BDNF

BDNF is not a hormone, but a protein and neurotrophin. It acts as a growth factor (neurotrophic factor) in the brain. Learning requires neurotrophic factors.
Stress decreases BDNF in the hippocampus.
In ADHD, BDNF is decreased in the hippocampus, striatum, and PFC, contributing to learning problems, as well as developmental problems.
Treatment with stimulants restores normal levels of BDNF and other neurotrophic factors, so that the ability to learn (not only of school or lecture material, but also in terms of meaningful changes in one’s own behavior as a result of an experience) is improved again. Endurance exercise also increases BDNF. Taurine increases BDNF in the striatum.

• 1. Control areas of BDNF
  • 1.1. Behavioral functions
  • 1.2. Disturbance patterns
• 2. BDNF receptors
  • 2.1. TrkB receptor (TrkB)
  • 2.2. Truncated TrkB receptor (TrkB-T)
  • 2.3. P75 receptor
• 3. BDNF change
  • 3.1. Stress and BDNF
    • 3.1.1. Stress reduces BDNF in the hippocampus
    • 3.1.2. Chronic stress increases BDNF in the nucleus accumbens
    • 3.1.3. Chronic / Acute Stress and Gender
    • 3.1.4. DAT deficiency
  • 3.2. Other changes from BDNF
• 4. Gene variants of BDNF
• 5. BDNF altered in ADHD?
• 6. Measurement of BDNF and other neurotrophins

1. Control areas of BDNF¶

1.1. Behavioral functions¶

BDNF, in cooperation with serotonin, controls many behavioral functions.

BDNF influenced:¹

• Brain development
• Activity-dependent synaptic plasticity²
• The long-term potentiation (LTP) underlying learning and memory³
  • A deactivation of the BDNF gene or the BDNF receptor in mice
    • Restricts their learning behavior⁴ where the required learning time for spatial learning was doubled⁵
    • Impairs long-term potentiation, which is essential for long-term memory⁴
    • Prevents the improvement of learning through endurance training⁶
    • These effects can be remedied by external supply of BDNF⁷
  • GABA inhibits long-term potentiation⁸
• Processes of neuronal plasticity
  • Direct
    • Cellular processes of neuronal plasticity
  • Indirect
    • Influence on other plasticity modifying processes
  • Short term
    • Potentiation of synaptic excitatory transmission by the depolarization of postsynaptic neurons
    • Facilitates the release of presynaptic neurotransmitters
  • Long-term
    • Persistent alteration of cell excitability and synaptic plasticity⁷

BDNF promotes hippocampal function, particularly the survival of nascent granule cells throughout adult life.⁹ BDNF modulates hippocampal plasticity and hippocampus-dependent memory.¹⁰

The transcription factor Cyclic AMP response element-binding protein (CREB1) is an important regulator of BDNF-induced gene expression. BDNF stimulates phosphorylation and activation of CREB in neurons.¹¹

BDNF influences glutamate metabolism in the brain. In about 30% of neurons, glutamatergic synaptic transmission is increased by 100 ng / ml each¹²

• BDNF by 143
• Neurotrophin-4/5 by 170

cAMP rapidly increases neurotrophin-3 (= BNDF-/NT-3 = tropomyosin receptor kinase B (TrkB) = tyrosine receptor kinase B) and causes BDNF-dependent long-term potentiation in the hippocampus.¹³

1.2. Disturbance patterns¶

BDNF is involved in various disturbance patterns, e.g..

• Depression¹⁴
  • BDNF decreases in the hippocampus
  • BDNF increased in the nucleus accumbens
• ADHD
  • BDNF decreased in the hippocampus, PFC, and striatum
• Schizophrenia
• Obsessive Compulsive Disorder
• Alzheimer¹⁴
  • BDNF decreased in parietal cortex,¹⁵ hippocampus and temporal cortex¹⁶ and entorhinal cortex¹⁷
  • NGF (nerve growth factor) was higher in dentate gyrus¹⁷
  • NT-3 was decreased in motor cortex¹⁷
• Dementia
• Huntington’s chorea
• Eating disorders
  • Anorexia nervosa
  • Bulimia nervosa
• Rett syndrome
• Epilepsy

2. BDNF receptors¶

BDNF receptors are predominantly located in memory-relevant brain regions such as the PFC and hippocampus.²

2.1. TrkB receptor (TrkB)¶

The TrkB receptor has a high affinity for BDNF.²

2.2. Truncated TrkB receptor (TrkB-T)¶

2.3. P75 receptor¶

The p75 receptor has low affinity for BDNF.²

3. BDNF change¶

3.1. Stress and BDNF¶

3.1.1. Stress reduces BDNF in the hippocampus¶

Stress decreases BDNF¹ and BDNF expression in the hippocampus of humans and rats. Chronic administration of antidepressants prevents this.¹⁸

BDNF was significantly reduced by singular¹⁹ such as repeated immobilization in the hippocampus and dentate gyrus, but not neurotrophin-4 or tyrosine receptor kinases (trkB or C).
In contrast, NT-3 was increased in hippocampus as well as dentate gyrus, but only during repeated immobilization (chronic stress), which was probably primarily mediated by corticosterone.
The reduction in BDNF occurred (only in the dentate gyrus) even in the absence of a corticosterone response (in rats that had had their adrenal cortex removed and thus could not secrete corticosterone).²⁰

The decrease of BDNF by stress in the hippocampus and the increase of BDFN by stress in the paraventricular hypothalamus might decrease with age, whereas the changes of NGF (nerve growth factor) and neurotrophin-3 (NT-3) do not seem to change with age.²¹

One study found that BDNF was decreased by chronic glucocorticoid administration in the PFC but not in the dorsal hippocampus.²²

3.1.2. Chronic stress increases BDNF in the nucleus accumbens¶

Chronic stress increases BDNF expression in the nucleus accumbens, which in turn correlates with depression-like behaviors, such as early passivity²³ or social phobia,²⁴ but only in stress-prone, not stress-resistant, rats.²⁵

In people with depression, BDNF is also elevated in the nucleus accumbens.²⁵

Stress also has significant effects on BDNF in the amygdala and PFC.⁹

Blocking ocular activity dramatically reduces BDNF in the visual cortex of the affected eye.¹⁴

3.1.3. Chronic / Acute Stress and Gender¶

In female rats, chronic stress decreased BDNF in prelimbic areas of the PFC, whereas acute stress increased BDNF in the dentate gyrus. In males, levels remained unchanged in both cases.²⁶

3.1.4. DAT deficiency¶

Rodents that do not form dopamine transporters show massive alterations of BDNF in PFC and striatum:

• In PFC
  • Decreased BDNF gene expression²⁷
  • Total BDNF and BDNF exon IV mRNA levels reduced²⁸
  • MRNA levels of BDNF exon VI unchanged²⁸
  • Decreased mBDNF levels and decreased trkB activation²⁸
  • Decreased activation of αCaMKII in the PFC²⁸
• In the dorsolateral striatum
  • MBDNF level in the homogenate increased²⁸
  • MBDNF level in the cytosol increased²⁸
  • MBDNF levels in the postsynaptic density reduced.²⁸
  • TrkB expression in the dorsolateral striatum postsynaptically reduced²⁸
    • TrkB is a high-affinity BNDNF receptor

3.2. Other changes from BDNF¶

BDNF is increased by¹

• Learning processes
• Enriched Environment / complex environments²⁹
  • Varied, stimulating environments increase BDNF in rats
• Antidepressants
• Physical activity
  • Endurance exercise significantly increases BDNF levels in the hippocampus and cerebral cortex.³⁰³¹³²
  • Chronic estrogen deficiency of 7 weeks (but not acute estrogen deficiency of 3 weeks) reduces the increase in BDNF by endurance exercise in mice.³³
• Dietary restriction increases BDNF in the dentate gyrus³⁴
• Light and the circadian daylight rhythm alter BDNF and neurotrophin-3.
  • In darkness, BDNF is high in the hippocampus (minimum 3.5 in light, maximum 17 in darkness)³⁵³⁶ in the cerebellum ³⁷ and in the nucleus suprachiasmaticus (SCN). In the SCN, BDNF levels were highest in darkness and dawn. In constant darkness, BDNF rhythm was evident in the SCN but not in the hippocampus.³⁸
  • Light increases, darkness decreases BDNF in the visual cortex,³⁹ the retina and superior colliculi³⁷ as well as in the cerebral cortex. At least in the cerebral cortex, this rhythm is modulated by norepinephrine.⁴⁰
• Sensory stimulation of tactile hair increases BDNF in the primary sensory cortex (barrel cortex).⁴¹⁴²
• Taurine significantly increased BDNF levels in the striatum in both SHR and WKY rats (whether low or high dose).⁴³

4. Gene variants of BDNF¶

BDNF Val/Met correlated in humans, compared with BDNF Val/Val, with

• A poorer episodic memory
• Abnormal hippocampal activation on fMRI
• Less N-acetyl-aspartate (NAA) in the hippocampus.¹⁰

5. BDNF altered in ADHD?¶

The study situation on BDNF in ADHD is very contradictory:

BDNF decreased in ADHD³⁰
BDNF, NT-3, NGF and FGF-2 (fibroblast growth factor-2) unchanged in ADHD (blood serum).⁴⁴
BDNF increased in ADHD (blood serum), as well as NGF, GDNF, galanin.⁴⁵

Learning problems are typical in ADHD. Decreased BDNF in the hippocampus causes learning problems. In chronic stress, on the other hand, BDNF appears to be increased in the nucleus accumbens in stress-sensitive rats (see above).

In conclusion, genetic circumstances, timing of MPH administration, age, sex, and brain region seem to matter for the effect MPH triggers on BDNF.

Blood serum levels of VEGF (vascular endothelial growth factor) were significantly decreased in ADHD in one study, and those of GDNF (glial-derived neurotrophic factor) were significantly increased. However, their blood levels did not correlate with ADHD symptom severity.⁴⁴ Another study found no altered blood serum levels of VEGF in children with ADHD.⁵⁷

In rats, MPH showed a significant increase in GDNF in the striatum and nucleus accumbens in a sex-independent manner.⁴⁹

6. Measurement of BDNF and other neurotrophins¶

BDNF can freely cross the blood-brain barrier.⁵⁸⁵⁹⁶⁰ BDNF blood serum level is reported to correlate with hippocampal size.⁶¹