Brain‐derived neurotrophic factor (BDNF) is the most‐abundant neurotrophin in the brain. In mammals, it is synthesized as a precursor called proBDNF, which is proteolytically cleaved to generate mature BDNF. The BDNF gene is located on chromosome 11p13, and a functional single nucleotide polymorphism (SNP) of this gene has been shown to produce a valine (Val)‐to‐methionine (Met) substitution in the proBDNF protein at codon 66 (Val66Met). Several papers suggest that this SNP is related to decreased hippocampal volume and (...) hippocampus‐mediated memory performance in humans. Recently, Chen et al.1 generated a variant BDNF mouse (BDNFMet/Met) that reproduces the phenotypic hallmarks in humans with a variant Met allele. In the behavioral analysis, BDNFMet/Met mice show increased anxiety‐related behaviors. This mini‐review examines the impact of Met substitution of proBDNF on anxiety‐related behaviors. BioEssays 29: 116–119, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Child maltreatment not only leads to epigenetic changes, but also increases the risk of related behavioral deficits and mental disorders. These issues presumably are most closely associated with epigenetic changes in the brain, but epigenetic changes in peripheral tissues like blood are often examined instead, due to their accessibility. As such, the reliability of using the peripheral epigenome as a proxy for that of the brain is imperative. Previously, our lab has found aberrant methylation at the Brain-derived neurotrophic factor gene (...) in the prefrontal cortex of rats following aversive caregiving. The current study examined whether aversive caregiving alters Bdnf DNA methylation in the blood compared to the prefrontal cortex. It was revealed that DNA methylation associated with adversity increased in both tissues, but this methylation was not correlated between tissues. These findings indicate that group trends in Bdnf methylation between blood and the brain are comparable, but variation exists among individual subjects. (shrink)

Thirty-eight individuals (mean age: 34.8 years old) participating in a 3-month yoga and meditation retreat were assessed before and after the intervention for psychometric measures, brain derived neurotrophic factor (BDNF), circadian salivary cortisol levels, and pro- and anti-inflammatory cytokines. Participation in the retreat was found to be associated with decreases in self-reported anxiety and depression as well as increases in mindfulness. As hypothesized, increases in the plasma levels of BDNF and increases in the magnitude of the cortisol awakening (...) response (CAR) were also observed. The normalized change in BDNF levels was inversely correlated with BSI-18 anxiety scores at both the pre-retreat (r = 0.40, p < 0.05) and post-retreat (r = 0.52, p < 0.005) such that those with greater anxiety scores tended to exhibit smaller pre- to post-retreat increases in plasma BDNF levels. In line with a hypothesized decrease in inflammatory processes resulting from the yoga and meditation practices, we found that the plasma level of the anti-inflammatory cytokine Interleukin-10 was increased and the pro-inflammatory cytokine Interleukin-12 was reduced after the retreat. Contrary to our initial hypotheses, plasma levels of other pro-inflammatory cytokines, including Interferon Gamma (IFN-γ), Tumor Necrosis Factor (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and Interleukin-8 (IL-8) were increased after the retreat. Given evidence from previous studies of the positive effects of meditative practices on mental fitness, autonomic homeostasis and inflammatory status, we hypothesize that these findings are related to the meditative practices throughout the retreat; however, some of the observed changes may also be related to other aspects of the retreat such as physical exercise-related components of the yoga practice and diet. We hypothesize that the patterns of change observed here reflect mind-body integration and well-being. The increased BDNF levels observed is a potential mediator between meditative practices and brain health, the increased CAR is likely a reflection of increased dynamic physiological arousal, and the relationship of the dual enhancement of pro- and anti-inflammatory cytokine changes to healthy immunologic functioning is discussed. (shrink)

Neurotrophins (NTs) are {?AUTHOR} a family of structurally related, secreted proteins that regulate the survival, differentiation and maintenance of function of different populations of peripheral and central neurons.1,2 Among these, BDNF (brain‐derived neurotrophic factor) has drawn considerable interest because both its synthesis and secretion are increased by physiological levels of activity, indicating a unique role of this neurotrophin in coupling neuronal activity to structural and functional properties of neuronal circuits. In addition to its classical neurotrophic effects, which are evident (...) within hours or days and which usually result from changes in cellular gene expression, BDNF exerts acute effects on synaptic transmission and is involved in the induction of long‐term potentiation. Many of these rapid effects of BDNF are mediated by its modulation of ion channel properties following TrkB‐mediated activation of intracellular second messenger cascades and protein phosphorylation. However, recent reports have shown that BDNF not only acts as a modulator of ion channels, but can also directly and rapidly gate a Na+ channel, thereby assigning BDNF the properties of a classical excitatory transmitter. Thus, BDNF, in addition its role as a potent neuromodulator, emerges as an excitatory transmitter‐like substance which acutely controls resting membrane potential, neuronal excitability, synaptic transmission and participates in the induction of synaptic plasticity. BioEssays 26:1185–1194, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Insights into the role of sleep in the molecular mechanisms of memory consolidation may come from studies of activity-dependent synaptic plasticity, such as long-term potentiation (LTP). This commentary posits a specific contribution of sleep to LTP stabilization, in which mRNA transported to dendrites during wakefulness is translated during sleep. Brain-derived neurotrophic factor may drive the translation of newly transported and resident mRNA.

A decrease in cortical excitability tends to be easily followed by an increase induced by external stimuli via a mechanism aimed at restoring it; this phenomenon is called “homeostatic plasticity.” In recent years, although intervention methods aimed at promoting motor learning using this phenomenon have been studied, an optimal intervention method has not been established. In the present study, we examined whether subsequent motor learning can be promoted further by a repetitive passive movement, which reduces the excitability of the primary (...) motor cortex before motor learning tasks. We also examined the relationship between motor learning and the brain-derived neurotrophic factor. Forty healthy subjects participated. Subjects were divided into two groups of 20 individuals each. The first group was assigned to perform the motor learning task after an intervention consisting in the passive adduction–abduction movement of the right index finger at 5 Hz for 10 min, while the second group was assigned to perform the task without the passive movement. The motor learning task consisted in the visual tracking of the right index finger. The results showed that the corticospinal excitability was transiently reduced after the passive movement in the RPM condition, whereas it was increased to the level detected in the control condition after the motor learning task. Furthermore, the motor learning ability was decreased immediately after the passive movement; however, the motor performance finally improved to the level observed in the control condition. In individuals carrying the Val/Val genotype, higher motor learning was also found to be related to the more remarkable changes in corticospinal excitability caused by the RPM condition. This study revealed that the implementation of a passive movement before a motor learning tasks did not affect M1 excitatory changes and motor learning efficiency; in contrast, in subjects carrying the Val/Val polymorphism, the more significant excitatory changes in the M1 induced by the passive movement and motor learning task led to the improvement of motor learning efficiency. Our results also suggest that homeostatic plasticity occurring in the M1 is involved in this improvement. (shrink)

A recurrent theme in eukaryotic genome regulation stipulates that the properties of DNA are strongly influenced by the nucleoprotein complex into which it is assembled. Methylation of cytosine residues in vertebrate genomes has been implicated in influencing the assembly of locally repressive chromatin architecture. Current models suggest that covalent modification of DNA results in heritable, long‐term transcriptional silencing. In October of 2003, two manuscripts1,2 were published that challenge important aspects of this model, suggesting that modulation of both DNA methylation itself, (...) as well as the machinery implicated in its interpretation, are involved in acute gene regulation. BioEssays 26:217–220, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Background: The present study compared the effects of a traditional resistance training and resistance training combined with cognitive task on body composition, physical performance, cognitive function, and plasma brain-derived neurotrophic factor levels in older adults. Methods: Thirty community-dwelling older adults were randomized into TRT and RT+CT. Exercise groups performed a similar resistance training program, twice a week over 16 weeks. Cognitive Training involved performing verbal fluency simultaneously with RT. Exercise sessions were performed 2-3 sets, 8-15 repetitions at 60-70% of 1-repetition (...) maximum. Body composition, physical function, cognitive performance, and BDNF levels were assessed before and after intervention period. Results: The physical performance was similarly improved in response to both TRT and RT+CT. However, exclusive improvements on cognitive function and BDNF levels were observed only after RT+CT. Conclusion: The RT program associated with a cognitive task, improved physical and cognitive performance in healthy older adults. (shrink)

Recent studies have found abnormal levels of brain-derived neurotrophic factor in a variety of central nervous system diseases. This suggests that BDNF may be involved in the pathogenesis of these diseases. Moreover, regulating BDNF signaling may represent a potential treatment for such diseases. With reference to recent research papers in related fields, this article reviews the production and regulation of BDNF in CNS and the role of BDNF signaling disorders in these diseases. A brief introduction of (...) the clinical application status of BDNF is also provided. (shrink)

Activating the ERK pathway (extracellular signal‐regulated kinase pathway) has proven beneficial in several models of Huntington's disease (HD), and drugs that are protective in HD models have recently been found to activate ERK. Thus, the ERK cascade may be a potential target for therapeutic intervention in this currently untreatable disorder. HD is caused by an expanded polyglutamine repeat in the huntingtin (Htt) protein that actuates a diverse set of pathogenic mechanisms. In response to mutant Htt, ERK is activated and directs (...) a protective transcriptional response and inhibits caspase activation. Paradoxically, Htt also interferes with several signaling events of the ERK pathway. Mutant Htt compromises the ERK‐dependent transcriptional response to corticostriatal BDNF signaling. Mutant Htt also hinders glutamate uptake from the synaptic cleft by down‐regulating ERK‐dependent expression of glutamate transporters, leaving cells vulnerable to excitotoxicity. Some of this cellular complexity can be capitalized on to achieve selective activation of ERK, which can be protective. (shrink)

The main aim of our study was to determinate whether a repeated bout (RB) (vs. first bout [FB]) of sprint interval cycling exercise (SIE) is sufficient to mitigate SIE-induced psychological and physiological biomarker kinetics within 48 h after the exercise. Ten physically active men (age, 22.6 ± 5.2 years; VO2max, 44.3 ± 5.7 ml/kg/min) performed the FB of sprint interval cycling exercise (12 repeats of 5 s each) on one day and the RB 2 weeks later. The following parameters were (...) measured: motor performance (voluntary, electrically induced and isokinetic skeletal muscle contraction torque, and central activation ratio [CAR]); stress markers (BDNF, cortisol, norepinephrine, and epinephrine); inflammatory markers (IL-6, IL-10, and TNF-); metabolic markers (glucose and lactate); muscle and rectal temperature; cycling power output; and psychological perceptions. The average cycling power output and neuromuscular fatigue after exercise did not differ between the FB and RB. There were significant decreases in cortisol and BDNF concentration at 12 h (P < 0.05) and 24 h (P < 0.001) after the FB, respectively. The decrease in cortisol concentration observed 12 h after exercise was significantly greater after the RB (P < 0.05) than after the FB. The immune-metabolic response to the RB (vs. FB) SIE was suppressed and accompanied by lower psychological exertion. Most of the changes in psychological and physiological biomarkers in the FB and RB were closely related to the response kinetics of changes in BDNF concentration. (shrink)

GraphicalExercise, neurotransmitters, growth factors, myokines, and potential effects on the brain.As human life expectancy increases, cognitive decline and memory impairment threaten independence and quality of life. Therefore, finding prevention and treatment strategies for memory impairment is an important health concern. Moreover, a better understanding of the mechanisms involved underlying memory preservation will enable the development of appropriate pharmaceuticals drugs for those who are activity limited. Exercise training as a non-pharmacological tool, has been known to increase the mean lifespan by maintaining (...) general body health and improving the cardiovascular and nervous systems function. Among different exercise training protocols, aerobic exercise has been reported to prevent the progression of memory decline, provided adequate exertion level, duration, and frequency. Mechanisms underlying exercise training effects on memory performance have not been understood yet. Convergent evidence suggest several direct and indirect mechanisms at molecular and supramolecular levels. The supramolecular level includes improvement in blood circulation, synaptic plasticity and neurogenesis which are under controls of complex molecular signaling of neurotransmitters, neurotrophic factors, exerkines, and epigenetics factors. Among these various factors, irisin/BDNF signaling seems to be one of the important mediators of crosstalk between contracted skeletal muscles and the brain during exercise training. This review provides an affordable and effective method to improve cognitive function in old ages, particularly those who are most vulnerable to neurodegenerative disorders. (shrink)

Transcranial magnetic stimulation studies have demonstrated increased cortical facilitation and reduced inhibition following aerobic exercise, even when examining motor regions separate to the exercised muscle group. These changes in brain physiology following exercise may create favorable conditions for adaptive plasticity and motor learning. One candidate mechanism behind these benefits is the increase in brain-derived neurotropic factor observed following exercise, which can be quantified from a venous blood draw. The aim of this study was to investigate changes in motor cortex excitability (...) and inhibition of the upper limb, and circulating BDNF, following high-intensity interval training on a stationary bicycle. Nineteen sedentary adults participated in a randomized crossover design study involving a single bout of high-intensity interval cycling for 20 min or seated rest. Venous blood samples were collected, and transcranial magnetic stimulation was used to stimulate the extensor carpi radialis, where motor evoked potentials were recorded pre- and post-condition. Following exercise, there was a significant increase in corticospinal excitability measured at 120% of resting motor threshold and a reduction in short-interval cortical inhibition. There was a non-significant 23.6% increase in BDNF levels. Collectively, these results reflect a net reduction in gamma aminobutyric acid ergic synaptic transmission and increased glutamatergic facilitation, resulting in increased corticospinal excitability. This study supports the notion that acute high-intensity exercise provides a potent stimulus for inducing cortical neuroplasticity, which may support enhanced motor learning. (shrink)

Major depressive disorder (MDD) is a severe mental illness that affects 5 to 20% of the general population. Current antidepressant drugs exerts only a partial clinical efficacy because approximately 30% of depressed patients failed to respond to these drugs and antidepressants produce remission only in 30% of patients. This can be explained by the fact that the complex pathophysiology of depression has not been completely elucidated, and treatments have been mainly developed following the “monoaminergic hypothesis” of depression without considering the (...) key role of other factors involved in the pathogenesis of MDD, such as the role of chronic stress and neuroinflammation. Chronic stress acts as a risk factor for the development of MDD through the impairment of neurotrophins signaling such as brain-derived neurotrophic factor (BDNF) and transforming-growth-factor-β1 (TGF-β1). Stress-induced depressive pathology contributes to altered BDNF level and function in MDD patients and, thereby, an impairment of neuroplasticity at the regional and circuit level. Recent studies demonstrate that aerobic exercise strongly increases BDNF production and it may contribute as a non-pharmacological strategy to improve the treatment of cognitive and affective symptoms in MDD. Here we will provide a general overview on the possible synergism between physical activity and antidepressants in MDD. Physical activity can synergize with antidepressant treatment by rescuing neurotrophin signaling in MDD patients, promoting neuronal health and recovery of function in MDD-related circuits, finally enhancing pharmacotherapeutic response. This synergism might be particularly relevant in elderly patients with late-life depression, a clinical subgroup with an increased risk to develop dementia. (shrink)

Several recent research findings have implicated brain-derived neurotrophic factor (BDNF) as a mediator of neuronal plasticity. The BDNF gene is under extensive epigenetic regulation, which modulates how much or how little environmental experiences become encoded within neurons and neural circuits. Future scientific progress within the postgenomic paradigm requires elucidation of the functional trajectory in neogenetic and environment interactions.

Identification of the molecular mechanisms underlying axonal branching in vivo has begun in several neuronal systems, notably the projections formed by dorsal root ganglion (DRG) neurons or retinal ganglion cells (RGC). cGMP signalling is essential for sensory axon bifurcation at the spinal cord, whereas brain‐derived neurotrophic factor (BDNF) and ephrinA signalling establish position‐dependent branching of RGC axons. In the latter system, the degradation of specific signalling components, via the ubiquitin‐proteasome system, may provide an additional mechanism involved in axon branching (...) of RGC. The process of arborisation is essential for neurons to innervate multiple targets and to build topographic maps. The various forms of branching found in different types of neurons are regulated by distinct signalling pathways activated by multiple extracellular cues in addition to axonal guidance factors. These signalling cascades, together with transcriptional programs, most likely interact and trigger the polymerisation or depolymerisation of the actin and tubulin cytoskeleton to regulate branching. (shrink)