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BDNF 2009
- 1. BDNF and PhysicalBDNF and Physical ActivityActivity Roger Ramsbottom, James Currie and MichaelRoger Ramsbottom, James Currie and Michael GilderGilder VIVIthth European Sports Medicine Congress, Antalya,European Sports Medicine Congress, Antalya, Turkey, 14-18Turkey, 14-18thth October 2009October 2009 Human Integrative Physiology Research GroupHuman Integrative Physiology Research Group School of Life Sciences Oxford Brookes UniversitySchool of Life Sciences Oxford Brookes University
- 2. BDNF – What is it?BDNF – What is it? ‘Brain Derived Neurotrophic Factor’
- 4. Role of BDNFRole of BDNF It is involved with learning and memory inIt is involved with learning and memory in adult mammalsadult mammals It is likely to be neuroprotectiveIt is likely to be neuroprotective
- 5. Exercise and hippocampal BDNFExercise and hippocampal BDNF mRNA and protein levels in ratsmRNA and protein levels in rats Cotman, C. W. and Brechtold, N. C. (2002) Exercise: a behavioral intervention to enhance brain health and plasticity Trends in Neurosciences 25 (6): 295-301.
- 6. BDNF; a physiological modulatorBDNF; a physiological modulator between exercise and brain health?between exercise and brain health? It is known that exercise is neuroprotectiveIt is known that exercise is neuroprotective - epidemiological evidence- epidemiological evidence Harvard Nurses Health StudyHarvard Nurses Health Study The Honolulu–Asia Aging StudyThe Honolulu–Asia Aging Study As yet no definitive physiologicalAs yet no definitive physiological mechanism explains this link - BDNF is amechanism explains this link - BDNF is a prime candidateprime candidate
- 7. Abbott et al. (2004)Abbott et al. (2004) Honolulu Heart ProgrammeHonolulu Heart Programme 2257 retired males in Hawaii (Oahu) 71-93 years2257 retired males in Hawaii (Oahu) 71-93 years WalkingWalking << 0.4 km a day0.4 km a day 1.8x risk of dementia1.8x risk of dementia compared to those walkingcompared to those walking >> 3.2 km a day3.2 km a day Regular Exercise Protects AgainstRegular Exercise Protects Against Cognitive Decline in the ElderlyCognitive Decline in the Elderly • Weuve et al. (2004)Weuve et al. (2004) Nurses Health Study, Harvard UniversityNurses Health Study, Harvard University • 18 000 women aged 71-81 • Women walking for 1.5 hours a week ↑ cognitive performance compared to those walking < 40 minutes
- 8. HumanHuman BDNF studiesBDNF studies
- 9. Cross sectional studyCross sectional study Serum samples were obtained from 44 healthySerum samples were obtained from 44 healthy human volunteers.human volunteers. These samples were assayed for BDNF protein.These samples were assayed for BDNF protein. BDNF levels were then compared toBDNF levels were then compared to participants’ cardio-respiratory fitness (estimatedparticipants’ cardio-respiratory fitness (estimated VVOO22max) and levels of habitual physical activitymax) and levels of habitual physical activity (via a validated questionnaire)(via a validated questionnaire)
- 10. Method: Estimation of aerobic fitness (VO2 max; L min-1 )
- 11. Initial hypothesisInitial hypothesis Physical Activity Serum BDNF
- 12. Currie, J., Ramsbottom, R., Ludlow, H., Nevill, A. and Gilder, M. (2009) Cardio-respiratory fitness, habitual physical activity and serum brain derived neurotrophic factor (BDNF) in men and women Neuroscience Letters 451: 152-155.
- 13. 1 2 3 4 5 6 1 2 3 4 5 6 7 8 Baecke Sport Score EstimatedVO2max(Lmin-1 ) r=0.536, P =0.000, n=43 20 40 60 80 100 120 1 2 3 4 5 6 7 8 Baecke Sport Score Seatedheartrate(bmin-1 ) r=-0.438, P =0.000, n=43
- 14. Low volume exerciser (Heart rate 84 b min-1 ) High volume exerciser (Heart rate 58 b min-1 ) PoincarPoincaréé plotsplots Gilder, M. and Ramsbottom, R. (2008) Measures of cardiac autonomic control in women with differing volumes of physical activity Journal of Sports Sciences 26 (7): 781-786.
- 15. 0.200 0.400 0.600 0.800 1.000 1.200 1 2 3 4 5 6 7 8 Baecke Sport Score Poincaredimension(SD12) r=0.272, P =0.233, n=21
- 16. How can CNS BDNF levels beHow can CNS BDNF levels be increased?increased?
- 17. Exercise and serum BDNF concentrationExercise and serum BDNF concentration Study Subjects Ex. Intensity [BDNF]-pre [BDNF]-post Return to baseline Vega (2006) athletes (n=8) aerobic (easy) 6.0 6.0-6.2 no change exhaustive 6.0 8.6 >15 min Gold (2003) 14W, 6M 16W, 9M (MS) 60%VO2max 4.72 6.9 >30 min 60%VO2max 4.44 6.9 >30 min Ferris (2007) 4W, 11M VTH-20 (low) 18.5 20.0 no measure VTH+10 (high) 19.0 21.0 no measure exhaustive 17.0 no measure22.5 (W, women; M, men; MS, multiple sclerosis; VTH, ventilatory threshold; BDNF concentration ng mL-1 ; 60%VO2max - moderate)
- 18. Exercise and serum BDNF concentrationExercise and serum BDNF concentration Study Subjects Ex. Intensity [BDNF]-pre [BDNF]-post Return to baseline Winter (2007) 27M sedentary 0.98 1.01 no measure moderate 0.85 0.97 no measure Tang (2007) 8W, 8M moderate 30.9 34.5 (10 min) 35 min Castellano (2008) 8W, 3M 60%VO2peak 20.15 18.00 not elevated 60%VO2peak 10.05 14.00 120 min (W, women; M, men; MS, multiple sclerosis; BDNF concentration ng mL-1 ; 60%VO2peak - moderate) intense 1.04 1.17 no measure 8W, 3M (MS)
- 19. Suwa, M. et al. (2006) Serum brain-derived neurotrophic factor level is increased and associated with obesity in newly diagnosed female patients with type 2 diabetes mellitus Metabolism Clinical and Experimental 55: 852-857. BDNF and energy metabolismBDNF and energy metabolism
- 20. BDNF and energy metabolismBDNF and energy metabolism Suwa, M. et al. (2006) Serum brain-derived neurotrophic factor level is increased and associated with obesity in newly diagnosed female patients with type 2 diabetes mellitus Metabolism Clinical and Experimental 55: 852-857.
- 21. Start Exercise End Exercise High fitness level Low fitness level Time (min) Serum[BDNF]ngmL-1 Revised HypothesisRevised Hypothesis
- 22. The Neurotrophin FamilyThe Neurotrophin Family
- 23. Synthesis and StorageSynthesis and Storage Synthesis is via a number of tissuesSynthesis is via a number of tissues – neuronsneurons – skeletal muscle cellsskeletal muscle cells – vascular endothelial cellsvascular endothelial cells Storage - main storage site outside of theStorage - main storage site outside of the CNS are plateletsCNS are platelets Uptake and release mechanism unknownUptake and release mechanism unknown
- 24. Characteristics of BDNFCharacteristics of BDNF Cotman, C. W. and Brechtold, N. C. (2002) Exercise: a behavioral intervention to enhance brain health and plasticity Trends in Neurosciences 25 (6): 295-301. (a) Transport to synapses (b) BDNF binds to TrkB - presynaptically to modify transmitter release - postsynaptically to modify postsynaptic sensitivity
- 25. Exercise induces growth factorExercise induces growth factor cascadescascades Cotman, C. W., Brechtold, N. C. and Christie, L-A. (2007) Exercise builds brain health: key roles of growth factor cascades and inflammation Trends in Neurosciences 30 (9): 464-472.
- 26. Currie, J., Ramsbottom, R., Ludlow, H., Nevill, A. and Gilder, M. (2009) Cardio-respiratory fitness, habitual physical activity and serum brain derived neurotrophic factor (BDNF) in men and women Neuroscience Letters 451: 152-155.
- 27. van Praag, H. (2009) Exercise and the brain: something to chew on Trends in Neurosciences 32 (5): 283- 290.
- 28. Currie, J., Ramsbottom, R., Ludlow, H., Nevill, A. and Gilder, M. (2009) Cardio-respiratory fitness, habitual physical activity and serum brain derived neurotrophic factor (BDNF) in men and women Neuroscience Letters 451: 152-155.
- 29. Relationship between aerobicRelationship between aerobic fitness and autonomic functionfitness and autonomic function 1 2 3 4 5 6 0.200 0.400 0.600 0.800 1.000 1.200 Poincare dimension (SD12) EstimatedVO2max(Lmin-1 ) r=0.462, P =0.035, n=21
- 30. Relationship between serum BDNFRelationship between serum BDNF concentration and autonomic functionconcentration and autonomic function 0 2 4 6 8 10 12 14 16 18 20 0.200 0.400 0.600 0.800 1.000 1.200 Poincare dimension (SD12) SerumBDNF(ngmL-1 ) r=-0.324, P =0.152, n=21
- 31. What next?What next? Phase II study is to examine the acute responsePhase II study is to examine the acute response to exercise. Looking at a spectrum of active -to exercise. Looking at a spectrum of active - sedentary participants.sedentary participants. Temporal profile of serum BDNF followingTemporal profile of serum BDNF following exercise?exercise? Magnitude of platelet BDNF release into serumMagnitude of platelet BDNF release into serum following exercise?following exercise?
- 32. Effects of exercise on geneEffects of exercise on gene transcriptiontranscription Cotman, C. W. and Brechtold, N. C. (2002) Exercise: a behavioral intervention to enhance brain health and plasticity Trends in Neurosciences 25 (6): 295-301.
Editor's Notes
- Brain Derived Neurotrophic Factor’, a BDNF is a 27-kDa homodimeric protein. A member of the ‘neurotrophin’ family. Neurotrophins were characterised by Rita Levi-Montalcini in the early 1950s. NGF was observed to cause sprouting of dendrites in cultured mouse embryonic cells when co-cultured with mouse sarcoma (containing NGF) called the ‘halo effect’.
- Although platelets are in the periphery BDNF has been shown to cross the BBB. As such peripheral blood borne BDNF levels may reflect how much BDNF protein is available to the CNS. This is the idea that many groups, including us, were working with! Pan – shown movement of BDNF from the periphery to the CNS. Jugular (rowers study has shown BDNF synthesised in the CNS appearing in blood. Hypothetical – movement (synthesis?) of BDNF in muscle across the blood-brain barrier to the CNS
- Evidence; BDNF is abundant in the hippocampus of rats and humans. BDNF has a neuroprotective role; it is absent in the hippocampus post mortem of peoples suffering from Alzheimer&apos;s disease. In rodent models an increase of BDNF in serum = improved learning/memory performance. Increased wheel running leads to greater spacial awareness in rodent models BDNF signalling is necessary for formation of synaptic connections. Rats synthesise certain synaptic proteins under the direction of BDNF during exercise. Block the BDNF receptor (via a BDNF receptor agonist) and thus prevent formation of these synaptic proteins. Vaynman, et al. 2006.
- In situ hybridization shows that expression of BDNF mRNA in the rat dentate gyrus (DG), hilus, CA1–CA3 regions and cortex is greater following exercise (seven days of voluntary wheel-running) than in sedentary animals. Messenger RNA is highlighted in the brain (b). Protein levels are significantly higher. (c) ELISA quantification of hippocampal BDNF protein levels in the hippocampus in sedentary (SED) and exercising (EX) animals, after five days of wheel-running (*P&lt;0.05). (d) Rats and mice acclimate rapidly to the running wheel and progressively increase their extent of daily running, in some cases up to a startling 20 kilometres (~12–13 miles) per night. BDNF protein levels correlate with running distance (average over 14 days running; R2 = 0.771)
- Epidemiological evidence: Nurses Health Study began in 1976. 121,700 registered US nurses complete medical history/health related behaviour questionnaires bi-annually. Telephone interviews & questionnaires have found higher levels of physical activity associated with better performance on memory tests and reduced risk of cognitive impairment (Weuve, J. et al., 2004). The Honolulu Heart Programme initiated in 1965 to study the impact of Western Diet on heart disease in a population of Japanese origin that immigrated to Hawaii. The Honolulu–Asia Aging Study has monitored this well characterised population into later life. The study found in a large sample of elderly men (n=2257) that amount of walking reported per day was associated with reduced risk of developing dementia (Abbott, R.D. et al., 2004). However neurotrophins are not the only link between successful neural aging and exercise. There is evidence that exercise improves cerebral perfusion (e.g. blood-flow) which is associated with reduced cognitive decline.
- Ferris, et al. 2007. Human study. (n = 15, 11 m, 4 f, aged 25 years +/- 1 year) Examined the relationship between serum BDNF, exercise intensity and cognitive function. Serum BDNF taken before and after low intensity/high intensity endurance ride on a cycle ergometer. Serum BDNF increased significantly after the higher intensity (above ventilatory threshold) but not after lower intensity exercise. Cognition improved after all exercise conditions but did not correlate with changes in BDNF. Tang, et al. 2008. Human study. (n = 16, 8 m and 8 f, aged 19-30 years) Examined the acute response to a 15 minute step test on serum BDNF levels. Bloods taken pre exercise (resting), 25 minutes post and 50 minutes post exercise. No information on the relative intensity for participants (other than heart rate at rest then post step test) nor information regarding participant’s physical activity status/level of fitness. BDNF levels were significantly elevated 25 minutes post exercise but returned to baseline after 50 minutes following the step test. Winter, et al. 2007. Human study. (n = 27 male athletes aged 22 +/- 2 years) Examined the relationship between exercise intensity, serum BDNF and memory retention. Serum BDNF and blood lactate determined. Assigned to one of three randomised groups; sedentary control, 40 minute low impact running or 2 x 3min sprints. After the high/low intensity training session (or resting) there followed a ‘learning session’ (participant’s learned words from novel language), Serum and blood lactate levels were recorded again. Memory retention was then tested immediately after, one week after and 8 months after this learning session. The high intensity group showed better memory retention and learning speed than the other two groups. The high intensity group also had elevated serum BDNF levels. Small sample size, each group n=9. Would have been interesting to monitor sedentary subjects to make comparisons with the athletes.
- We set out to determine if the relationship between physical activity and resting serum BDNF levels was the same in humans as animal models. Hypothesis based on animal models and free wheel running (neurological studies on rodents)
- The relationship we observed in our human population (blood measure) was contrary to that observed in rodents (brain levels of BDNF). In humans resting serum BDNF and aerobic power were found to be negatively correlated.
- Seems to be that the amount of sport is the driver for these observations
- Left – compressed plot Right – broader plot (more time between R-R intervals)
- This is linking the poster data High Baecke Sport score – links with low levels of BDNF, greater Poincaré Dimension, lower seated HR and higher estimated VO2 max. All parameters of ‘health’ linked to high sport score.
- In animal models the amount of time spent doing voluntary exercise correlates with resting serum & CNS BDNF levels. In rats muscle paralysis by botox injection or hindlimb suspension to prevent mechanical movement lead to a decrease of BDNF mRNA in the muscle and spinal cord that can be restored to normal levels with resumption of exercise. Animals provided with wheels show a gradual increase of BDNF over several weeks. Animals denied exercise exhibit a gradual decrease in hippocampal BDNF over two weeks. This was reversible - if once again given access to a running wheel a single bout of exercise caused BDNF to return to levels that would normally be induced after several weeks of exercise exposure. Given rise to the theory that, in rodents at least, exercise primes a ‘molecular memory’ for BDNF. Berchtold, et al. 2005. In animals and humans an acute peak of serum BDNF in the minutes following exercise is observed.
- [BDNF]-pre indicates resting levels. Seems that BDNF conc. Goes up with exercise intensity. Ferris BDNF significant higher (versus resting) with exercise at VTH+10.
- BDNF appears to have a peripheral function – with metabolic regulation. So in humans here with pre-diabetic patients we have an increase in serum BDNF. (Contrast this with Currie et al. (2009) So maybe and increase in BDNF is not always associated with ‘good’ function. (Animal studies show in increase in brain [BDNF] with an increase in free wheel running).
- Does habitual physical activity alters an individual’s acute response to exercise? Phase I showed higher aerobic power associated with lower resting (baseline) serum BDNF – this is denoted in the graph (at the moment this is speculation until we can examine low versus high fit individuals and look at the kinetics of BDNF release). Increased fitness… = an increased acute release of BDNF into the serum immediately following a bout of exercise? (greater peak [graph]?) = an increased uptake of BDNF across the BBB? (greater trough at end of exercise [graph]?)
- LNGFR = ‘Low Affinity Nerve Growth Factor Receptor’ AKA ‘p75’ receptor. BDNF acts via 2 receptors. In vivo BDNF produces different effects in different tissues and at different times during/after an organisms development, depending on the balance between TrkB and p75 receptor signals. BDNF can act acutely on neurons. The high affinity TrkB receptors control membrane proteins including ion channels and neurotransmitter receptors. BDNF can also act more slowly on neurons. Once BDNF binds the TrkB receptor it forms dimers. Dimerisation of TrkB activates the intracellular tyrosine-kinase domain of the receptor, phosphorylating a variety of proteins that initiate signalling cascades. This signal transduction alters gene transcription in the neuron. This protein synthesis can produce synaptogenesis and dendritic branching.
- Explain; CNS = Central nervous system
- Transport nerve to muscle (but also may be retrograde transport, muscle back to nerve) Acting as a neurotransmitter. Can cross e.g. blood brain barrier. Up regulation of NMDA receptors. Ca2+ coming in. BDNF acting as a modulator of synaptic function, making neurones more sensitive (up regulation of NMDA receptors, increased number of receptors)
- The self report ‘Baecke Questionnaire’ confirmed that physical activity was also a predictor for serum BDNF – greater physical activity correlated with low resting serum BDNF. Nufuji et al, 2008 have findings that support this: Used step count (with an accelerometer worn on the arm), a self reporting questionnaire and resting serum samples. Found the group of trained men (n=12) had lower serum BDNF than the group of sedentary men (n=14). They also found BDNF negatively correlated with total daily energy expenditure and movement related energy expenditure.
- The Baecke Questionnaire involved answering questions about time and energy spent: At work During in leisure Engaged in sporting activities. You are given a score for each component, a higher score indicating greater habitual physical activity. The total score (previous slide) reflects the sum of these three lifestyle components. The ‘work’ and ‘leisure’ components did not correlate significantly with BDNF levels. The ‘sport’ component, however, did. It appears (at least in our population, n=44) that time spend engaged in sporting activities was the significant lifestyle factor affecting resting BDNF.
- The Baecke Questionnaire involved answering questions about time and energy spent: At work During in leisure Engaged in sporting activities. You are given a score for each component, a higher score indicating greater habitual physical activity. The total score (previous slide) reflects the sum of these three lifestyle components. The ‘work’ and ‘leisure’ components did not correlate significantly with BDNF levels. The ‘sport’ component, however, did. It appears (at least in our population, n=44) that time spend engaged in sporting activities was the significant lifestyle factor affecting resting BDNF.
- We have to ask why is there an inverse relationship between physical activity and blood borne BDNF protein. Clearly the physiology of rodents and humans are different! Two main candidates: The storage/release of BDNF into and out of platelets could be differently regulated in humans. Exercise increases platelet count but decreases properties of aggregability and adhesion. The uptake of BDNF from the periphery into the CNS maybe more efficient in physically active humans, resulting in lower resting serum levels.