals were allowed to rest on the platform for 60 seconds. The escape latencies to find the platform were recorded.

An Association Between Learning Speed and NR2B

However, analysis of the possible involvement of NR2B or syntaxin proteins on cognitive function showed an association between the learning speed and NR2B levels following co-application of DHA diet and exercise, but not in the controls. The results also showed an association between the learning speed and levels of STX-3 following the combined DHA diet and exercise regimens, but not in the control group. Given that GAP-43 has been implicated for axonal remodeling and learning and memory, the researchers also evaluated the possibility that exercise and the DHA diet could contribute to elevate the capacity of the brain for plasticity. The results showed that exercise and the DHA diet increased GAP-43 levels compared to the control group. Exercise potentiated the elevation of GPA-43 that occurred after DHA treatments, such that the DHA/Exercise group reached 153% of control values.

DHA May Affect Synaptic Plasticity and Cognitive Function

By involving select proteins, which are integral components of synaptic membranes, DHA may affect synaptic plasticity and cognitive function, according to the researchers. In particular, DHA influences hippocampal STX-3, a plasma membrane-bound protein associated with the action of DHA on cell membrane expansion. Also included in their findings, when exercise is concurrent to the use of DHA, there was a greater elevation of STX-3. Exercise can influence DHA function on synaptic plasticity and cognitive function by interacting with molecular systems that stabilize DHA to plasma membrane.


DHA is an important constituent of
neuronal membrane phospholipids in
the hippocampus.


Voluntary exercise enhances the effects of DHA supplementation to elevate hippocampal levels of STX-3 but not other syntaxins, such as STX-1. It has been shown that plasma membrane STX-3 can act in response to local increases in DHA. In the study, the fact that neither the DHA diet nor exercise altered STX-1 levels argues in favor of the specificity of STX-3. Along this line of thought, converse to STX-3, STX-1 does not seem to affect neurite outgrowth; neither does the omega-3 fatty acid deficiency affect hippocampal STX-1.

The current study suggests that a potential mechanism by which the DHA diet and exercise can promote neurite outgrowth is by the use of STX-3. In additional support for a role of diet and exercise on neurite outgrowth, voluntary exercise alone or in combination with DHA supplementation increased levels of the axonal growth-associated molecule, GAP-43. Previous studies have documented a potential link between DHA and neurite outgrowth, i.e., DHA administration has resulted in increase of hippocampal GAP-43 mRNA, and growth of the neurite branches. But the new results showed that the protein levels of STX-3 and GAP-43 changed in proportion to the amount of exercise for individual animals, which had received DHA dietary supplementation in addition to exercise. Given that the feeding remained steady throughout the experiment, it is likely that exercise was a crucial factor for the reported influence of DHA on STX-3 and GAP-43 hippocampal levels.


Proper levels of membrane-bound
DHA are crucial to maintaining
membrane fluidity and
neuronal signaling, with strong
implications for mental health.


Implications of Exercise and DHA Diet on Hippocampal Plasticity And Cognition

Consistent with the proposed role of DHA and exercise in learning and memory, the UCLA study shows that both DHA diet and exercise significantly increased protein levels of the NMDA receptor subunit NRB2. When the rodents were learning performance in the Morris water maze, the researchers found that NR2B levels correlated with their water maze performance, with animals exposed to the DHA diet and exercise showing the highest NR2B levels.

These findings are in agreement with other studies reporting higher NR2B levels in the rodent hippocampus in association with improved learning and memory. In fact, NR2B is abundantly expressed in growth cones of growing neurites and is a critical component of molecular signaling pathways regulating synaptic growth and plasticity.

It has further been reported that dietary omega-3 fatty acid depletion leads to a significant NR2B decrease while omega-3 fatty acids enrichment results in NR2B elevation. Similarly, voluntary exercise up-regulates hippocampal NR2B mRNA and enhances long-term potentiation. Treatment with a specific NR2B antagonist abolishes this exercise-induced enhancement of LTP in the mouse dentate gyrus. The UCLA findings additionally provide novel evidence that DHA diet and exercise can have additive effects on NR2B with potential effects on hippocampal plasticity and cognitive function.

NMDA Performance Improved by DHA

Beside the influence of diet and exercise on levels of NR2B receptors, they can indirectly affect the function of NR2B and other receptors through their membrane interactions. As discussed above, the flexibility of the membrane is crucial for the function of embedded receptors and signal transduction. Accordingly, it is possible the influence of the DHA diet and exercise can contribute to the performance of NMDA and other receptors important for synaptic function. It is also significant that the effects of the diet and exercise also were expressed on levels of GAP-43, which has been associated with neurite growth expansion and learning and memory.

Maintaining Memory Membranes by Supporting Stability

The UCLA researchers found that exercise can complement the action of DHA dietary supplementation on the modulation of molecular systems important for the maintenance of plasma membranes. Membrane stability and fluidity are fundamental for synaptic function and processing of higher order information. The results of the current study suggest that the DHA diet and exercise may help to maintain synaptic and cognitive function by supporting membrane stability.

DHA deficiency has been associated with the incidence of various mental diseases such as depression and schizophrenia, and DHA dietary supplementation can reduce the effects of brain trauma in rodents. Low consumption of omega-3 fatty acids may also increase the risk of getting Alzheimer’s disease, while their high consumption could do the opposite. Omega-3 fatty acid dietary supplementation may also decrease the incidence or improve the clinical outcome of patients with other neurodegenerative disorders such as multiple sclerosis, Parkinson’s disease and Huntington’s disease. The UCLA study results also suggest that exercise is a crucial modulator of the efficacy of dietary factors on brain function. Accordingly, the overall evidence indicates that DHA diet and exercise is a powerful strategy that can be applied to alleviate numerous neurological disorders.


Exercise can influence DHA function
on synaptic plasticity and
cognitive function by interacting with
molecular systems that
stabilize DHA to plasma membrane.


DHA diet and exercise paradigms

As the old adage states, there are ultimately only two types of gunslingers in the Wild West, the quick and the dead. While those bad old times are over, as well as the need to constantly prove oneself, there are still plenty of opportunities to think quickly and gain a personal or economic advantage, so keep taking your omega-3, or start if you are not already doing so.

The overall findings reveal a mechanism by which exercise can interact with the function of DHA dietary enrichment to elevate the capacity of the adult brain for axonal growth, synaptic plasticity, better cognitive function, and faster learning speed.

References

  1. Chytrova G, Ying Z, Gomez-Pinilla F. Exercise contributes to the effects of DHA dietary supplementation by acting on membrane-related synaptic systems. Brain Res. 2010 Jun 23;1341:32-40.
  2. Hebb DO. The Organization of Behaviour. A Neuropsychological Theory. John Wiley, New York, 1949.
  3. Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ. Genetic enhancement of learning and memory in mice. Nature. 1999 Sep 2;401(6748):63-9.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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