Brain-derived neurotrophic factor (BDNF) Suggest an improvement to this article

Brain-derived neurotrophic factor, or BDNF, is a growth factor with broad relevance for aging, brain function, behavior, metabolism, energy expenditure, and satiety. BDNF serves as a cell signaling protein, plays key roles in numerous signaling pathways associated with a variety of disorders ranging from depression, schizophrenia, and addiction to obesity and diabetes, and may serve as a hormone. It is perhaps best known for its influence on the formation, growth, survival, and development of neurons and for its role in mediating the beneficial cognitive effects associated with exercise. The decline of BDNF function during aging has important implications for changes to learning and memory in dementia and Alzheimer's disease.

BDNF levels are strongly linked to several metabolic and neurological disorders. In general, lower BDNF levels are correlated with poor health. Interestingly, some disease states are associated with higher (rather than lower) BDNF levels and this may be due to the body's attempt to compensate for cell loss or dysregulated metabolism. BDNF also plays a role in celiac disease and irritable bowel syndrome.

The links between exercise, diet, and mental wellness are well known. Both exercise and diet markedly affect BDNF levels. Reductions in caloric intake and carbohydrates can produce large increases in BDNF levels, and exercise increases BDNF in a manner directly proportional to exercise intensity. Elevated body temperature has also been shown to increase BDNF levels, which raises the possibility of sauna use as a means of boosting BDNF. use as a means of boosting BDNF.

In addition to the areas described above, this article provides an overview of the effects of mental training and meditation practices on BDNF levels; how BDNF may be a useful treatment for neurodegenerative diseases and traumatic brain injury; the links between BDNF and depression, anxiety, and anorexia; BDNF's effects on appetite and possibly aggression; the role of BDNF in regulating blood sugar levels; and the effects of dietary supplements on BDNF levels. Some of the experimental challenges and open questions in BDNF research are also covered.

BDNF plays critical roles in gene expression

BDNF is a member of a family of proteins called neurotrophins, which affect the formation of new neural synapses and help maintain existing synapses by binding to specific receptors located at the synaptic membrane. These interactions trigger a cascade of chemical modifications to proteins within the neuron that in turn lead to changes in gene expression levels. As such, BDNF function is important for appetite, coordination, balance, hearing, memory, and learning.

The primary site of BDNF production is the brain, but it is also produced in many other tissues, including the heart, lungs, kidneys, liver, prostate, intestinal epithelium, skeletal muscle, spleen, and thymus. The BDNF protein can be found in multiple forms (proBDNF, mature BDNF, and BDNF propeptide) that can exist inside or outside of the cell. The exact form written about in any given scientific publication is not always specified, with standard detection methods likely measuring all forms present. Levels of mature BDNF and BDNF propeptide are approximately ten times higher than proBDNF levels in the brain.^[1]

Other proteins in the neurotrophin family include nerve growth factor, neurotrophin 3, neurotrophin 4, cerebral dopamine neurotrophic factor (which has relevance for Parkinson's disease), and mesencephalic astrocyte derived neurotrophic factor (which has relevance for stroke).^{[2] [3]}

Controversy exists as to whether BDNF traverses the blood-brain barrier

Although the majority of BDNF is produced in the brain, the degree to which it traverses the blood-brain barrier is a subject of some controversy. The blood-brain barrier is made up of endothelial cells that line small blood vessels that extend into the brain. The barrier isolates the brain from circulating blood to maintain an environment that allows for undisturbed communication between nerve cells and to prevent immune inflammation of nervous tissue.^[4]

The endothelial cells of the blood-brain barrier also prevent diffusion of potentially harmful molecules or pathogens into the central nervous system. BDNF's relatively large size and hydrophilic surface likely restrict its passage across the barrier.^[5] However, these features appear to apply to the proBDNF form of the protein, and whether the smaller, mature form of BDNF can traverse the barrier is unclear.

In addition, the barrier can undergo changes in composition over time and at specific locations. Inflammation has been recognized as a driver of these changes such that passage of small ions and solutes or even whole white blood cells may occur.^{[6] [7]} Thus, the ability of BDNF to enter or exit the central nervous system varies, likely depending on a person's physiologic state and health.

Some evidence for BDNF passage through this barrier comes from mouse studies involving the intravenous injection of radionuclide-labeled BDNF protein. Radioactivity from the decay of these isotopes was detected in the parenchyma (inner regions) of the brain far from the endothelial membrane of the barrier.^[8] Another experiment investigating BDNF transmission determined the concentration of BDNF in human plasma using antibodies to capture, isolate, and measure quantities present. Researchers found far higher levels of BDNF present in the jugular vein of human volunteers during vigorous exercise than in the radial artery of the arm. This suggests that (at least during periods of intense physical exertion) BDNF is released from the brain into systemic circulation.^[9] Additional studies suggest that this effect may be due to increased temperature increasing the permeability of the blood-brain barrier.^[10]

An example of the relevance of this phenomenon comes from research demonstrating that blood BDNF levels among women who had attempted suicide were consistently lower than those of women who had not attempted suicide. This correlation points to a possible etiology for mental illness, and it suggests that BDNF levels in the blood could be a useful biomarker for underlying conditions that are not easily assessed by mental health practitioners.^[11]

Regardless of whether the central nervous system and the circulatory system are in direct communication with regard to BDNF pools, it appears that circulating BDNF levels are highly correlated with various neurological and psychiatric conditions, underscoring the potential benefits of assessing BDNF levels in the future in the clinical setting.

BDNF provides a possible link between exercise and improved brain health

Exercise has been shown to reduce the incidence of neurodegenerative disease and cognitive decline generally.^[12] Many studies have investigated the potential links between changes in BDNF levels following exercise and cognitive improvement, but results are somewhat mixed. This may be due to differences in study design and measurement methods. Both exercise intensity and duration are important determinants of how much BDNF is produced. For example, one study involving healthy men between the ages of 18 and 25 years demonstrated that either vigorous or moderate exercise for 40 minutes increased serum BDNF more than vigorous or moderate exercise for 20 minutes. Overall, exercise caused an average 32 percent increase in serum BDNF levels compared to baseline levels, resulting in concentrations that were 45 percent higher than those who did not exercise.^[13]

Studies have also found that increases in post-exercise BDNF levels are transient, lasting less than an hour after exercise has concluded.^[14] The transient nature of exercise-induced increases in BDNF could be a significant contributor to variations in study outcomes. In general, studies indicate that aerobic exercise is effective in temporarily increasing peripheral BDNF levels at all ages, regardless of health status.^{[15] [16]} Due to practical limitations, it is impossible to measure brain BDNF levels and neurogenesis in humans after they exercise. But animal studies have consistently shown that exercise increases BDNF and neurogenesis in the brain.^[17]

A six-month study of changes in brain volumes among a group of people aged 63 to 80 years showed enhanced effects in those who participated in a dance program compared to a group engaged in repetitive forms of exercise. People in the dance group experienced significantly larger volume gains in multiple areas of the frontal and temporal cortex as well as the superior temporal gyrus (a part of the brain important for episodic memory, which is degraded by Alzheimer's disease). The exercise group had fewer and smaller increases in volume, restricted mainly to the cerebellum and visual areas. The most notable difference occurred in the corpus callosum, which saw sizable increases among the dancing group and no change among the exercisers. The corpus callosum consists of a bundle of nerve fibers connecting the two hemispheres of the brain and is important for brain development. Dance group members exhibited much larger increases in BDNF plasma levels than did members of the standard exercise group.^[18]

Surprisingly, no significant differences could be found in changes to cognitive functioning between the two groups. The authors speculated that either the cognitive tests were not sufficiently sensitive or that a longer intervention program might be needed to observe changes in cognitive ability.

Animal studies allow for a more extensive examination of the importance of BDNF. In one study, mice engaged in a one-week period of voluntary exercise followed by a multi-day water maze trial, which tested the ability of the mice to recall the location of a submerged platform.^[19] Mice that were allowed to exercise required less time to find the platform than those that remained sedentary prior to the trial. But blocking BDNF by using a selective inhibitor during the exercise period resulted in total loss of these effects as the mice returned to a sedentary performance level. Mice that were the fastest learners and had the best recall also had the highest expression levels of BDNF mRNA present in their cells.These results offer strong evidence that BDNF is central to the animals' ability to learn and remember spatial information.

BDNF participates in the mind-body connection

Yoga is an ancient Indian practice that engages the mind and body through physical poses, breathing techniques, and meditation. Robust scientific evidence has demonstrated that yoga benefits both mental and physical health. A study of 26 experienced meditators in a three-month yoga and meditation retreat observed a threefold increase in mean BDNF plasma levels among participants relative to pre-retreat levels.^[20] The average self-reported scores for depression and anxiety (which were considered low even at the beginning of the retreat) decreased by approximately 60 percent. Mixed results were seen in changes to several inflammatory markers. Some changes were consistent with an expectation of a reduced inflammatory immune status, but plasma levels of multiple proinflammatory factors actually increased over the course of the retreat. The study's authors speculated that the net effect of the retreat may have been to optimize the surveillance capabilities of the immune system.

Intense mental training increases BDNF levels

Direct mental training has been shown to have a significant impact on BDNF levels. A randomized controlled trial of 44 sedentary, elderly women with mild cognitive impairment found that those who participated in eight weeks (24 sessions) of computer-based mental training experienced a large increase in working memory (approximately 22 percent) while those engaged in exercise or neither activity saw small declines over this period. Mental training also increased processing speed by 10 percent and decreased errors during testing by 19 percent, whereas exercise or sedentary behaviors elicited very small changes. Changes seen in post-training performance remained relatively constant even six months after the post-training measurements were taken. Plasma BDNF levels among participants receiving mental training increased by 26 percent during the eight-week period, compared with a 13 percent decline among those not engaged in mental training or physical exercise. Almost no change was measured in the physical exercise group.^[21]

This study suggests that mental training promotes sustained increases in circulating BDNF levels, and these changes may be associated with large, long-term improvements in cognitive functioning.

Increased BDNF levels during exercise may be driven by increased core body temperature

Heat therapy such as sauna use as a means of boosting BDNF. bathing has been linked to a reduced risk of developing cardiovascular disease, dementia, and Alzheimer's disease.^[22] A study of the effects of head-out immersion in hot water found a 66 percent increase in serum BDNF levels following a 20-minute immersion in 42°C (108°F) water. Core body temperature increased to 39.5°C (103.1°F) during this time. Serum BDNF remained significantly higher than before immersion for 15 minutes after the end of the immersion period. Plasma cortisol levels dropped significantly over the immersion period.^[10] These findings raise the possibility that increases in BDNF levels during exercise could be driven by increased core body temperature rather than increased motor activity. Also, since head temperature tends to be higher than other parts of the body during exercise, higher BDNF levels present in the radial artery of the arm may be due to temperature-induced release of BDNF from platelets.^[23]

• Learn more about whole body hyperthermia in this overview article.

BDNF shows promise as a treatment strategy for neurodegenerative diseases

BDNF's roles in brain development and in maintaining brain health have made it a candidate for research into possible treatment strategies for various neurological disorders. Studies on differences in brain structure, changes in BDNF levels or localization over time, in vitro experiments, and direct interventions using animal models can help reveal whether changes in BDNF features are a cause and/or an effect of these diseases.

Lower levels of BDNF are present in Parkinson's disease

Parkinson's disease is a progressive neurodegenerative disorder characterized by tremors, muscle stiffness, and slow movement, as well as a number of possible non-motor symptoms such as gastrointestinal problems, skin rashes, depression, and anxiety. Motor symptoms of Parkinson's disease are caused by low dopamine levels due to loss of dopamine-producing neurons in a region of the brain called the substantia nigra. Parkinson's disease is treated by administering L-DOPA, a precursor of dopamine, which, unlike dopamine itself, can cross the blood-brain barrier. In addition to serving as an external source of dopamine, L-DOPA stimulates the release of neurotrophic factors (including BDNF) in the brain. While this method of treatment can help to lessen symptoms, it is unable to reverse or even halt disease progression.

Lower BDNF levels in both the brain and circulation have been observed in people with Parkinson's disease and in animal models of the disease.^{[24] [25] [26]} This reduction is in part due to loss of dopamine neurons, but the neurons that remain produce lower levels of BDNF compared to healthy neurons.^[27] Decreased BDNF has been noted in the nigrostriatal pathway, a major dopaminergic pathway that links certain areas within the substantia nigra to other areas of the brain.

In a rat model of early stage Parkinson's disease, selective overexpression of BDNF in dopaminergic neurons achieved significant improvements in distance traveled, walking time, and grooming behaviors.^[28] More pronounced effects were achieved when BDNF-targeted therapy was combined with the use of a dopamine receptor agonist in an aged rat model.^[27] The combined treatment led to a full recovery of the animals' gait, coordination, and balance. Substantial recovery (up to 80 percent) of dopamine-producing neurons in the substantia nigra and nerve fibers in the striatum was also achieved.

Primates that receive direct injections of BDNF into the cerebrospinal fluid show marked improvements in motor function. Monkeys that received injections containing BDNF experienced a slower progression of Parkinson's disease symptoms compared with those injected with a placebo. In addition, tissue sections taken from the substantia nigra of treated monkeys showed significantly less neuronal cell loss compared to tissue samples from the untreated group.^[29]

A comparison of blood serum BDNF levels in patients with Parkinson's disease, patients with essential tremor (a neurological disorder that causes involuntary shaking), and healthy people found that low serum BDNF may be useful as a biomarker for early stage Parkinson's disease and in distinguishing between people with Parkinson's and those with essential tremor. Interestingly, patients with more severe cases of Parkinson's disease were found to have higher levels of serum BDNF. The study's authors speculated this may have been due to the use of L-DOPA as a treatment.^[30] However, an earlier study that also noted this trend in serum BDNF levels among Parkinson's disease patients found no significant difference between BDNF levels in treated versus untreated patients. So it appears that increasing BDNF levels in later stages of Parkinson's disease may be due to the body's attempt to compensate for more severe disease symptoms.^[31]

• Learn more about Parkinson's disease in this episode featuring Dr. Giselle Petzinger.

Brain BDNF expression is reduced in people with Alzheimer's disease

Alzheimer's disease is the most common neurodegenerative disease and the leading cause of dementia worldwide.^[32] Notably, women are twice as likely to develop Alzheimer's disease as men. During the early stages of Alzheimer's disease, a person may begin having problems with short term memory, word recall, or facial recognition. Symptoms progress to difficulty with planning, reasoning, and problem solving; over time, more systemic problems can emerge (difficulty in walking, sitting, or swallowing). The pathogenesis of the disease is associated with the formation of extracellular plaques of amyloid-beta protein in the brain. These plaques lead to the accumulation of insoluble masses of tau protein (often referred to as tau "tangles") inside nearby cells, which eventually result in cell death. Many studies have found lower levels of BDNF expression in several areas of the brain in people with Alzheimer's disease.^[33] Post-mortem analysis of neurons from Alzheimer's patients and those who died from causes unrelated to dementia show BDNF present throughout the brain in areas responsible for many important functions, including learning, memory formation, emotion, sensory integration, decision making, reward perception, motor function, executive function, and stress response. However, BDNF was largely absent in neurons with tau tangles in Alzheimer's disease patients.^{[34] [35]}

Some studies have found that patients with Alzheimer's disease also have lower peripheral blood levels of BDNF and that this difference is exaggerated among patients who have not yet received any treatment.^[36] Other research indicates that the association between Alzheimer's disease and circulating BDNF concentration is inconsistent but that decreased BDNF is correlated with the APOE4gene variant.^[37] People who carry one APOE4allele have a twofold greater risk of developing Alzheimer's disease; those with two alleles have a 15-fold increased risk.^[38]

A long-term study including more than 2,000 dementia-free participants aged 60 years and older found that low serum BDNF levels at baseline were correlated with risk for developing dementia, but this association was statistically significant only among women, in people aged 80 years or older, or in people with a college degree.^[39] Notably, the data revealed that for each standard deviation increase in BDNF level, any given participant was found to have a 23 percent lower risk of developing future dementia. The relationship between serum BDNF levels and dementia risk remained statistically significant even after accounting for APOE4 status. The study also found no significant association between Alzheimer's disease risk and any of 133 BDNF gene variants studied, including the Val66Met polymorphism described below. Animal studies have found that BDNF treatment may improve Alzheimer's disease symptoms.^[40]

• Learn more about the role that the APOE4 polymorphism plays in Alzheimer's disease in this article by Dr. Rhonda Patrick. #### The Val66Met BDNF polymorphism exerts variable associations with Alzheimer's disease

The Val66Met BDNF polymorphism is a variant of the BDNF gene that results in a single amino acid substitution of methionine in place of valine within the BDNF protein. This variant results in lower secretion of BDNF by neurons following motor stimulation but does not appear to affect basal levels of secretion.

Reports vary on the association of BDNF Met (the less common form of the BDNF gene that codes for methionine) with Alzheimer's disease incidence, but the combination of APOE4 with BDNF Met has been linked to more rapid deterioration of memory and language performance among older people who have not been diagnosed with dementia. Assessments of episodic memory based on a battery of cognitive tests demonstrated that the rate of cognitive decline experienced by healthy, older people who had amyloid-beta protein accumulation in their brain and who were APOE4 and BDNF Met carriers was roughly three times the rate of decline among those carrying only the BDNF Val allele (the more common form of the gene that retains valine).^[41] By itself, the BDNF Met allele does not seem to reliably predict the likelihood of developing cognitive impairment or dementia. Among some populations this variant is even associated with a lower incidence of dementia compared to the predominant, BDNF Val, allele.^{[42] [43]} This may help explain the sizable difference in BDNF Met frequencies in Asian (about 50 to 70 percent) versus Caucasian (about 20 to 50 percent) populations.^{[44] [45]} However, multiple studies have shown that BDNF Met significantly increases the probability and rapidity of disease progression in cases where a background of pathology is already in place.^{[46] [47]}

Production and transport of BDNF is altered in Huntington's disease

Huntington's disease is characterized by a number of motor, cognitive, and psychiatric symptoms. Symptoms of Huntington's disease can begin at virtually any age, but most people who have the disease tend to begin experiencing problems between the ages of 30 and 50 years. Symptoms can include difficulty concentrating, depression, mood swings, muscle rigidity, speech problems, poor coordination, involuntary jerking or writhing ("chorea"), impaired gait, or abnormal eye movements.

Huntington's disease is caused by mutations in the HTT gene, which encodes the huntingtin protein. Ordinarily, this gene has between 10 and 35 repeats of a sequence of three nucleotides, called CAG repeats. People with Huntington's disease can have well over 100 CAG repeats, which promotes the production of an abnormally large huntingtin protein. This protein aggregates into insoluble clumps, causing neuronal cell loss. The number of CAG repeats in the HTT gene is correlated with the risk for depression, with both low and high numbers of repeats – within the overall range of 10 to 35 – increasing the likelihood of having a depressive episode.^[48] At the cellular level, huntingtin has two known functions: It promotes production of BDNF in multiple regions of the brain and it also regulates the direction of transport of material between the cortical and striatal regions. Striatal neurons appear to be dependent on the cortex to help maintain an adequate supply of BDNF. Mutant huntingtin drives both lower transport of BDNF to the striatum as well as lower production of BDNF protein in the striatal cells.^[49] This twofold effect helps to explain why the striatum suffers more intensive damage than other brain regions in people with Huntington's disease.

Data regarding the blood levels of BDNF in Huntington's disease versus healthy people are inconsistent. This may be due to differences in measurement methods or even to the variability in disease characteristics as they are manifested in different people. Multiple studies found no significant difference in blood plasma BDNF levels in people with Huntington's disease compared with healthy people.^{[50] [51]} However, one of these reports found that salivary levels of BDNF were significantly lower in both symptomatic and pre-symptomatic cases of Huntington's disease compared to healthy people, suggesting that salivary levels of BDNF may be useful long-term predictors of the likelihood of developing Huntingon's disease. The authors of the study speculated that BDNF may be released by nerves innervating the salivary glands so that levels in saliva might be more closely correlated with brain levels than are blood concentrations.

BDNF shows promise as a therapeutic target for neurodegenerative disorders

The deficit in BDNF levels observed in neurodegenerative disorders raises the possibility of using BDNF directly as a treatment for these conditions. However, its effectiveness may be limited by its in vivo half-life and rate of transmission across the blood-brain barrier.^[52] Additionally, the range of tissues over which BDNF functions raises the possibility of unwanted side effects.

Gene therapy strategies may succeed in overcoming some of these challenges, but clinical studies are lacking. Vectors for delivering gene therapies to the brain from circulation can also be hampered by difficulty traversing the blood-brain barrier. Several studies have shown neuroprotective effects of direct administration of BDNF into the brain in animal models of Alzheimer's disease, Huntington's disease, and Parkinson's disease, but BDNF administration does not appear to stimulate neurogenesis in these cases. Rather, it is limited to inhibiting further loss of neurons. An aged primate model showed an approximate 60 percent improvement in short term spatial memory following BDNF administration. Brain section analysis showed increased levels of BDNF within the hippocampus, suggesting transport of BDNF from the entorhinal cortex to this region, consistent with normal distribution patterns of BDNF in healthy animals. The entorhinal cortex links the neocortex (the largest and evolutionarily newest structure within the cerebral cortex) with the hippocampus. A significant increase in entorhinal neuronal cell body size (about 20 percent) was also observed in treated animals.^[53]

Another possible approach to increasing brain BDNF levels may be the use of 2,4 dinitrophenol, or DNP, a drug first used medicinally in the United States during the 1930s as a weight-loss drug. DNP belongs to a class of compounds known as mitochondrial uncouplers. It enters mitochondria and essentially "short-circuits" the cell's means of producing energy; however, since the cell reacts to boost energy production, the net effect is to increase energy output.^[54] Treatment of mice with DNP produced more than a threefold increase in BDNF expression in the cerebral cortex. Treated mice also showed statistically significant increases in memory retention.^[55] In another mouse study, DNP treatment substantially improved resistance to a seizure-inducing drug, with a greater than 50 percent reduction in total time experiencing seizures.^[56]

BDNF facilitates regeneration of damaged neurons

Stem cells have the ability to regenerate damaged tissue. This is achieved in part by secretion of various growth factors, including neurotrophins like BDNF. Stem cells can be found in many tissues throughout the body, including the brain. Neural stem cells are responsible for generating new neurons and glial cells, and several studies have tested their abilities in animal models of neurodegenerative diseases.^[57] Researchers have also genetically modified neural stem cells to produce large amounts of BDNF in the hope of intensifying their effects. These modifications improved the stem cells' ability to survive the transplant, increased numbers of neural cell offspring, and enhanced complex neural network formation. Mice that have been genetically altered to have conditions similar to Alzheimer's disease fail to engage in nesting behavior, but mice that received modified cells demonstrated improved nesting behavior and better spatial memory than those receiving unmodified stem cells.^[58]

BDNF exerts variable effects during traumatic brain injury

Traumatic brain injury, or TBI, is the leading cause of death among young people worldwide, and no specialized forms of treatment are available.^{[59] [60] [61]} TBI causes neuronal cell death in two distinct phases. In the first phase, which occurs within minutes of injury, nerve cells and blood vessels are lost due to immediate tissue deformations caused by the physical force of impact. During the second phase, which occurs over the course of several hours, additional cells are lost due to the disruption of normal biochemical processes that maintain brain function. Damage to the blood-brain barrier contributes to this disruption by allowing inflammatory agents to enter the brain. The resulting swelling and rise in intracranial pressure causes additional cell death due to lack of oxygen and nutrients.^[62] BDNF exerts variable effects during TBI, depending on the severity of injury as well as other factors.

A study of 203 people who suffered severe brain injury demonstrated that serum BDNF levels were significantly lower among injured people than those of healthy people. Conversely, cerebrospinal fluid BDNF levels were consistently above normal levels. In healthy people, serum and cerebrospinal fluid BDNF levels tended to be directly related to each other (higher BDNF levels in the central nervous system were associated with higher serum BDNF) ^[63]

Serum and cerebrospinal fluid BDNF levels were strongly associated with death rates, with lower serum levels prevalent among those who died within a week of their injury. In addition, higher average cerebrospinal fluid levels were observed in cases resulting in deaths that occurred from eight days to one year following injury. Platelets release BDNF during blood clotting, so it is feasible that high sustained levels of cerebrospinal fluid BDNF could be due to extensive hemorrhaging, which would be associated with a lower chance of survival.

"Low-signaling" gene variants are mutated forms of the BDNF gene that result in lower motor stimulated secretion of BDNF from neurons. One study found that two BDNF low-signaling variants, including the Val66Met polymorphism, were found to reduce mortality risk among older people with TBI, but increased the risk of death among younger people with TBI. Additional studies have also demonstrated the neuroprotective effects of the Val66Met polymorphism among older people with a TBI.^[64] The age-dependent differences in the risk of death associated with genetic variants of BDNF could be due to the change in BDNF receptors that occurs with age. As a person ages, receptors for proBDNF tend to increase, while those for mature BDNF decrease. This tends to promote apoptosis (the self-destruction of cells) rather than survival. Lower BDNF secretion under these conditions would favor survival of neurons. This could also help explain the higher overall rates of mortality due to TBI among older people.^{[65] [66] [67]}

BDNF and mental health

An abundance of evidence suggests that changes in BDNF levels correlate with mental health status and treatment.

BDNF levels among people with depression may inform treatment decisions

A meta-analysis of 11 studies of people with and without depression, found that serum BDNF levels were consistently lower among adults diagnosed with depression. An additional analysis of eight studies of serum BDNF before and after chronic antidepressant therapy showed a uniform increase in BDNF following treatment.^[68] The consistent difference in BDNF levels in people with depression versus people without depression provides strong evidence for an association between depression and BDNF. However, the author of the analysis pointed out that low BDNF levels have been linked to a variety of medical conditions (including several other psychiatric disorders) and this might limit BDNF's usefulness as a biomarker for any one ailment. Yet, the consistent increase in BDNF levels caused by entirely different classes of antidepressants (selective serotonin reuptake inhibitors, or SSRIs, tricyclics, lithium, and others) seen in this and other studies indicates that blood BDNF levels must be linked to activity in the brain. In fact, evidence exists to support the use of serum BDNF levels to inform treatment decisions. A pilot study of 41 people suffering from major depression found that the failure of serum BDNF levels to increase within two weeks of beginning antidepressant treatment and the absence of improvement on a commonly used depression rating scale could be used to reliably predict future treatment failure.^[69]

As another example, a single study of the possible contribution of diet to depression found that low dietary quality was associated with depressive symptoms, but in this case people tended to have higher BDNF levels.^[70] Another study supporting a strong link between BDNF and depression found that BDNF expression levels were lower among people with major depression.^[71] Treatment with an SSRI antidepressant restored BDNF to normal levels. The authors speculated that peripheral tissues may play a significant role in the origins of this disorder. Experiments involving peripheral infusion of BDNF in rodents have reduced behaviors associated with depression and anxiety.^[68]

Low BDNF levels are common in anxiety disorders

A meta-analysis of eight studies involving nearly 1,200 participants found that low BDNF levels (in both plasma and serum) are associated with anxiety disorders. The analysis also revealed pronounced differences in BDNF plasma levels among specific types of anxiety. Participants with several distinct forms of anxiety were included in the study, including those with generalized anxiety disorder, social anxiety, post-traumatic stress disorder, or PTSD, obsessive compulsive disorder, or OCD, and panic disorder. BDNF plasma levels were much lower in cases of OCD than other forms of anxiety. Based on the combined data, BDNF levels in people with PTSD appeared to be in line with those found in healthy people, though one study actually showed significantly higher BDNF levels among those who had experienced more recent trauma (within one year).^[72]

Two of the included studies found that women with anxiety tended to have significantly lower levels of BDNF than men. Lower BDNF levels have also been described among women with depression, and in this case the association was linked to higher body weight.^[73] Whether this same factor is related to sex differences in BDNF levels among people suffering with anxiety remains unknown. These differences may be important in explaining the significantly larger frequency of Alzheimer's disease seen among women.

High BDNF levels are seen in anorexia nervosa

A paired sibling study of 110 women diagnosed with anorexia nervosa found an average 12 percent increase in average plasma BDNF levels compared to unaffected siblings. This is consistent with BDNF's known role in regulating appetite and also the results of animal studies where direct injection of BDNF into the brain induces starvation. Several genetic variants of BDNF were evaluated, and while the Val66Met variant was associated with women with eating disorders, other variants showed an even stronger association. The authors concluded that the true causative variant was not Val66Met and that the association with this particular mutation was likely coincidental due to the close spacing of many other known genetic variants located along the DNAl. Due to the close physical proximity, or linkage, of these mutations along the DNA strand, the researchers were unable to identify a single root cause of the disorder. This is because sequences of DNA that are closely spaced along the same chromosome tend to be inherited as a group, so any associated disorder can't be uniquely tied to any single mutation.^[74]

BDNF expression is influenced by dietary factors and nutritional status

Many studies have shown a connection between dietary factors, nutritional status, and BDNF levels. High levels of sugar and fat intake have been linked to low levels of BDNF, while omega-3 fatty acid supplementation has been shown to maintain BDNF levels even after brain injury.^[34] Several plant-based compounds have also been found to affect BDNF levels. Lastly, probiotics have also been found to increase serum levels of BDNF in addition to their ability to improve cognitive function.

Omega-3 fatty acids may maintain normal BDNF levels after brain injury

Omega-3 fatty acids are a type of polyunsaturated fatty acid that are required for normal development and maintenance of many tissues. There are three different types of omega-3s that are important to human health: alpha-linolenic acid, or ALA, eicosapentaenoic acid, or EPA, and docosahexaenoic acid, or DHA. ALA is found in plant oils, including those present in walnuts and flaxseeds. EPA and DHA are both found in fish, fish oils, and other marine animal oils. ALA cannot be synthesized metabolically and must be obtained directly through diet. ALA can be converted into EPA or DHA, but this conversion process is very inefficient in humans.^[75] A randomized, double blind placebo controlled study of patients admitted to an intensive care unit found a significant association between fish oil supplementation and serum levels of pro-BDNF. The authors of the study assigned 110 seriously injured patients between the ages of 18 and 82 years to receive either 2,100 milligrams of fish oil or a placebo daily. The participants' serum BDNF levels increased in both the fish oil supplementation and placebo groups over a period of 12 weeks and changes in serum BDNF levels were virtually identical in the two groups. However, increases in pro-BDNF were nearly five times greater in the group that received fish oil than the placebo group.^[76]

Interestingly, over the course of the study, larger increases in BDNF and pro-BDNF levels typically occurred in those with less severe depression, but the degree of this correlation weakened somewhat over time in the intervention group, while it intensified in the placebo group. This result suggests that naturally occurring short term changes in BDNF levels may be a useful biomarker for risk of developing depression following a physical injury or other trauma.

In a rat model of traumatic brain injury, animals that were fed a diet supplemented with fish oil for four weeks before sustaining a brain injury were able to perform equally well in a water maze as uninjured animals.^[77] BDNF levels in the hippocampus of injured rats on the fish oil diet were not statistically different from those of uninjured rats on the standard diet, whereas rats fed the standard diet experienced a large drop in BDNF after injury. These findings suggest that omega-3 fatty acids in the fish oil were able to maintain BDNF at normal levels despite the presence of a traumatic brain injury.

The authors of the study also compared levels of oxidized protein present in hippocampal tissue between four groups (standard diet with and without injury and supplemented diet with and without injury). They found that rats on a regular diet that sustained injury had dramatically higher levels of oxidation than all other groups.

BDNF increases with intake of certain plant-based dietary compounds

Lion's mane (Hericium erinaceus) restores BDNF in stressed animals

Hericium erinaceus, or H. erinaceus, commonly known as lion's mane, yamabushitake, or monkey head mushroom, is a medicinal mushroom that has immune-modulating effects and may have anti-tumor and neuroprotective properties.

A study in mice demonstrated that when the animals were subjected to repeated stress, they experienced a significant drop in hippocampal levels of BDNF. Dietary administration of H. erinaceus extract completely restored BDNF levels. The imposed stress also increased expression of interleukin 6 and tumor necrosis factor alpha – proinflammatory proteins associated with many disorders, including depression and Alzheimer's disease. H. erinaceus treatment significantly reduced expression of both of these proteins, though their concentrations remained higher than those in unstressed mice.^[78]

A clinical study of 77 people evaluated the effects of H. erinaceus supplementation combined with a low calorie diet on symptoms of depression, anxiety, and sleep quality. All participants were overweight, obese, or binge eaters and also had a mood or sleep disorder. Participants who received 1200-milligram doses of H. erinaceus extract for eight weeks experienced greatly reduced symptoms of depression and anxiety and also improved sleep quality. Furthermore, these effects persisted for an additional eight weeks after supplementation was ended. Those who were placed on a low calorie diet without the supplement did not experience improvements in any of these areas. Supplementation also resulted increased serum levels of pro-BDNF at the end of the supplementation period, which was maintained for eight weeks thereafter. Serum BDNF levels were unchanged following the supplementation period but fell over the next eight weeks. Unfortunately, the study did not include a placebo and BDNF levels were not measured in the group not receiving supplements.^[79]

DHF, a type of flavonoid, may increase BDNF production and signaling

Many flavonoids exert beneficial health effects in humans. 7,8-dihydroxyflavone, or DHF, a type of flavonoid found in several plant species, can activate the pro-growth associated receptor for BDNF. DHF can cross the blood-brain barrier, allowing for intravenous administration, but it can also be taken orally.^[80] DHF treatment has achieved positive results in many animal models of disease and injury. Some of these are described here.

Mouse models of radiation therapy show a loss of hippocampal BDNF expression and cognitive impairments consistent with reduced neurogenesis. One week after mice were exposed to radiation, the mice received a five-day course of intravenous DHF and were followed for three months by maze testing. DHF-treated mice showed large improvements in memory, and their neurons developed into fully mature cells at normal rates compared with a 46 percent reduction in neurogenesis seen in untreated, irradiated mice.^[81]

Rats exposed to chronic mild stress for eight weeks exhibited lower than normal rates of weight gain, lower general movement, and lower consumption of sucrose solution (an indicator of poor appetite) than rats not exposed to stress. Treatment with DHF increased sucrose consumption during weekly testing to levels far above those of chronically stressed and unstressed rats. No differences in weight gain were seen among the treated rats. Chronically stressed rats also returned to normal levels of motor activity following treatment, but unstressed rats had no change in activity levels due to DHF treatment. DHF treatment also reduced anxiety among treated rats, as demonstrated by fear avoidance during elevated maze testing. Significant increases in hippocampal BDNF protein concentrations occurred among the treated animals. Major reductions in serum corticosterone levels also manifested after high dose DHF treatment in both stressed and unstressed animals.^[82]

Intravenous DHF treatment reduced motor deficits in a mouse model of Parkinson's disease. Treated mice showed improvements in balance and coordination. Concentrations of alpha-synuclein protein present in neurons of diseased mice decreased to normal levels, and dopaminergic neuron loss in the substantia nigra and striatum decreased. Alpha-synuclein overexpression may be a cause of neuronal cell loss in Parkinson's disease. Dramatically reduced levels of two important antioxidants (glutathione and superoxide dismutase) were also restored to normal levels in DHF-treated mice.^[83]

Oral administration of DHF in a mouse model of Alzheimer's disease prevented extensive synapse loss observed in untreated mice. DHF administration in normal mice also increased synaptic density to above normal levels. Transgenic mice that received DHF showed an ability to learn and remember as well as or perhaps even better than normal mice (either treated or untreated). Amyloid-beta plaques were also significantly reduced in treated mice even though overall concentration of amyloid-beta protein was nearly identical in treated and untreated transgenic mice. The inability to reduce the quantity of amyloid-beta protein present was attributed to the comparatively low oral bioavailability of DHF; another study using intravenous injection did show reduction in amyloid-beta levels.^{[33] [84]}

Resveratrol normalizes BDNF in stressed animals

Data from mouse studies have shown that depressed levels of BDNF in the hippocampal regions of the brain in chronically stressed animals can be normalized by supplementation with resveratrol, a bioactive compound present in red grapes. Surprisingly, this treatment also resulted in improvements in stress-induced irritable bowel syndrome-like symptoms. These effects were achieved in part by differentially controlling BDNF levels in the brain and gut.

• Learn more about resveratrol in our overview article.

Probiotic boosts serum BDNF

Multiple lines of evidence point to a strong connection between BDNF levels and the gut microbiome, the collection of microorganisms that live within the human digestive tract.^{[85] [86]} A 12-week study of 100 people diagnosed with mild cognitive impairment found improvements in attention, working memory, and verbal memory among participants taking a daily 800 milligram dose of lactobacillus plantarum probiotic supplement for 12 weeks compared to those taking a placebo.^[87]

Probiotic supplementation also drove a strong correlation between serum BDNF levels and cognitive performance. This relationship appeared to be reversed in the placebo group, but was not statistically significant in that case. The greatest improvements in cognitive function in people receiving the probiotic were typically seen in cases with the largest increases in serum BDNF levels. Individual changes in BDNF levels varied considerably, with several cases experiencing small declines. These results suggest that the microbial effects on serum BDNF and cognition involve the combination of many factors. Despite these caveats, probiotic supplementation appeared to promote rapid and significant benefits to many participants.

Another study of the effects of l. plantarum in an Alzheimer's mouse model showed substantial reductions in amyloid-beta levels in the brain due to probiotic treatment as well as increased levels of hippocampal BDNF.^[88]

BDNF reduces appetite and alters behavior in animals

Several studies have shown that BDNF signaling reduces appetite in animals. Mice that have been genetically engineered to lack one copy of the BDNF gene develop obesity by early adulthood due to overeating, and males exhibited an increased tendency to engage in aggressive behavior toward other males. These traits are typically associated with dysfunction of serotonin-producing neurons, a characteristic exhibited among the BDNF-deficient mice with age. Treatment with a SSRI successfully reduced aggressive behavior to normal levels and also partially reduced food consumption.^[89]

Serotonin levels also appear to affect BDNF expression in the brain. Researchers found that mice lacking the gene for tryptophan hydroxylase (and therefore unable to produce serotonin) had significantly higher levels of BDNF in the hippocampus and also the prefrontal cortex. A partial reduction in serotonin levels achieved by deletion of the serotonin transporter gene did not affect BDNF levels.^[90]

A mutated form of the BDNF gene known as the minor C allele is more common in people having a higher body mass index, a correlation that is consistent among people from multiple racial backgrounds. This particular mutation affects a part of the genetic transcript that does not go on to become a part of the protein but instead, reduces expression of two other expressed forms of the gene. One author of the study commented that the C allele could contribute to obesity and that treating carriers of this gene variant by boosting BDNF levels may help to reverse this condition.^[91]

Dietary restriction influences BDNF levels

Dietary restriction in the form of daily reduced caloric intake or intermittent fasting without malnutrition have been linked to numerous health benefits including reduced inflammation, improved cognitive function, and longer lifespan. Several studies have found that reduced energy intake also affects BDNF levels.

BDNF and low carbohydrate diet

A study on the effects of a four week low-carbohydrate diet (25 percent protein, 60 percent fat, 15 percent carbohydrates) involving 12 men and women meeting the criteria for metabolic syndrome found an average 20 percent increase in circulating serum BDNF levels among participants. This was accompanied by an average 14 percent reduction in the time required to finish a dynamic test of cognitive speed and flexibility based on their ability to quickly identify a visual stimulus presented in a disorienting context. Low BDNF levels were prevalent among those with a higher percentage of body fat, higher fasting glucose levels and triglyceride levels, and increased insulin resistance. The study also found that participants freely consumed an average of 40 percent fewer calories while on the low-carbohydrate diet.^{[92] [93]}

When the dietary modifications were combined with high intensity interval training on a stationary bike three days a week, participants’ serum BDNF levels increased by 38 percent but no additional improvements were noted in mental acuity testing. Despite this, the participants' own assessment of their cognitive functioning did increase 8 percent with the diet intervention alone and 16 percent with diet and exercise, compared to their assessment at the beginning of the study. The increases in serum BDNF achieved are especially noteworthy given that serum BDNF levels were measured at least 72 hours after completion of exercise. The sustained increases in BDNF seen here may have been due to weight loss, the high intensity interval exercise format, or perhaps some other factor(s). A similar study of 17 healthy overweight and obese men and women found an approximate 50 percent increase in serum BDNF levels following a three-month reduced calorie diet requiring a 25 percent reduction in caloric intake (55 percent carbohydrates, 20 percent proteins, and 25 percent fat).^[94] Given that reduced BDNF often accompanies neurodegenerative disorders and that caloric restriction appears to boost BDNF output, some researchers have hypothesized that a calorie restricted diet may prove an effective therapy for these conditions.

BDNF and type 2 diabetes

Type 2 diabetes is a metabolic disorder characterized by high blood glucose levels due to an acquired resistance to insulin, a hormone produced by the pancreas. BDNF administration reduces blood glucose levels in mouse models of type 2 diabetes. BDNF receptors located on the pancreatic cells that produce insulin promote insulin release by these cells. And secretion of BDNF from skeletal muscle affects glucose tolerance in mice by stimulating release of insulin from the pancreas. Muscle specific deletion of the BDNF gene in mice resulted in physiological characteristics identical to those resulting from pancreas specific deletion of the pro-growth BDNF receptor. Thus it appears that BDNF secreted by muscle is acting in a hormonal fashion to promote insulin release from the pancreas.^[95] Metformin is a drug that helps increase insulin sensitivity in people with type 2 diabetes. Metformin administration in mice raised serum BDNF, promoted BDNF expression in the substantia nigra, and increased BDNF secretion from olfactory cells. These results are consistent with the reported neuroprotective effects of this drug.^[96]

BDNF and leaky gut

BDNF's role as a growth factor can produce counterintuitive effects related to gastrointestinal disorders. Studies in mice have shown that BDNF is important in maintaining the intestinal barrier, which is vital in containing pathogens or other undesirable material in the intestinal cavity. Mice that lacked one copy of the BDNF gene had fewer intestinal microvilli, increased mitochondrial swelling, and higher levels of epithelial cell apoptosis compared to normal mice. BDNF deficient mice also suffered from lower expression of tight junction proteins, which are essential in linking adjacent epithelial cells to prevent uncontrolled transit of material across the gut barrier.^[97]

Celiac disease primarily affects the small intestine and is characterized by autoimmune destruction of intestinal microvilli triggered by gluten, a protein found in wheat and other grains. Serum BDNF concentrations are significantly higher among children with celiac disease at the time of diagnosis or after having been on a gluten-free diet for at least one year, compared to healthy children.^[98] This may be the result of a compensatory mechanism to improve epithelial function in response to inflammation.

While the anti-apoptotic properties of BDNF are apparently beneficial in maintaining intestinal barrier integrity, they may also lead to a worsening of symptoms in cases of irritable bowel syndrome due to up-regulation of BDNF and subsequent nerve growth. Higher levels of BDNF were also associated with increased intestinal sensitivity in these cases.^[99]

Data inconsistencies complicate assessment of relationships between BDNF and aging

Plasma BDNF measurements from approximately 500 middle aged and elderly people showed a direct correlation between steady-state high levels of plasma BDNF and several known risk factors for cardiovascular disease and metabolic syndrome, independent of age.^[100] However, data on levels of circulating BDNF are frequently inconsistent. One study of a group of people ranging in age from 20 to 60 years found that BDNF plasma levels decrease significantly with age.^[101] In another study involving 259 people ranging from 18 to 70 years of age, serum levels showed a small but consistent increase with age.^[23] Another report stated that serum levels decreased among older adults ranging from 55 to 80 years old. ^[102]

Differences between reported concentrations in plasma and serum may be due to how these different blood products are prepared.^[103] Anti-clotting agents are commonly added to plasma preparations and these additives can draw water out of cells prior to their removal to yield plasma. This effect can dilute measured concentrations of BDNF as well as any other freely circulating compounds that are present.^[104] Also, since platelets release their internal stores of BDNF during the clotting process, they may release BDNF at some point during the extraction or fractionation of blood into its components, resulting in inflated measurements of BDNF concentrations. Clotting duration and temperature have both been shown to affect BDNF serum concentrations.^[105] Furthermore, platelet counts tend to decline with age and there may be other age-related changes in platelet function that could affect comparisons of BDNF levels between different studies, depending on the ages of people involved.^[106]

Conclusion

BDNF is a finely regulated and extremely versatile protein that is crucial to brain and nerve growth and function, and perhaps to fundamental elements of human metabolism, as well. Its presence in multiple capillary beds and systemic circulation demonstrates nature's propensity to adapt useful molecules to a variety of different contexts. Clinically, the use of BDNF as a marker for disease may prove to be of value in making more accurate diagnoses and treatments.

Many important aspects of BDNF's function have been elucidated. Forms of activity that require greater coordination between mind and movement produce larger increases in circulating levels of BDNF and are associated with greater changes in brain anatomy. Aerobic exercise is generally associated with relatively brief increases in BDNF, and heat therapy studies suggest these changes may be driven by increases in body temperature. Mental training results in prolonged increases in cognitive performance and substantial (and likely sustained) increases in BDNF. Alterations in BDNF levels (either in blood or saliva) seem to be present in multiple neurodegenerative diseases but these changes are likely symptomatic rather than causative in these cases. Lower peripheral levels of BDNF are seen in depression and some forms of anxiety, and restoration of BDNF is a likely corollary to successful antidepressant treatment.

Some small molecules (dinitrophenol and dihydroxyflavone) are effective at increasing brain BDNF levels or activating BDNF pathways. Stem cell transplants are another promising approach to restoring lost BDNF function. Dietary means of boosting BDNF include consumption of foods high in omega 3 fatty acids (particularly the animal based DHA and EPA varieties), lion’s mane mushroom, and lactobacillus plantarum probiotic supplementation. Reduced caloric intake also appears to dramatically increase circulating BDNF. Resveratrol may be able to selectively increase brain levels of BDNF without increasing the risk of bowel irritability. Lastly, BDNF appears to play a fundamental role in glucose metabolism by acting hormonally to invoke insulin release by the pancreas.

Despite the considerable progress that has been made in understanding the many roles of BDNF, research on BDNF faces many complicating factors that commonly take the form of differences in methodology. The choice of whether to measure plasma or serum levels, the method of preparation of these components, the selection of participants in studies, the timing of measurements relative to the activities being studied, and the means of detecting differences in cognitive performance are all highly variable. Furthermore, the motivation for particular experimental designs is often not even mentioned much less justified. Lastly, the near universal inability to resolve different forms of BDNF protein during experiments has likely resulted in lost opportunities to reveal how BDNF is used under various conditions.