Plasticizing the Brain: Improving Cognition By BDNF Manipulation

Our brain is regarded by some as one of the most valuable organs. Without a brain, a person is basically a vegetable. And with a brain, we are more than just a vegetable. With the brain we can think, plan for the future, talk, walk, command our body, interpret sensory information, remember information and so on. Amazingly, we can change the visual information of text into semantic meanings. For these reasons and more, it is highly important to keep our brains running in tip-top condition.

I choose to focus on the subject of BDNF because cognitive decline, dementia, Alzheimer’s disease, and other neurological problems are associated with decreased levels of BDNF in the brain. So in this article, I will inform you of different methods available to the person to increase BDNF levels in the brain in order to avoid neurodegeneration, and to achieve memory & cognitive enhancement. While at the same time warning you of particular doings & substances that cause a decrease in BDNF. So that you can make the most with the brain that you have.

If you are wondering what BDNF is, you can catch up on BDNF by reading my article explaining its significance to brain health.

How Good Sleep & Partial Sleep Deprivation Increase BDNF

Owl_Eyes_All_About_Sleep:: Sleep homeostatic circadian pressures
Sleep is very important for the mind to function properly, and for proper maintenance of the body. It’s no wonder people the term, “beauty sleep” for the extra sleep utilized by people to maintain their youthful and beautiful apperance. Which makes sense, given that during sleep the “anti-aging” hormone called Melatonin is released.

Sleep is a very important part of our lives, which you may be able to tell given the fact that we sleep for almost a third of it. Sleep is the time we dedicate to our bodies & brains for restoration & healing.

Although our body does heal itself while we are awake, sleeping allows for a more efficient, rapid healing of the damages that we accrue during the day. One example of damage that I am referring to is free radical damage.

Metabolism generates reactive oxygen species (a.k.a. free radicals), because we use oxygen in the process of producing ATP fuel to run our bodies (a.k.a. aerobic respiration). While we are awake, our metabolism is high, and as a result our exposure to free radical damage is high. But when we are sleeping, our metabolism is lower and therefore our bodies experiences less free radical damage- making sleep the ideal time for efficient restoration and healing.

During our sleep, the metabolic waste products in the brain are removed faster than while we are awake. Additionally, the body releases a powerful free-radical scavenger and wide-spectrum antioxidant called Melatonin, which also functions to protects nuclear and mitochondrial DNA.

And directly to the point of my article, proper sleep is also required for proper production of BDNF in the brain. Here’s a study[1] that summarizes a couple of important relationships between sleep and BDNF:

The protein brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors involved in plasticity of neurons in several brain regions. There are numerous evidence that BDNF expression is decreased by experiencing psychological stress and that, accordingly, a lack of neurotrophic support causes major depression. Furthermore, disruption in sleep homeostatic processes results in higher stress vulnerability and is often associated with stress-related mental disorders. Recently, we reported, for the first time, a relationship between BDNF and insomnia and sleep deprivation (SD). Using a biphasic stress model as explanation approach, we discuss here the hypothesis that chronic stress might induce a deregulation of the hypothalamic-pituitary-adrenal system. In the long-term it leads to sleep disturbance and depression as well as decreased BDNF levels, whereas acute stress like SD can be used as therapeutic intervention in some insomniac or depressed patients as compensatory process to normalize BDNF levels. Indeed, partial SD (PSD) induced a fast increase in BDNF serum levels within hours after PSD which is similar to effects seen after ketamine infusion, another fast-acting antidepressant intervention, while traditional antidepressants are characterized by a major delay until treatment response as well as delayed BDNF level increase.

Here’s what I understand from the study. Stress reduces BDNF. And stress reduces good sleep. Likewise bad sleep causes stress and makes you more susceptible to stress. And logically chronic sleep deprivation causes BDNF levels to drop significantly from the increased stress susceptibility.

Now, there is a reason why stress harms sleep quality. Preventing you to fall asleep is an obvious one. But if you look at it more scientifically, you’ll notice that our body’s primary sleep hormone is melatonin. Melatonin is secreted by the pineal gland located in the brain, and melatonin secretion is activated by darkness. Which helps explain why we fall asleep at night.

Continuing my explanation, there is a stress hormone called cortisol that our body secretes in response to increasing amounts of stress- the more stressed out you are, the more cortisol the body dumps into your bloodstream. This is important because cortisol has an inverse relationship with melatonin. In other words, cortisol stops the secretion of melatonin. Which explains why we can’t fall asleep at night when we are stressed out.

Sleep deprivation causes increased cortisol levels, and increased oxidative stress. Oxidative stress damage the cells in the body, including the brain. So oxidative stress both explains the mental fatigue that you feel from sleep deprivation and extreme amounts of exercise. Or any exercise, if your body is not used to it.

But overall, chronic sleep deprivation is really damaging to our cognition. Sleep deprivation can causes a person to fall into a high-stress state, experience increased anxiety, depression, degeneration of the hippocampus, thereby decreased ability in learning & memory, dysfunction of the mental & physical faculties, and more. And sleep deprivation can cause mental illness. Which makes sense, given that mental illness is caused by a dysfunction of the brain. In other words, sleep is a requirement for our brain to function properly.

Sleep Deprivation Paradox

The interesting thing is that partial sleep deprivation, which I would imagine to be like for a day or two, significantly boosts BDNF levels. Although that doesn’t mean that I will try to stay awake at night for the purpose of boosting brain power. Anything that dysregulates or disrupts good daily routines or habits should be avoided. I also find that I am very prone to temptations and wasting time when I feel mentally fatigued. I’m sure you know what I mean ( ͡° ͜ʖ ͡°). To summarize what I am trying to say, short-term gains by skipping sleep (like the productivity you see in all-nighters) can causes larger long-term productivity losses, especially if you already have poor discipline.

How Stress Decreases BDNF & Shrinks the Brain

The inverse relationship between Stress & BDNF

stressed out guy working on a laptop with php apple github CSS NODE JS Stack Overflow logos
Staring in front of the computer for hours on end can be quite stressful, and chronic stress leads to lower BDNF expression.

Stress is definitely an ailment of our modern era. Although people will always be exposed to stress, in our time stressors are ever so more prevalent. We use artificial lights at night that disrupt our circadian rhythm and thereby our sleep. Social media is inadvertently designed to keep people in a state of anxiousness & unfocused. And most jobs force us to treat our bodies in unnatural ways- specifically we are more sedentary than ever, even though our bodies are designed to move.

Illness causes stress, and stress causes illness.

Stress not only targets the body, but also the brain. One way is that chronic psychological stress reduces the amount of BDNF produced in the brain.

Acute stress may actually increase the level of BNDF in the hippocampus. But chronic stress reduces the overall level of BDNF in that brain region.

“Animal evidence indicates that stress exacerbates the effects of reduced BDNF on both hippocampal networks and autonomic arousal. For instance, stress in laboratory animals reduces BDNF synthesis, resulting in atrophy of CA3 pyramidal hippocampal neurons. Further, BDNF knockout mice demonstrate impaired arousal responses and increased anxiety-related behavior.”[2]

Stressful life events can significantly lower the level of BDNF in the brain. Stress during childhood has an even more detrimental effect, given that childhoods is when the brain is undergoing the most development, thereby being more susceptible to different stressors.

In fact, higher cortisol levels from stress causes a person’s hippocampus to shrink in volume, which is frightening because we need our hippocampus for learning and making new memories[3]. Without the hippocampus, we would be stuck in the past unable to learn like patient H.M.

One type of stress is prolonged sleep deprivation. Another type of stress is an inflammatory diet, such as the “western diet”. Knowing this, scientists devised a study[4] where they combined and administered both of these stressors on lab rats to examine the deleterious effects of stress on the brain:

In this study, we examined the combined effect of sleep deprivation and Western diet on hippocampus-dependent spatial learning and memory… Sleep deprivation was induced in rats using the modified multiple platform model simultaneous with the administration of Western diet for 6 weeks. Thereafter, spatial learning and memory were tested using radial arm water maze… The results of this study revealed that sleep deprivation, Western diet, or a combination of both impair short- and long-term memory (P < 0.05). The magnitude of the impairment induced by the combined treatment at the 24-h long-term memory was higher than that caused by each factor alone (P < 0.05). In addition, the combined treatment reduced the levels of hippocampal BDNF, a reduction that was not detected with each factor alone. Moreover, the combined treatment reduced the hippocampal activities of SOD, catalase, GPx, ratio of GSH/GSSG, and elevated TBARS level (P < 0.05). In conclusion, the combination of sleep deprivation and Western diet decreases BDNF levels and increases oxidative stress in the hippocampus, thus inducing memory impairment that is greater than the impairment produced by each factor alone.

In this study, scientists were testing how the rat’s spatial learning & memory ability, which is tied to brain’s hippocampus, was effected by sleep deprivation and poor diet stressors. Stress or “oxidative stress” impairs learning and memory, damages neurons and interferes with neuronal communication. Spatial learning refers to an organism’s ability to perceive, analyze, and understand visual information in the world around them. The hippocampus is the part the brain responsible for the formation of new memories, including spatial memories.

Now to understand this study, it would be useful to know what a “multiple platform model” (MMPM) means. Well, MMPM is a sleep deprivation model. The MMPM uses equipment consisting of a plastic tank and several platforms, which are stuck to the bottom of the tank. When the tank is filled with water (1-2cm to the surface of platform), rats are forced to stand on the platforms because of their instinctive fear of water. And when they fall asleep, they will fall into the water and wake up.

A western diet most likely refers to a diet mainly composed of fast foods that are rich in macro-nutrients like carbohydrates, but piss-poor in more valuable micronutrients like vitamins & minerals. This is important, because our healing, immune, and antioxidant defense functions rely on particular vitmains & minerals to function properly. Some vitamins reduce oxidative stress by acting as antioxidants. Furthermore, a western diet implement fried foods that are rich with oxidized fats that can have an oxidative or inflammatory effect on the body. Finally, a western diet is also quite lacking in antioxidants, fiber, and other dietary factors that supports the health of a person- or in this case, a rat.

The study finds that both short-term and long term memory was harmed. And also found that a combination of bad sleep and bad diet increase the negative effects synergistically. Particularly, diet and sleep are 2 of the 3 cores of health for a human being or mammal. Sleep is required for recovery. And a good diet not only provides nutrients for growth, development, and metabolism, but also improves the body’s resistances to various different stressors. That’s why it was observed by statisticians that societies that received an abundance of nutrition have longer life spans than others with poor nutrition. Another example is that vitamin C reverses the impairments causes by chronic sleep deprivation, including metabolic, hormonal and lipid peroxidation dysfunctions[5]. So you could say that supplementing antioxidants like vitamin C in the diet can improve stress tolerance.

And in general, the production of BDNF relies on a good diet and good sleep. Stress, chronic sleep deprivation, a poor diet, and inflammation all are factors which lead to lower BDNF levels and poorer brain health.

How Inflammation Decreases BDNF & Causes Neurodegeneration

man standing in front of fire
For some people, inflammation is like the body being set on fire…

Inflammations lowers the gene expression of BDNF in the brain, which means that less BDNF proteins are ultimately produced. Less BDNF means that there is less neurogenesis & brain plasticity, and thereby one’s cognitive ability is hampered. Our cognitive function is closely tied with neurotrophins that support the health of our brain’s neurons. A decrease of neurotrophins like BDNF leads to poorer brain function & brain health.

The study below further elaborates on the negative effects of inflammation on BDNF[6]:

Several in vivo studies demonstrated that inflammation clearly affects the expression of BDNF within the brain. In particular, it has been reported that the administration of pro-inflammatory cytokines or of the cytokine-inducer lipopolysaccharide, (LPS; Raetz and Whitfield, 2002) causes a significant reduction of BDNF gene expression. For example, the mRNA levels of BDNF were significantly decreased in the rat hippocampus 4 h after intraperitoneal injection of IL-1β or LPS (Lapchak et al., 1993) and a similar reduction was also observed in several cortical regions and at protein level (Guan and Fang, 2006; Schnydrig et al., 2007). Interestingly, the effect of the systemic inflammatory challenge was not restricted to BDNF: other neurotrophins such as nerve growth factor (NGF) and neurotrophin-3 (NT-3) were similarly reduced although with different magnitude (Guan and Fang, 2006).

So as you can tell inflammation, particularly chronic inflammation, is very bad for the brain. Inflammation ruins hippocampus-dependent memory such as spatial memory, and increases cell apoptosis in the brain. You’ll personally notice that you experience brain fog when you are under an inflammatory state- such as when you skip sleep, when you are on an unhealthy or inflammatory diet, and when you are sick.

Inflammation is also associated in age-related cognitive decline, neurodegenerative diseases, and mental illnesses such as schizophrenia and major depression.

People who are depressed are shown to have increased levels of inflammation in their body & brain. Likewise, people who have an illness that involves inflammation are also shown to experience depressed. That’s one reason why you tend to be in a bad mood when you have the cold. Well, that and sneezing with 2.9 G’s of force after every few minutes.

As mentioned before, inflammation causes a decrease in BNDF proteins. Decreasing BDNF causes a decrease in hippocampal neurogenesis. And a decrease of hippocampal neurogenesis is found to cause depression. That’s why you’ll notice that SSRI anti-depressant medications combat depression by specifically raising the level of neurogenesis in the hippocampus.

So if you think about it, making changes to decrease your body’s level of systemic inflammation, if it is abnormally high to begin with, is a way to increase the level of BDNF produced in the brain.

How Diet Type & Micronutrients Influence BDNF Levels

Diet can influence the structure & function of our brain through the regulation of neurotrophins.

Animals with high level of BDNF in the hippocampus learn spatial memory tasks a lot faster than the control. The plasticity of neurons and synapses depends on the level of BDNF. If there is less BDNF, then there is less neuronal and synaptic plasticity. Note that the plasticity refers to the brain’s ability to form and reorganize synaptic connections, and strengthen synaptic connections through LTP. Our learning ability depends on brain plasticity, given that one way that information is stored is through the changes of our synapses.

So by adjusting our diet, we can adjust the level of BDNF present in the brain.

Omega-3 Fatty Acids & BDNF

Omega-3 fatty acids, such as docosahexaenoic acid (DHA), influences signal transduction (process by which a signal is transmitted through a cell) and gene expression. Omega-3 fatty acids are also found to help protect neurons from dying. In one study[7], scientists found that supplementing omega-3 fatty acid helps the brain recover from the effects of traumatic injuries. Some effects of brain injuries (like fluid percussion injury) includes increased oxidative stress and impaired learning ability. Brain injuries also reduce the level of BDNF in the brain. But supplementing Omega-3 fatty acids in the diet counteracts these negative effects of sustaining a brain injury, including bringing the level of BDNF back to normal.

Antioxidants Protect BDNF Expression

Artistic Interpretation of Brain on Free Radicals
Free radicals can both damage brain cells, but also encourage an adaptive response, like the release of neurotrophins from exercise. So it depends on the stimuli.

Oxidation seems to have a significant influence over BDNF levels and brain function. Oxidative stress decreases BDNF and thereby decreases synaptic plasticity, thereby harming a person’s ability to learn. But antioxidants counteract the effects of oxidative stress, allowing BDNF to come back to normal levels, reducing oxidative damage, as well as normalize the Synapsin I and CREB levels- both of which is associated with learning and memory. For example, one study[8] showed that the supplementation of Vitamin E had these beneficial effects as an antioxidant. Polyphenols found in plants are another source of antioxidants.

Polyphenols, Flavonoids, Phytochemicals & BDNF

Dietary habits can influence the occurrence of neurodegenerative diseases like Alzheimer’s and Parkinson’s disease. Diets that employ a variety of plant-base foods tend to be better for cognitive function. Plants can contain therapeutic compounds with high antioxidant capacity and anti-inflammatory properties, that bestow a neuroprotective effect and brings levels of BDNF back up to normal in the brain. Such compounds include polyphenols, flavonoids, catechins, epicatechins, etc.

close up cocoa pod opened with clean white seeds corn cob
Picture by Aude, via Wikimedia Commons Cococa has a bunch of polyphenols that are shown to improve cardiovascular health and improve cognitive function. Specifically, Cocoa flavanols are found to enhance the function of the Dentate Gyrus, which is responsible for spatial memory encoding.

For example, Green tea’s catechin polyphenols activate many cellular mechanisms that provide a neuroprotective effect. These include therapeutic activities like iron chelation, scavenging of radicals, activation of survival genes and cell signaling pathways, and regulation of mitochondrial function and possibly of the ubiquitin-proteasome system[9].

In another study[10], scientists observed that there was an inverse association between flavonoid intake and the risk of suffering dementia.

In yet another study[11], Green tea polyphenols were shown to help transiently correct the negative effects of a certain gene defects that caused symptoms that mimic Down’s syndrome:

Individuals with partial HSA21 trisomies and mice with partial MMU16 trisomies containing an extra copy of the DYRK1A gene present various alterations in brain morphogenesis. They present also learning impairments modeling those encountered in Down syndrome. … DYRK1A [gene] is involved, during development, in the control of brain volume and cell density of specific brain regions… DYRK1A is also involved in the control of synaptic plasticity and memory consolidation. Increased gene dosage results in brain morphogenesis defects, low BDNF levels and mnemonic deficits in these mice. Epigallocatechin gallate (EGCG) — a member of a natural polyphenols family, found in great amount in green tea leaves — is a specific and safe DYRK1A inhibitor. We maintained control and transgenic mice overexpressing DYRK1A on two different polyphenol-based diets, from gestation to adulthood. The major features of the transgenic phenotype were rescued in these mice.

As you can take away from the study excerpt, the DYRK1A gene is closely resembles the Down Syndrome phenotype. And the EGCG polyphenols from green tea is shown to inhibit the DYRK1A gene. Which leads to a decrease in Down syndrome symptoms in mice. The scientists postulate that the EGCG in green tea works by increasing levels of BDNF closer back to normal levels in the brain.

In the human fetus afflicted with Down syndrome, there is 50% less BDNF in the hippocampus compared to a regular human fetus. Having so little BDNF right from the start would obviously cause a huge detriment to the development of the brain. Which helps explains why people afflicted with Down syndrome acquire Alzheimer’s disease in half the time of a regular person.

And finally, cocoa polyphenols bestow neuroprotection by increasing activation of the BDNF/TrkB signaling pathway on both Amyloid Beta (Aβ) plaque treated cells and on Aβ oligomers treated cells. This results in the counteraction of neurite dystrophy (neurite = any projection from neuron i.e. axon, dendrite), reduced cell viability, increased cell apoptosis, and etc. caused by Aβ plaques. Know that the increased presence of Amyloid Beta in the brain is the hallmark of Alzheimer’s disease[12].

Saturated Fat, Refined Sugar & BDNF

A study[13] showed that rats on a diet rich in saturated fat and refined sugar (HFS) was shown to significantly reduce the level of BDNF in the hippocampus, and subsequently impaired spatial learning ability and neuroplasticity. The study further showed:

…animals maintained on the HFS diet showed a decrease in levels of: (i) synapsin I mRNA and protein (total and phosphorylated), important for neurotransmitter release; (ii) cyclic AMP-response element-binding protein (CREB) mRNA and protein (total and phosphorylated); CREB is required for various forms of memory and is under regulatory control of BDNF; (iii) growth-associated protein 43 mRNA, important for neurite outgrowth, neurotransmitter release, and learning and memory.

My bias is that not all sources of saturated fat is necessarily bad for you. I would like to distinguish animal from plant-based saturated fats. Animal fats tend to sequester the toxins the animal absorbs from the environment. A similar example is that bigger fish tend to have a higher ratio of mercury levels than smaller fish.

Bad BDNF Genetics & Food Cravings

BDNF has an influence on our food cravings. Likewise, as I have alluded to above, the foods that we eat has an influence on the level of BDNF in the brain.

First know that in mature Central Nervous System, BDNF proteins are most abundantly found in the hippocampus and the hypothalamus of the brain. Its important to know that BDNF and its receptor counterpart TrkB are found in hypothalamic nuclei (nuclei is a group of neurons) that are associated with food satiety and locomotor activity.

In mice that have a bad variant of the BDNF gene[14] (i.e. with only one functional BDNF allele), you’ll observe that they suffer eating disorders and obesity. Interestingly, administering BDNF to these mice temporarily reverses the eating disorder and obesity.

What this means is that the level of BDNF in the hypothalamus directly relates to how satiated we are after eating a certain amount of food. When there is less BDNF in the hypothalamus, we are inclined to eat more. On the other hand, high levels of BDNF in the hypothalamus improves our ability to be satiated from eating food.

This relationship helps explain why people eat more when they are depressed, given that depression suppresses BDNF levels in the brain.

I also realized that diet plays a big role in the amount of BDNF produced in the brain. For example, choosing a diet that naturally influences the body to produce more BDNF than usual may be a valid tactic to help weight loss. Given that an abundance of BDNF suppresses cravings.

How Exercise Boosts BDNF & Brain Function

black pants white shirt cool black guy with black hair in running position with bright white-blue sky
Exercise is one of the simplest, and one of the most effective ways to improve cognitive function. It really is the first fundamental building blocks that a person should invest in for cognitive enhancement

Exercise is one of the best ways to improve cognitive function, in my personal experience. Exercise has a multitude of benefits, from promoting neuroplasticity, angiogenesis, increasing output of neurotrophic factors (e.g. BDNF, IGF-1, VEGF), improving executive functions, to increasing gray matter volume in all parts of the brain.

Permeability of BDNF Across Blood-Brain Barrier

Consider that the BDNF molecule is able to cross the blood-brain barrier. This means that the BDNF proteins synthesized in the peripheral areas of the body, in response to exercise, also increases the BDNF signaling in the brain.

Benefits of BDNF

Exercise-induced increases of BDNF cause positive epigenetic changes, improvements to cognitive function, mood, and memory. BDNF increases hippocampal neurogenesis, improves the brain’s synaptic plasticity and facilitates the repair of neurons.

How Exercise Affects BDNF Levels in Hippocampus

In one study[15], scientists setup 2 groups of mice: one group that was given a running wheel to exercise voluntarily for 30 days, and another group that was not given a running wheel to act as the control. Normally, mice run about 5 kilometers per day. After 30 days, the scientists sacrificed the mice and found the amount of BDNF proteins doubled in the hippocampus region of the brain of exercise group, compared to the control.

How Aerobic Exercise Affect BDNF Levels

Another study[16] found that:

Aerobic exercise caused a ~32% increase in serum BDNF in adult human males while serum BDNF decreased 13% in sedentary control subjects. Vigorous intensity (80% heart rate reserve), long duration (40 min) exercise offered the greatest probability of a significant BDNF elevation. Long duration exercise offered the greatest numerical benefits in terms of BDNF integral. Neither intensity nor duration affected the mean elevation in BDNF amplitude caused by exercise.

According to the study, the human test subjects who exercised actually showed approximately a 45% increase in serum BDNF, compared to sedentary controls. The interesting thing is that the sedentary group actually had a decrease in serum BDNF. There are a few explanations as to why the sedentary group had decreased BDNF circulation. One reason is that observing people exercising and having blood taken away from them was psychologically stressful. And being sedentary makes a person more prone to stress than when exercising.

Another reason could be that sitting down for period of time was itself stressful, or did not stimulate the brain function particularly much. Sitting is stressful, as odd as that sounds. That’s why you’ll actually feel exhausted after a long road trip, plane ride, etc. that involves sitting down for long periods of time. And of course, sitting does not engage the brain as much as exercise does, thus lowering the requirement for BDNF signaling.

BDNF Before, During, and After Exercise

The intensity and duration of the exercise did not make a significant different in pre-post BDNF levels- in other words, right before and right after the exercise session. However, the intensity x duration relationship showed a significant increase of BDNF during the exercise[16]:

Comparing integrals for the two vigorous intensity conditions, subjects in the 40 min period showed an increase in the volume of BDNF circulated that was 2.7 times greater than that seen in the 20 min period group; the moderate intensity 40 min group showed an increase that was 1.4 times greater than the 20 min group… it follows that the volume of circulating BDNF over time (measured with the integral) is a more important indicator of BDNF function than is the magnitude of peak BDNF concentration at one fixed time point.

As you can see for aerobic exercise, the longer and more vigorous the exercise is, the more BDNF proteins are released into the bloodstream during the exercise session. But one thing that I found odd at first was that sometimes the amount of BDNF in the blood serum would actually decrease after the exercise.

Chronic Exercise Decreases BDNF but Increases Signaling Efficiency – Improves BDNF Sensitivity

Another study[17] goes into depth about the issue of serum BDNF decreasing after exercise. In this study, there were two groups of test subjects. One group exercised regularly. The other group exercised infrequently, and was more sedentary. It was found that the level of BDNF after the exercise would actually decrease past the baseline for the exercise group. But for the sedentary group, the level of BDNF would go back to the baseline.

This does not mean that exercise is bad for BDNF. The researchers propose that BDNF levels sink below the baseline level after exercise due to utilization. In other words, the body that experiences chronic exercise is able to use up BDNF more efficiently than those who are unused to exercise.

Consider that not utilizing a signaling protein or hormone is actually a bad thing. For example, some diabetic patients have something called “insulin resistance”, which is when there is a downregulation or decrease in the amount of insulin receptors in the body. With fewer insulin receptors, less of the insulin hormone is used up. And thereby the insulin hormone is less effective at telling the body to absorb the glucose from the blood stream, leading to higher blood glucose levels and associated diabetic complications.

So chronic exercise improves the efficiency or potency at which BDNF can signal the body to repair, grow, and develop neurons. Specifically, chronic exercise upregulates or increases BDNF’s associated receptor, TrkB. BDNF bestows its signaling effect by attaching to the TrkB receptor. Without a receptor, BDNF would not be able to work. Just like insulin cannot work without its associated receptor.

To summarize, Chronic exercise increases TrkB receptors. More TrkB receptors improves the potency of BDNF signaling. And thereby more of the serum BDNF is utilized, explaining why BDNF protein levels drop below baseline for those who exercise frequently. Hopefully this also means that BDNF becomes more potent in the brain as well.

By improving BDNF and TrkB signaling, exercise also bestows an antidepressant effect on the person.

Antidepressant Effect of Exercise

Anti-depressants cause an increase the level of BDNF in the brain’s hippocampus. Likewise, exercise increases the level of BDNF in the hippocampus. Low levels of neurogenesis in the hippocampus is thought to cause depression. So raising neurogenesis in the hippocampal region of the brain is thought to relieve depression. And the amount of BDNF signaling protein in the hippocampus influences the rate of neurogenesis. Such that what increases hippocampal BDNF, increases hippocampal neurogenesis.

In other words, exercise is another option available to the person to help relieve depression. In fact, I have experienced a strong anti-depressive effect myself when I picking up the beneficial habit of running with the intent of enhancing cognitive function. From a mostly sedentary lifestyle, I now go running almost everyday for about an hour and afterwards experience a type of satisfaction and sense of well-being. When I skip exercise for a day, it feels like something is missing and I am generally in less of a good mood.

Our mood and happiness has a very strong influence on our cognitive function, learning ability, and thereby our productivity. Higher levels of BDNF in the hippocampus, thereby higher hippocampal neurogenesis, not only improves our mood, but also improves a person’s short term memory, learning ability, and spatial memory.

Exercise Boosts Ketone Production & Thereby BDNF Expression

Exercise eat up a lot of caloric resources in the body. Initially the glucose & glycogen reserves are used up during exercise. And then the body turns to breaking down fat molecules into the highly fuel-efficient ketones.

Ketones boost the production of BDNF[15]. Exercise encourages the breakdown of fat, which become ketones to fuel the metabolism of the cells.

You’ll notice that not all types of exercise is the same. Endurance exercise that lasts for an hour or more causes the body to breakdown fats into ketone fuel. Exercise of shorter duration relies more on glucose & reserves of glycogen in the body. This may be one reason why you’ll find long-term aerobic exercise to proffer more cognitive benefit compared to short-term anaerobic exercise. But generally speaking, the more you exercise, the more cognitive benefit you reap.

Given that the presence of ketones encourages the production of BDNF, it makes sense why fasting sees a similar benefit. Fasting involves the abstinence of food, forcing the body to breakdown fats into BDNF-boosting ketones.

Reviewing How Exercise Benefits the Body & Brain

Exercise benefits learning and memory, alleviates depression, protects from neurodegeneration and risks that lead to cognitive decline- such as diabetes, hypertension, and cardiovascular disease.

Exercise also increases synaptic plasticity, potentiates synaptic strength, and improves systems or factors that support neuroplasticity like neurogenesis, metabolism, and vascular function. The broad range of benefits that exercise bestows on the brain comes from exercise causing an increase in central and peripheral growth factors and growth factor cascades, as well as epigenetic changes in gene expression that benefits brain plasticity.

For example, exercise activates the gene that produces the BDNF protein. Furthermore, exercise enhances the BDNF/TrkB receptor signaling. And increases in level of BDNF and other growth factors stimulates neurogenesis, increases the brain’s resistance to insult & injury.

Exercise also causes oxidative stress to the cells of our body. Normally, oxidative stress is something that can impair our cells and neurons. But the overall benefits of exercise outweigh the harms of oxidative stress experienced during the exercise session. Additionally, I believe that exercising regularly actually has anti-inflammatory effects in the long run as a part of the body’s recovery process, which may mean that a lifestyle that incorporates regular exercise produces less free radical damage than a stationary lifestyle. Or at least less free radical damage than you’d think.

Furthermore, regular exercise forces the body to adapt to experiencing higher levels of free radicals. You’ll notice that athletes have generally better antioxidant defense systems and immune systems. For example, the glutathione levels in athletes are higher than people who lead a sedentary lifestyle.

My Experience with the Beneficial Effects of Exercise

If you consider that our bodies are meant to move, it makes sense that exercise stimulates the brain in a certain way that promotes cognitive function. I find that regular exercise benefits my attention, focus, concentration, memory, analytic ability, information processing speed, clarity of mind, motivation and discipline. I find that with regular exercise, I can be inspired a lot more easily and can come up with ideas with increased frequency.

Without exercise, these positive traits are severely diminished and I find that I pursue addictive behaviors much more. In other words, I observe that exercise enhances my executive function. Without exercise, I find that I procrastinate a lot more for quick pleasures, like watching YouTube videos & anime, playing video games, browsing senselessly, etc. But with exercise, I feel like I can cut off my consumption of entertainments and put steps towards fulfilling my future goals.

How Mastication of Chewing Gum Enhances Hippocampal BDNF

Interestingly enough, chewing is actually quite important to our cognitive function. The elderly loose their teeth as they age, and are no longer able to chew properly. Not only does this cause an inconvinience for consuming solid foods, but also negatively effect cognitive function. You see, there are a lot of neural circuits that connect the masticatory (chewing) organs to the hippocampus. So mastication influences the function & health of the hippocampus.

So a lack of mastication causes a decline in hippocampal function. Likewise, an abundance of mastication causes an improvement to hippocampal function. Remember that the hippocampus is responsible for the formation of new memories and spatial memories.

Yellow-Orange frereana Yagcar Maydi
Boswellia frereana Gum-Resin used for Mastication-induced Memory Improvement & Incense

During mastication, there is an increase in cerebral cortical blood flow, and activation in the cortical areas that deal with somatosensory, supplementary motor and insular cortices. Blood oxygen levels are increased in the prefrontal cortex and the hippocampus- both regions essential for learning & memory. Finally, mastication upregulates BDNF and its associated receptor, TrkB[18].

By the way, the gum that I chew personally is a type of frankincense from the Boswellia Frereana tree called “Maydi”. Not only does it fall under the benefits of chewing, but also has different phytochemicals with anti-inflammtory effects. The scholars of Somaliland and places near it chew frankincense to improve their memory. Some describe that chewing Maydi “opens the mind”, in their experience.

BDNF Boosting Nootropic Supplements

Nootropics are defined as substances that a person can use to improve their cognitive function. Indeed, there are substances that exists which directly or indirectly increase the level of BDNF in the brain. Directly means that the substance directly stimulates the body’s production of BDNF. Indirectly means that the substances influences the state of the body so that BDNF can be produced properly. For example, stress inhibits the amount of BDNF produced in the brain. That’s why people who suffer chronic stress experience memory loss and decreased learning ability. So to indirectly boost BDNF levels in the brain, a person can take a substances which relaxes him/her and reduces stress, like Bacopa Monnieri, Chamomile, or Tulsi.

How Monoamine Oxidase Inhibitors & Antidepressants Influence BDNF

Monoamine Oxidase Inhibitors (MAOI) and antidepressants influence BDNF protein expression by enhancing monoamine neurotransmission. BNDF protein levels affects the amount of neurogenesis that occurs in the brain, particularly in the hippocampus.

The level of neurogenesis in the hippocampus influences our mood and cognitive function. Low neurogenesis and low synaptic plasticity in the hippocampus leads to slower learning and memorization of information, as well as depression. Whereas high levels of neurogenesis and synaptic plasticity speeds up a person’s learning and memorization ability, as well as lift depression and improve mood.

5-HT serotonin neurotransmitter pills on leaf
Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract (GI tract), blood platelets, and the central nervous system (CNS) of animals, including humans. It is popularly thought to be a contributor to feelings of well-being and happiness.

So the question is, what influences neurogenesis and synaptic plasticity in the hippocampal region of the brain? A neurotransmitter called serotonin does. Norepinephrine is also a target of licensed antidepressant medication.

What antidepressants do is increase the amount of serotonin and norepinephrine neurotransmitters in the brain. The antidepressants flood the synapses with serotonin and norepinephrine neurotransmitters with their associated receptor, by preventing their re-uptake back into the neuron. It’s like damming up a river. The river no longer flows naturally, and instead the water pools in the dam.

So just increasing serotonin levels does not directly alleviate symptoms of depression. After all, licensed antidepressants don’t work immediately. Instead, it is observed that antidepressants take some time before depressive symptoms start abating.

As an explanation, remember that our body tries to reach homeostasis. Such that the excess amount of serotonin stimulates an adaptive response in the brain, and this adaptive response leads to an increased levels of neurogenesis, particularly in the hippocampus. The neurogenesis is specifically what is thought to alleviate depression and associated symptoms.

This reveals the possibility that a lack of serotonin in the brain may not be the cause of depression.

After all, the opposite was suggested according to one study, where scientists were investigating the altered serotonin signaling of a mouse model, mice that were tryptophan hydroxylase (Tph)2-deficient (Tph2 −/−), that lacked sufficient amounts of brain serotonin. What the scientists found was that these mice actually had increased levels of BDNF in the hippocampus and prefrontal cortex. Indicating that a complete lack of brain serotonin induces BDNF expression.[19]

My conjecture is that you can achieve a similar effect without the use of SSRI antidepressants, by simply finding a way to increase serotonin levels in the brain at a safe level. You can do this safely with weak MAO inhibitors. Monoamine Oxidase are enzymes the break down neurotransmitters like serotonin. So an inhibitor of this enzyme (a.k.a. MAOI) can increase the level of serotonin in the brain. A well known example is coffee[20]. Specifically, coffee contains compounds that act as MAO inhibitors.

How Melatonin Increases BDNF & Heals the Brain

Melatonin is a powerful antioxidant that is produced from within the body to initiate sleep, specifically released by the body when the person is in a dark environment.

Melatonin Combats the Negative Effects of Sleep Deprivation.

In one study[21], supplemented melatonin is shown to reverse the negative effects of sleep deprivation and improve cognitive function. Sleep deprivation impairs cognitive function by increasing oxidative stress, disrupting the antioxidant defense system in the body, and by decreasing BDNF & CaMKII proteins.

Specifically, sleep deprivation decreases the amount of BDNF and CaMKII in the cerebral cortex and hippocamal CA1, CA3 and dentate gyrus regions, whereas melatonin improved the amount of BDNF and CaMKII in those regions.

Note that CaMKII stands for calcium-calmodulin dependent kinase II, which is a substance that is important for Long-Term Potentiation (LTP) of the synapses- thereby also important for learning and memory. Because the preservation of information (memory) in neurons occurs through the strengthening of their synapses.

How Turmeric Boosts BDNF by Lowering Stress & Inflammation

yellow orange turmeric powder in a chrome pan
Turmeric is a main ingredient in Indian cooking that is used in almost every dish. The addition of turmeric is thought to explain why Indians experience lower rates of cognitive decline.

Turmeric is an age old herb that has been used extensively in India for its medicinal quality, which is also added to food to impart an earth taste as well as medicinal attributes to the food. It goes by Hippocrates’s saying, “Let food be they medicine, and medicine be they food”.

So how does Turmeric relate to BDNF levels in the brain. Well, Turmeric boosts BDNF levels by acting as an anti-inflammatory. Inflammation is something that reduces the amount of BDNF produced. So logically, it would stand that an anti-inflammatory would return the production of BDNF back to normal levels. Of course, given that many of us live in a way that promotes inflammation in the body (poor diet, sedentary lifestyle i.e. sitting in one place for many hours), many of us tend to have more inflammation than what is normally healthy.


There is an active chemical inside of turmeric called “curcumin” which imparts significant antidepressant effects and other therapeutic benefits. Specifically, scientists have found curcumin to reverse the negative effects of chronic stress[22]. For example, curcumin reverses the thickening of the adrenal cortex, the elevation of serum corticosterone levels, and the reduction of glucocorticoid receptor (GR) mRNA expression causes by chronic stress. Furthermore, chronic curcumin administration reverses chronic stress’s effect of decreasing BDNF levels and reducing the ratio of phosphorylated cAMP response element-binding protein (pCREB) to CREB levels (pCREB/CREB) in the hippocampus and frontal cortex of stressed rats. In otherwords, chronic stress causes those parts of the brain to experience lowered neurogenesis, neuroplasticity, and less energy or fuel availability. And curcumin can reverse that.

Other Supplements & Methods for Boosting BDNF

Other methods available for increasing BDNF protein amounts and improving BNDF/TrkB signaling include:

  • Sunlight exposure is associated with the level of BDNF found in the blood; BDNF is lower in the fall-winter period, but higher during the spring-summer period.
  • fasting – I’ve mentioned about ketone fuels enhancing BNDF levels in the exercise section of my article; instead of exercise, fasting is another method available for the person to encourage the body to produce ketone fuels

Other supplements that I want to investigate for the possibility for boosting BDNF levels, or enhance BDNF/TrkB signaling in the brain include:

Learning Stimulates Neuroplasticity & Brain Development

I believe that stimulating the brain simply by using it is a very simple, but very powerful way to boost levels of BDNF in the brain and improve cognitive function. As people have said before, you “use it or lose it”. Indeed, a persons mental performance on a particular task is strongly dependent on practice- utilizing the brain in a particular activity multiple times until the brain can adapt and undergo neuroplastic changes to “learn” the information or skill.

Video Games

Playing video games is a very brain-intensive task. One study has found that video games can improve a person’s working memory[23]. Which is a sign that the stimuli of video games causes a neuroplastic change in the brain.

I personally have used to play an excess of video games as a child growing up, all the way to college. I slowly tapered off my video game usage, as the time I had available to me decreased. What video games made me realize is that I have very limited time, and that spending time in one thing meant that I had less time in other activities. The problem with video games is that they are designed to promote addictive behaviors. You’ll notice that there exists a lot of people who play video games for long periods of time. And within that subset, there are people whose lives are ruined because they do nothing but play video games.

Considering this, I thought that it would have been a great benefit to me if I could have actually put all of that effort into something useful instead. Like building a business, or learning an actual skill that would go towards earning money for my livelihood. Now that I consider it, even socializing with other people would have been more rewarding.

To summarize, although video games can improve brain function in certain aspects, I generally do not recommend video games. The effort you put in could be used to learn another skill. Video games are addictive, and eat into an invaluable resource- time. And I find that exercise and reading are both more rewarding and better ways to enhance cognitive function in a useful fashion.

Related Links

Supplements and Tools for Improving BDNF Synthesis


  1. BDNF in sleep, insomnia, and sleep deprivation. [Ann Med.]
  2. Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety [Molecular Psychiatry]
  3. Higher cortisol levels are associated with smaller left hippocampal volume in first-episode psychosis. [Schizophr Res.]
  4. The Combined Effect of Sleep Deprivation and Western Diet on Spatial Learning and Memory: Role of BDNF and Oxidative Stress [J. Mol. Neurosci.]
  5. Vitamin C Prevents Sleep Deprivation-induced Elevation in Cortisol and Lipid Peroxidation in the Rat Plasma [Niger J Physiol Sci.]
  6. Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity [Front Cell Neurosci.]
  7. Dietary Omega-3 Fatty Acids Normalize BDNF Levels, Reduce Oxidative Damage, and Counteract Learning Disability after Traumatic Brain Injury in Rats [J Neurotrauma.]
  8. The interplay between oxidative stress and brain‐derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition [Eur. J. Neurosci.]
  9. Catechin polyphenols: neurodegeneration and neuroprotection in neurodegenerative diseases. [Free Radic Biol Med.]
  10. Intake of flavonoids and risk of dementia [Eur J Epidemiol.]
  11. Green Tea Polyphenols Rescue of Brain Defects Induced by Overexpression of DYRK1A [PLoS One.]
  12. Cocoa Powder Triggers Neuroprotective and Preventive Effects in a Human Alzheimer’s Disease Model by Modulating BDNF Signaling Pathway [J Cell Biochem.]
  13. A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning [Neuroscience]
  14. BDNF regulates eating behavior and locomotor activity in mice [The EMBO Journal]
  15. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate [eLife.] “…Exercise doubles BDNF… [eLife.]
  16. The Effects of Aerobic Exercise Intensity and Duration on Levels of Brain-Derived Neurotrophic Factor in Healthy Men [J Sports Sci Med.]
  17. Different Circulating Brain-Derived Neurotrophic Factor Responses to Acute Exercise Between Physically Active and Sedentary Subjects [J Sports Sci Med.]
  18. Chewing Maintains Hippocampus-Dependent Cognitive Function [Int J Med Sci.]
  19. Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin [Eur. Arch. Psychiatry Clin. Neurosci.]
  20. Human monoamine oxidase enzyme inhibition by coffee and beta-carbolines norharman and harman isolated from coffee. [Life Sci.]
  21. Melatonin ameliorates cognitive impairment induced by sleep deprivation in rats: Role of oxidative stress, BDNF and CaMKII [Behav. Brain Res.]
  22. Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB [Brain Res.]
  23. Action video gaming and cognitive control: playing first person shooter games is associated with improvement in working memory but not action inhibition [Psychological Research]

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