Exercise-induced Brain-derived Neurotrophic Factor Research Articles

Exercise-induced BDNF promotes PPARδ-dependent reprogramming of lipid metabolism in skeletal muscle during exercise recovery.

Post-exercise recovery is essential to resolve metabolic perturbations and promote long-term cellular remodeling in response to exercise. Here, we report that muscle-generated brain-derived neurotrophic factor (BDNF) elicits post-exercise recovery and metabolic reprogramming in skeletal muscle. BDNF increased the post-exercise expression of the gene encoding PPARδ (peroxisome proliferator-activated receptor δ), a transcription factor that is a master regulator of lipid metabolism. After exercise, mice with muscle-specific Bdnf knockout (MBKO) exhibited impairments in PPARδ-regulated metabolic gene expression, decreased intramuscular lipid content, reduced β-oxidation, and dysregulated mitochondrial dynamics. Moreover, MBKO mice required a longer period to recover from a bout of exercise and did not show increases in exercise-induced endurance capacity. Feeding naïve mice with the bioavailable BDNF mimetic 7,8-dihydroxyflavone resulted in effects that mimicked exercise-induced adaptations, including improved exercise capacity. Together, our findings reveal that BDNF is an essential myokine for exercise-induced metabolic recovery and remodeling in skeletal muscle.

Mechanisms of the Beneficial Effects of Exercise on Brain-Derived Neurotrophic Factor Expression in Alzheimer's Disease.

Brain-derived neurotrophic factor (BDNF) is a key molecule in promoting neurogenesis, dendritic and synaptic health, neuronal survival, plasticity, and excitability, all of which are disrupted in neurological and cognitive disorders such as Alzheimer's disease (AD). Extracellular aggregates of amyloid-β (Aβ) in the form of plaques and intracellular aggregates of hyperphosphorylated tau protein have been identified as major pathological insults in the AD brain, along with immune dysfunction, oxidative stress, and other toxic stressors. Although aggregated Aβ and tau lead to decreased brain BDNF expression, early losses in BDNF prior to plaque and tangle formation may be due to other insults such as oxidative stress and contribute to early synaptic dysfunction. Physical exercise, on the other hand, protects synaptic and neuronal structure and function, with increased BDNF as a major mediator of exercise-induced enhancements in cognitive function. Here, we review recent literature on the mechanisms behind exercise-induced BDNF upregulation and its effects on improving learning and memory and on Alzheimer's disease pathology. Exercise releases into the circulation a host of hormones and factors from a variety of peripheral tissues. Mechanisms of BDNF induction discussed here are osteocalcin, FNDC5/irisin, and lactate. The fundamental mechanisms of how exercise impacts BDNF and cognition are not yet fully understood but are a prerequisite to developing new biomarkers and therapies to delay or prevent cognitive decline.

Exploring the Preliminary Effects of Resistance Training on Total Brain-Derived Neurotrophic Factor (BDNF) Levels in Elderly Individuals: A Pilot Study

Background: Studies have shown that exercise modulates brain-derived neurotrophic factor (BDNF) levels, and resistance training, in particular, has received increasing attention for its potential to enhance BDNF production. Most studies investigating exercise-induced BDNF changes have focused on free or mature BDNF, while the measurement of total BDNF, encompassing both proBDNF and mature BDNF, may provide a more comprehensive understanding of BDNF regulation. This pilot study aimed to explore the preliminary effects of resistance training on total BDNF levels in elderly individuals participating in a resistance training program.
 Methods: A small sample of participants (n=6) was recruited and engaged in a structured resistance training program for 12 weeks, with 6 participants in a control group. Total BDNF levels were measured at baseline and post-intervention using reliable laboratory assessments. Additionally, an isokinetic dynamometer was used to determine muscle strength to explore the effect of the resistance training program on muscle performance.
 Results: The findings revealed a significant increase in total BDNF levels following the 12 week resistance training intervention (p<0.05). However, improvements in physical performance measures, knee extension peak torque and isometric maximal voluntary contraction, were not observed.
 Conclusion: In conclusion, this pilot study provides preliminary evidence of the positive effects of a 12 week resistance training intervention on total BDNF levels. The measurement of total BDNF levels serves as an important marker in assessing the response to resistance training. Further research with larger sample sizes and longer intervention periods is warranted to further explore the relationship between resistance training and total BDNF levels and to confirm these preliminary findings. Understanding the impact of resistance training on total BDNF levels can have implications for optimizing training programs and potentially improving exercise-related outcomes.
 Keywords: muscle strength, exercise, brain-derived neurotrophic factor, neuroplasticity, healthy ageing.

Exercise-induced Brain-derived neurotrophic factor regulation in the brain dysfunctions

This review explains how exercise can prevent the neurodegeneration and addresses the important role of Brain-derived neurotrophic factor as an indicator of symptoms of ageing brain dysfunction. In addition, it explains the cellular and molecular mechanisms of exercise on regulation of Brain-derived neurotrophic factor in brain, that it's dysregulation appears in many pathological conditions. It is known that mitochondrial dysfunctions associated with upregulation of reactive oxygen species, has vital role in various neurodegenerative disorder. Neurotrophins factor have numerous beneficial effects on neuroplasticity and neurosurvival and the goal of many drug therapies is to increase neurotrophins. Unfortunately, pharmacological methods are time consuming and costly, and, after a while drug resistance develops. Exercise as an adjunct intervention has promising results but various factors affect the results that should be carefully investigated in the studies. Exercise can increase brain mitochondrial biogenesis and attenuates effects of the ageing process on the brain. Regulation of Brain-derived neurotrophic factor by exercise is related to antidepressant effects and enhance of cognitive function and mitochondrial capacity that negates the ageing dysfunctions. The mechanisms of exercise-induced adaptations in neurodegenerative dysfunctions remain undiscovered and assesses the effect of exercise on neurodysfunction has encountered many difficulties. Therefore, further studies are needed to resolve existing inconsistencies. However, there is a positive relationship between regular exercise and Brain-derived neurotrophic factor regulation, which can prevent or reduce symptoms of brain diseases, especially in ageing. Dans le présent article de synthèse, nous tenterons d’expliquer comment l’exercice physique peut prévenir la dégénérescence neuronale en étudiant le rôle clés du facteur neurotrophique dérivé du cerveau en tant qu’indicateur des symptômes du dysfonctionnement cérébral lors du vieillissement. En outre, nous éluciderons les mécanismes cellulaires et moléculaires de l’exercice physique dans la régulation, dans le cerveau, du facteur neurotrophique dérivé du cerveau, dont la dérégulation apparaît dans de nombreuses conditions pathologiques. Il a été constaté que les troubles mitochondriaux liés à la surrégulation des espèces réactives de l’oxygène jouent un rôle vital dans divers troubles neurodégénératifs. Les neurotrophines disposent d’effets bénéfiques sur la plasticité neuronale ainsi que sur la survie neuronale, et de nombreux traitements médicamenteux visent à augmenter les neurotrophines. Malheureusement, les méthodes médicamenteuses sont lentes et coûteuses, et la résistance aux médicaments se développe après un certain temps. L’exercice physique en tant qu’intervention complémentaire a des résultats prometteurs, et pourtant divers facteurs affectent les résultats, ce qui doit être soigneusement étudié dans les études. L’exercice physique peut augmenter la biogenèse mitochondriale du cerveau et réduire les effets du processus du vieillissement sur le cerveau. La régulation du facteur neurotrophique dérivé du cerveau par l’exercice est associée à des effets antidépresseurs ainsi qu’à une augmentation de la fonction cognitive et de la capacité mitochondriale, ce qui annule les troubles du vieillissement. Les mécanismes d’adaptation créés grâce à l’exercice physique dans les troubles neurologiques restent inconnus, et l’évaluation de l’effet de l’exercice physique sur le dysfonctionnement neurologique a rencontré de nombreuses difficultés. Par conséquent, d’autres études semblent nécessaires afin de résoudre les contradictions existantes. Cependant, il existe une relation positive entre l’exercice régulier et le facteur neurotrophique dérivé du cerveau, qui peut prévenir ou réduire les symptômes des maladies du cerveau, en particulier lors du vieillissement.

Mechanisms Underlying Exercise-Induced BDNF Stimulated Memory Improvements in Rodents

Introduction: Increases in Brain-Derived Neurotrophic Factor (BDNF), are known to be associated with improvements in memory and can be increased by exercise. This suggests that these memory improvements could be induced from exercise associated increases in BDNF in key memory related areas of the brain such as the hippocampus. However, the underlying neurobiology outlining how exercise may affect memory remains elusive. Thus, the focus of this review is to understand the relationship between exercise induced increases in BDNF and memory improvements, and to identify potential pathways of activation that may induce these effects. Methods: An in-depth literature review was performed to analyze the mechanisms of memory involving exercise induced increases of BDNF in rodents. Both primary and review articles were used, found through Google Scholar, PubMed, and the George Washington University Gelman Library databases, and were found using search terms that included exercise, memory, rodents, and BDNF. Results: Pathways found to be potentially involved in this mechanism include the TrkB ERK1 pathway, TrkB activation of β-CaMKII, PI3-K and MAPK pathways, and the BDNF/TrkB/SYN pathway, with the SIRT1/PGC1a/FNDC5 pathway being a potential upstream pathway to induce BDNF activity. It was also found that exercise induced BDNF increases can recover memory impairments in different neurodegenerative states, such as in rodent models of Alzheimer’s disease and Down syndrome. Discussion: The collected studies demonstrate that exercise induced increases in BDNF expression are related to improved memory at least partially due to increased BDNF expression in memory associated brain regions, such as the hippocampus. The underlying neurobiology is still unclear, although potential pathways for this mechanism have been identified. Conclusion: These results of this review expose avenues of research to better understand the underlying neurobiology of exercise enhanced BDNF effects on memory improvements. The identified link between exercise and memory improvements via exercise induced BDNF increases can be potentially applied and used for future investigations into clinical therapeutic treatments for improving memory through exercise.

Exploring Exercise-induced BDNF Pathways that affect Tau Dephosphorylation and Episodic Memory in Alzheimer’s Disease: A Systematic Review

Introduction: Research has indicated that exercise improves memory and cognitive function, which can be attributed to an increase in exercise-induced brain-derived neurotrophic factor (BDNF). BDNF has also been suggested to reverse tau aggregation seen in Alzheimer’s disease (AD) via tau dephosphorylation, which can thereby improve memory function. A tyrosine receptor (TrkB) mechanism has been proposed between BDNF and the subsequent tau dephosphorylation. However, the effects of exercise-induced BDNF on tau dephosphorylation and episodic memory remain unclear. Thus, the purpose of the systemic review is to clarify a pathway linking exercise, BDNF, tau dephosphorylation, and episodic memory in AD models. Methods: A comprehensive literature search of peer-reviewed primary and review articles was conducted in the field of neuroscience and memory. Key search terms used in the database were: BDNF, tau, phosphorylation, TrkB, exercise, memory, and Alzheimer’s disease. Results: Evidence suggests that exercise-induced BDNF enhances episodic memory in animal and human studies, and has therapeutic potential for alleviating AD symptoms. Furthermore, bath incubation of BDNF administered to AD-induced human and rodent tissue has demonstrated a rapid tau dephosphorylation effect, specifically through a protein kinase pathway involving PI-3K and AKT, following TrkB binding. Discussion: The memory enhancements demonstrated from increased BDNF production are dependent on exercise. Exercise-induced episodic memory enhancements may be explained by BDNF’s ability to dephosphorylate tau via a TrkB mechanism. Specifically, the PI-3K/AKT pathway is the subsequent downstream signal involved in tau dephosphorylation, since BDNF administration to AD-induced neurons resulted in no dephosphorylation in the presence of a PI-3K inhibitor. Lastly, given BDNF’s ability to dephosphorylate tau in AD models and shift tau accumulation away from the soma, it indicates that exercise may form part of an effective treatment for individuals with AD. Conclusion: Although the research surrounding BDNF and tau dephosphorylation on episodic memory enhancements is extensive, gaps remain about BDNF’s effects in an exercise-induced setting. Further research needs to be conducted to confirm whether exercise-induced BDNF indicates similar effects on episodic memory. This research is also clinically relevant in AD treatment, whereby exercise has the potential to be prescribed concurrently with other therapies.

A Single Bout of High-intensity Interval Exercise Increases Corticospinal Excitability, Brain-derived Neurotrophic Factor, and Uncarboxylated Osteolcalcin in Sedentary, Healthy Males

Exercise induces neuroplasticity in descending motor pathways facilitating motor learning, and as such it could be utilized as an intervention in neurorehabilitation, for example when re-learning motor skills after stroke. To date, however, the neurophysiological and molecular mechanisms underlying exercise-induced neuroplasticity remain largely unknown impeding the potential utilization of exercise protocols as ‘motor learning boosters’ in clinical and non-clinical settings. Here, we assessed corticospinal excitability, intracortical facilitation (ICF) and short-interval intracortical inhibition (SICI) using transcranial magnetic stimulation (TMS) and serum biochemical markers including brain-derived neurotrophic factor (BDNF), total and precursor cathepsin B (tCTSB, proCTSB), uncarboxylated and carboxylated osteocalcin (unOCN, cOCN) and irisin using ELISA. Measurements were carried out in sedentary, healthy males before and after a single session of high-intensity interval exercise (HIIE) or in individuals who rested and did not perform exercise (No Exercise). We found that HIIE increased corticospinal excitability, BDNF and unOCN, and decreased cOCN. We also determined that greater increases in BDNF were associated with increases in unOCN and irisin and decreases in cOCN only in participants who underwent HIIE, suggesting that unOCN and irisin may contribute to exercise-induced BDNF increases. Conversely, no changes other than a decrease in serum unOCN/tOCN were found in No Exercise participants. The present findings show that a single session of HIIE is sufficient to modulate corticospinal excitability and to increase BDNF and unOCN in sedentary, healthy males.

Evaluation of Hypoglycemic Therapy Through Physical Exercise in n5STZ-Induced DiabetesRats.

BackgroundDiabetes mellitus is a syndrome with multiple etiologies involving insulin, in which there is a lack of production and/or loss of sensitivity to this hormone resulting in insulin resistance. Treatment and control of this disease requires changes in diet, use of medication, and lifestyle, such as physical activity. These modifications may compromise quality-of-life if there is no proper guidance for the treatment or alert to possible complications caused by the disease.MethodsThis study aimed to evaluate biochemical and hematological parameters, and to assess brain derived neurotrophic factor levels in diabetic Wistar rats submitted to chronic physical exercise.ResultsThe results demonstrated an increase in plasma concentration of brain-derived neurotrophic factor (BDNF) in association with hyperglycemia reduction in diabetic animals.DiscussionThe results obtained suggest that there is a regulation of glucose homeostasis between peripheral tissues and the central nervous system. Exercise-induced BDNF also improved levels of glycemia, body weight, and dyslipidemia. In hematological evaluation, BDNF increase was positively correlated with an improvement in leukocyte parameters. Electrophoresis analyses demonstrated a reduction in levels of pro-inflammatory proteins, lipoprotein fractions, and albumin preservation in diabetic animals trained with elevated concentration of plasma BDNF.ConclusionIn conclusion, this study demonstrated that chronic exercise was able to elevate BDNF levels in plasma, which resulted directly in positive hypoglycemic activity in diabetic animals and a reduction of the metabolic syndrome associated with diabetes mellitus.

Exercise-induced BDNF production by mononuclear cells of sedentary and physically active obese men.

Obesity and low physical activity changes the redox state and neurotrophin secretion by leukocytes. However, the role of exercise on brain derived neurotrophic factor (BDNF) production and oxidative stress markers of peripheral blood mononuclear cells (PBMC) remains unknown. This study aimed to verify the impact of acute maximal exercise on oxidative stress markers and the BDNF production by stimulated PBMC from sedentary and physically active obese men. PBMC from twelve sedentary obese (SED group) and twelve regular exercisers (EXE group) obese men were collected before, immediately and 1-h after maximal exercise. PBMC were stimulated with lipopolysaccharide (LPS) to evaluate the BDNF and nitrite production, lipid peroxidation, and antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) activities. PBMC from EXE group presented higher BDNF production (P=0.03) and lower TBARS levels than SED group at baseline. Maximal exercise increased BDNF and nitrite production, and lipid peroxidation immediately and 1-h after the bout in both groups. The EXE group presented higher superoxide dismutase activity immediately after bout and higher catalase activity 1-h after bout in PBMC. On the other hand, PBMC from SED group had lower superoxide dismutase activity immediately after exercise. Furthermore, PBMC from EXE group presented higher BDNF production and SOD activity and lower TBARS concentrations than SED group immediately after maximal exercise. Maximal exercise changes the redox state and enhances BDNF production by LPS-stimulated PBMC in obese individuals.

Acute high-intensity interval exercise induces greater levels of serum brain-derived neurotrophic factor in obese individuals.

High-intensity interval exercise (HIIE) has been shown to be a time-efficient exercise strategy that provides similar or superior physiological benefits as traditional continuous moderate-intensity exercise (CME). Our previous study demonstrated an equivalent elevation on the BDNF response in both obese and normal-weight individuals following 30 min of acute CME. To discover a time-efficient exercise strategy to improve brain health in an obese population, the present study found that obese individuals elicit a greater level of BDNF following acute HIIE versus CME than normal-weight individuals. These findings indicate that acute HIIE may be an effective strategy to upregulate BDNF expression in obese individuals.

Impact of high intensity interval exercise on executive function and brain derived neurotrophic factor in healthy college aged males

BackgroundPrefrontal cortex (PFC)-dependent executive function is enhanced immediately following high intensity interval exercise (HIIE). Brain-derived neurotrophic factor (BDNF) is considered a biomarker associated with enhanced execute functioning capacity at rest and in response to exercise. However, the mechanisms responsible for the acute exercise-induced BDNF response in plasma and serum differ, and it is likely that the utilization of BDNF in plasma and/or serum as a biomarker of improved executive function following HIIE may be limited. Therefore, this study examined the impact of HIIE on the plasma and serum BDNF response to understand the efficaciousness of BDNF as a peripheral biomarker associated with improvements in PFC-dependent executive function. Thirteen healthy males (age: 23.62 ± 1.06 years) participated in a randomized, counterbalanced study, performing the Wisconsin Card Sorting Task (WCST) immediately following a 5-minute seated rest (control) and participation in a HIIE protocol administered two weeks apart. HIIE consisted of ten maximal bouts of all out pedaling on a cycle ergometer for 20 s (separated by 10 s of active recovery) against 5.5% of the subject's body weight. Whole blood was collected for the assessment of BDNF in both plasma and serum. Compared to the control session, HIIE elicited significant improvements in WCST performance, yet improvements in PFC-dependent executive function were independent of BDNF concentrations in plasma and serum. Results from this investigation demonstrate that a single session of low-volume, supramaximal HIIE significantly increases PFC-dependent executive function, thereby providing additional evidence to support the powerful benefits on HIIE on cognitive functioning.

F47. COGNITIVE REMEDIATION AND PHYSICAL EXERCISE IN MULTI-EPISODE SCHIZOPHRENIA: STUDY PROTOCOL FOR A RANDOMISED CONTROLLED TRIAL

BackgroundCognitive remediation (CR) and physical exercise have separately shown promising results in schizophrenia cognitive improvement, despite this, the impact on daily functionality is still limited. Physical exercise increases Brain Derived Neurotrophic Factor (BDNF) levels, promoting neuronal and cognitive plasticity, which can maximize the impact of CR. We are conducting a randomised controlled trial to determine the efficacy of an intensive program that combines CR and physical exercise on cognition and related outcomes for patients with schizophrenia. In addition, we investigate functional and structural brain effects of this intervention and its association to BDNF.MethodsThis study protocol describes a randomized controlled trial in which 74 patients are randomly assigned to either CR and physical exercise or CR and health promotion. The interventions are 12-week long and consist of three weekly sessions (90min of CR and 40min of either aerobic exercise or health promotion). To be included in the study, patients must be diagnosed with schizophrenia or schizoaffective disorder, aged 28–60 years, and do low physical activity, as measured by International Physical Activity Questionnaire, IPAQ. Exclusion Criteria for participation in the study are the presence of neurological or substance use disorders, IQ < 70 and somatic illnesses that contraindicate physical exercise. Healthy control participants (n=18) are screened for the presence of lifetime Axis I psychotic disorders and for the presence of a first-degree relative with schizophrenia. Primary outcome measures are cognitive performance, functional outcome, negative symptoms, BDNF levels and neuroimaging measures. Secondary outcome measures are quality of life and metabolic parameters. All measures are blindly assessed at baseline, at 3 months follow up and at 15 months follow up.This trial was approved by the Comité Ètic d’Investigació Clínica de l’Hospital del Mar (CEIC) 2015/6209/IResultsThis poster is a study protocol. We will correct data from now on.DiscussionThe results of this trial will provide valuable information about whether cognitive remediation efficacy for patients with schizophrenia can be enhanced by aerobic exercise-induced BDNF upregulation.TRIAL REGISTRATIONThe trial is registered at www.clinicaltrials.gov (NCT02864576)

Exercise Induced Neuroplasticity to Enhance Therapeutic Outcomes of Cognitive Remediation in Schizophrenia: Analyzing the Role of Brai nderived Neurotrophic Factor.

Cognitive impairment is a major manifestation of schizophrenia and a crucial treatment target as these deficits are closely related to patients' functional outcomes. Cognitive remediation is the gold-standard practice to address cognitive deficits in schizophrenia. There is clear evidence stating that cognitive remediation improves cognitive function and promotes structural neuroplastic changes in patients with schizophrenia, with brain-derived neurotrophic factor (BDNF) expression emerging as a potential biomarker for its efficacy. This is particularly important as there is clear evidence relating atypical BDNF expression to cognitive impairment in patients with schizophrenia. Despite the valuable role of cognitive remediation in the management of schizophrenia, there is still a need to develop methods that allow maximizing its efficacy. In this review, we present a hypothesis arguing that cognitive remediation efficacy for patients with schizophrenia can be enhanced by aerobic exercise-induced BDNF upregulation. There have been a few trials reporting that combining aerobic exercise with cognitive training was superior to cognitive training alone to improve cognitive functioning in patients with schizophrenia. Furthermore, there is preliminary evidence suggesting that combined aerobic and cognitive training can increase peripheral BDNF levels. Thereby, engaging in aerobic exercise in close temporal proximity to cognitive remediation may allow achieving a state of neuroplastic readiness in the brain, facilitating cognitive functioning enhancement. Although this hypothesis still lacks evidence, future clinical trials using cognitive remediation for schizophrenia should explore strategies to maximize neuroplasticity and achieve optimal cognitive improvements.

Filling the void: a role for exercise-induced BDNF and brain amyloid precursor protein processing.

Inactivity, obesity, and insulin resistance are significant risk factors for the development of Alzheimer's disease (AD). Several studies have demonstrated that diet-induced obesity, inactivity, and insulin resistance exacerbate the neuropathological hallmarks of AD. The aggregation of β-amyloid peptides is one of these hallmarks. β-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid precursor protein (APP) processing, leading to β-amyloid peptide formation. Understanding how BACE1 content and activity are regulated is essential for establishing therapies aimed at reducing and/or slowing the progression of AD. Exercise training has been proven to reduce the risk of AD as well as decrease β-amyloid production and BACE1 content and/or activity. However, these long-term interventions also result in improvements in adiposity, circulating metabolites, glucose tolerance, and insulin sensitivity making it difficult to determine the direct effects of exercise on brain APP processing. This review highlights this large void in our knowledge and discusses our current understanding of the direct of effect of exercise on β-amyloid production. We have concentrated on the central role that brain-derived neurotrophic factor (BDNF) may play in mediating the direct effects of exercise on reducing brain BACE1 content and activity as well as β-amyloid production. Future studies should aim to generate a greater understanding of how obesity and exercise can directly alter APP processing and AD-related pathologies. This knowledge could provide evidence-based hypotheses for designing therapies to reduce the risk of AD and dementia.

Changes in fMRI activation in anterior hippocampus and motor cortex during memory retrieval after an intense exercise intervention

Strong evidence indicates that regular aerobic training induces beneficial effects on cognitive functions. The present controlled fMRI study was designed to investigate the impact of a short-term intense aerobic exercise on the pattern of functional activation during the retrieval of learned pair-associates in 17 young and healthy male adults compared to 17 matched control subjects. We further aimed to relate putative changes in hippocampal activation to postulated changes in the exercised-induced brain derived neurotrophic factor (BDNF). The supervised exercise program was performed on a bicycle ergometer and lasted six weeks, with three aerobic sessions per week.We found profound improvement of physical fitness in most subjects indicated by the target parameter ‘individual anaerobic threshold’. Significant improvements in the cognitive performance were detected in the exercise group, but also in the control group. We observed significant differences in the activation pattern of the left anterior hippocampus during the pair-associates task after the intervention. We could also show a significant positive correlation between changes in exercise-induced BDNF and left anterior hippocampal activation. Moreover, we observed the brain’s motor network to be significantly stronger activated after the exercise intervention. Thus, our results suggest BDNF dependent activation changes of the hippocampus in addition to previously described structural changes after exercise.

APOEε4 impacts up-regulation of brain-derived neurotrophic factor after a six-month stretch and aerobic exercise intervention in mild cognitively impaired elderly African Americans: A pilot study

Possession of the Apolipoprotein E (APOE) gene ε4 allele is the most prevalent genetic risk factor for late onset Alzheimer's disease (AD). Recent evidence suggests that APOE genotype differentially affects the expression of brain-derived neurotrophic factor (BDNF). Notably, aerobic exercise-induced upregulation of BDNF is well documented; and exercise has been shown to improve cognitive function. As BDNF is known for its role in neuroplasticity and survival, its upregulation is a proposed mechanism for the neuroprotective effects of physical exercise. In this pilot study designed to analyze exercise-induced BDNF upregulation in an understudied population, we examined the effects of APOEε4 (ε4) carrier status on changes in BDNF expression after a standardized exercise program. African Americans, age 55years and older, diagnosed with mild cognitive impairment participated in a six-month, supervised program of either stretch (control treatment) or aerobic (experimental treatment) exercise. An exercise-induced increase in VO2Max was detected only in male participants. BDNF levels in serum were measured using ELISA. Age, screening MMSE scores and baseline measures of BMI, VO2Max, and BDNF did not differ between ε4 carriers and non-ε4 carriers. A significant association between ε4 status and serum BDNF levels was detected. Non-ε4 carriers showed a significant increase in BDNF levels at the 6month time point while ε4 carriers did not. We believe we have identified a relationship between the ε4 allele and BDNF response to physiologic adaptation which likely impacts the extent of neuroprotective benefit gained from engagement in physical exercise. Replication of our results with inclusion of diverse racial cohorts, and a no-exercise control group will be necessary to determine the scope of this association in the general population.

Changes in mRNA levels for brain-derived neurotrophic factor after wheel running in rats selectively bred for high- and low-aerobic capacity

We evaluated levels of exercise-induced brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) within the hippocampal formation in rats selectively bred for 1) high intrinsic (i.e., untrained) aerobic capacity (High Capacity Runners, HCR), 2) low intrinsic aerobic capacity (Low Capacity Runners, LCR), and 3) unselected Sprague–Dawley (SD) rats with or without free access to running wheels for 3weeks. The specific aim of the study was to determine whether a dose–response relationship exists between cumulative running distance and levels of BDNF mRNA. No additional treatments or behavioral manipulations were used. HCR, LCR, and SD rats were grouped by strain and randomly assigned to sedentary or activity (voluntary access to activity wheel) conditions. Animals were killed after 21days of exposure to the assigned conditions. Daily running distances (mean±standard deviation meters/day) during week three were: HCR (4726±3220), SD (2293±3461), LCR (672±323). Regardless of strain, levels of BDNF mRNA in CA1 were elevated in wheel runners compared to sedentary rats and this difference persisted after adjustment for age (p=0.040). BDNF mRNA was not affected by intrinsic aerobic capacity and was not related to total running distance. The results support that BDNF mRNA expression is increased by unlimited access to activity wheel running for 3weeks but is not dependent upon accumulated running distance.

Beneficial effects of moderate voluntary physical exercise and its biological mechanisms on brain health

This article reviewed the beneficial effects of moderate voluntary physical exercise on brain health according to the studies on humans and animals, which includes improving psychological status and cognitive function, enhancing psychological well-being, decreasing the risks of Alzheimer's disease (AD) and dementia, and promoting the effects of antidepressant and anxiolytic. The possible underlying neurobiological mechanisms are involved up-active and down-active pathways. The up-active pathway is associated with enhancements of several neurotransmitters systems afferent to hippocampus, including norepinephrine (NE), serotonin (5-Hydroxytryptamine, 5-HT), acetylcholine (ACh) and gamma-aminobutyric acid (GABA). The down-active pathway is mainly concerned with up-regulation of the brain-derived neurotrophic factor (BDNF) and neurogenesis. It is suggested that NE activation via beta-adrenergic receptors may be essential for exercise-induced BDNF up-regulation. The possible intracellular signaling pathways of NE-mediated BDNF up-expression may be involved in GPCR-MAPK-PI-3K crosstalk and positive feedback.

GMF-Knockout Mice are Unable to Induce Brain-Derived Neurotrophic Factor after Exercise

We earlier reported that overexpression of glia maturation factor (GMF) in cultured astrocytes enhances the production of brain-derived neurotrophic factor (BDNF). The current study was conducted to find out whether BDNF production is impaired in animals devoid of GMF. To this end GMF-knockout (KO) mice were subjected to exercise and the neurotrophin mRNAs were determined by real-time RT-PCR. Compared to wild-type (WT) mice, there is a decrease in exercise-induced BDNF in the KO mice. The observation was correlated with the finding that, in WT mice, exercise increases GMF expression. The results are consistent with the hypothesis that GMF is necessary for exercise-induction of BDNF, and that GMF may promote neuroprotection through BDNF production.

Coupling energy metabolism with a mechanism to support brain-derived neurotrophic factor-mediated synaptic plasticity

Synaptic plasticity and behaviors are likely dependent on the capacity of neurons to meet the energy demands imposed by neuronal activity. We used physical activity, a paradigm intrinsically associated with energy consumption/expenditure and cognitive enhancement, to study how energy metabolism interacts with the substrates for neuroplasticity. We found that in an area critical for learning and memory, the hippocampus, exercise modified aspects of energy metabolism by decreasing oxidative stress and increasing the levels of cytochrome c oxidase-II, a specific component of mitochondrial machinery. We infused 1,25-dihydroxyvitamin D3, a modulator of energy metabolism, directly into the hippocampus during 3 days of voluntary wheel running and measured its effects on brain-derived neurotrophic factor-mediated synaptic plasticity. Brain-derived neurotrophic factor is a central player for the effects of exercise on synaptic and cognitive plasticity. We found that 25-dihydroxyvitamin D3 decreased exercise-induced brain-derived neurotrophic factor but had no significant effect on neurotrophin-3 levels, thereby suggesting a level of specificity for brain-derived neurotrophic factor in the hippocampus. 25-Dihydroxyvitamin D3 injection also abolished the effects of exercise on the consummate end-products of brain-derived neurotrophic factor action, i.e. cyclic AMP response element-binding protein and synapsin I, and modulated phosphorylated calmodulin protein kinase II, a signal transduction cascade downstream to brain-derived neurotrophic factor action that is important for learning and memory. We also found that exercise significantly increased the expression of the mitochondrial uncoupling protein 2, an energy-balancing factor concerned with ATP production and free radical management. Our results reveal a fundamental mechanism by which key elements of energy metabolism may modulate the substrates of hippocampal synaptic plasticity.