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
- 2. BDNF receptors
- 3. BDNF change
- 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
- 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
- Direct
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
- 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
- In the dorsolateral striatum
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
- 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).
Studies on the effect of MPH on BDNF
BDNF appears to be decreased in the morning and evening in ADHD-HI and ADHD-C, and only in the evening in ADHD-I. MPH probably does not alter BDNF in ADHD-HI and ADHD-C, whereas MPH decreases BDNF in ADHD-I.46 An increase or decrease of BDNF by MPH could be age-dependent.4748
MPH decreased the previously elevated blood serum levels of BDNF, NGF, GDNF, and galanin.45
MPH increased BDNF in the dorsal striatum only in male rats as well as in the nucleus accumbens in a sex-independent manner.4950
In the PFC, MPH decreased BDNF, whereas atomoxetine increased it.50 One study found that rats that received MPH as young animals had higher BDNF levels in the PFC as they aged.51
Another study found that MPH caused a significant 42% decrease BDNF in the striatum in female rats and a significant 50.4% increase BDNF in the striatum in male rats. BDNF in the nucleus accumbens was unchanged here.52
In the dentate gyrus, only MPH, but not atomoxetine, appears to increase synaptic plasticity in rats, and a very high dose of 10 mg/kg body weight was used here. This is 5 to 15 times a usual drug dose.53
One study found no relevant effect of MPH on BDNF receptor expression in rats.54 Another study found that chronic MPH administration (1 to 3 mg/kg) increased BDNF mRNA expression in muscleblind-like 2 (Mbnl2) knockout mice.55 Another study found increased BDNF expression in the ventral tegmentum of adult rats after combined MPH/fluoxetine administration in youth.56
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
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