growth factor (gf) cascades and exercise and the regulation of cognition, mood and motor control:...
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![Page 1: Growth Factor (GF) Cascades and exercise and the regulation of cognition, mood and motor control: Are GFs a common mechanism? Carl W. Cotman Director,](https://reader035.vdocuments.mx/reader035/viewer/2022062511/551921a65503462f428b4b7d/html5/thumbnails/1.jpg)
Growth Factor (GF) Cascades and exercise and the regulation of
cognition, mood and motor control:
Are GFs a common mechanism? Carl W. Cotman
Director, Institute of Brain Aging
University of California, Irivne
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Outline
• Part I. Exercise regulates learning, neurogenesis and angiogenesis via growth factor cascades
• Part II. Exercise improves learning and reduces β-amyloid accumulation and inflammation in Alzheimer mouse models
• Part III. Environmental enrichment antioxidant diet improve learning in aged canines
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Exercise induces growth factor cascades and regulates peripheral risk factors for brain dysfunction
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BDNF (Brain Derived Neurotrophic Factor) is necessary for learning:
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BDNF – Brain Derived Neurotrophic Factor, “Brain Fertilizer”
• Necessary for learning and long term synaptic change
• Stimulates synaptic growth and neurogenesis• Linked to “depression” in rodents• Protects neurons from injury including those in
motor systems
How to get more?• Exercise?
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Is BDNF increased with exercise in brain?
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Exercise increases BDNF mRNAHIPPOCAMPUS:
Rats: 1 week exercise (male sprague-dawley, 3 months)
Berchtold et al., 2002
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Exercise Enhances Learning in the Morris Water Maze
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Blocking BDNF action (anti-TrkB) during the exercise period on memory retention using the probe trial on the Morris Water Maze task
(Vaynman, et al., 2004)
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Take home:
• Thus exercise improves the state of readiness of learning, faster and lower threshold, including theta long term potentiation, a synaptic analogue of learning.
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Practical Questions
• How long lasting is the increase in BDNF after stopping exercise? 2wks
• How frequent is necessary? 3-4X/wk
• Can the increase be recovered rapidly if exercise is stopped for a period? Yes, if within 2wks
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Other targets of exercise
Neurogenesis, Angiogenesis
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Neurogenesis
• Occurs in select brain regions, e.g., hippocampal dentate gyrus
• Correlates with improved learning; new cells have a low threshold for synaptic transmission
• A mechanism in antidepressant action • Linked to IGF-1 and BDNF• Increases with running and is sustained with age
but at reduced levels (van Praag, 2005; Kronenberg, 2005)
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(van Praag, 2005)
Neurogenesis in the young and aged dentate gyrus.
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New neurons?
• Exercise can increase brain vessels and the generation of new neurons in brain.
• Humans?
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Pereira et al., 2007
Exercise selectively increases dentate gyrus cerebral blood volume in mice.
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Pereira et al., 2007
Exercise-induced increases cerebral blood volume and correlates with neurogenesis in mouse
hippocampus
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Pereira et al., 2007
Exercise increases cerebral blood volume (CBV) in human hippocampus. Exercise had a selective effect on dentate gyrus CBV. Before exercise (open bars) and after exercise (filled bars).
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Growth factor cascades regulate learning, neurogenesis, and angiogenesis (Cotman,2007, Trends in
NS).
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Effects of exercise on normal aging
Behavior Neuroanatomy Cellular/molecular References
Human Improves learning & memory, slows cognitive decline, risk for dementia
Reduces brain atrophy, prevents decline in cerebral blood flow, increases bloodflow (neurogenesis?)
Needs investigation Rogers et al. 1990; Hill, et al. 1993; Laurin et al. 2001; Yaff e et al. 2001; Colcombe et al. 2003; Weuve et al. 2004; Rovio et al. 2005; Colcombe et al. 2006; Larson et al. 2006; Pereira et al., 2007
Animal Improves learning & memory, slows cognitive decline
Slows decline in neurogenesis, lowers threshold for LTP induction, increases angiogenesis
BDNF, prevents decline in precursor cell activity in dentate gyrus
Farmer et al. 2004; Adlard et al. 2005; van Praag et al. 2005; Ding et al. 2006; Kronenberg et al. 2006
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Part II: Is exercise an effective intervention in Alzheimer’s disease
transgenic mouse models ?
• Will voluntary running improve learning and memory?
• Reduce β-amyloid in the brain?
• Stimulate neurogenesis?
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Animal model
• Widespread plaque deposition, including the hippocampus andcortex
Chishti et al., JBC 276: 21562-21570, 2001.
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Voluntary Exercise Paradigm (Adlard, etal., 2005)
• Utilized TgCRND8 mouse model
• Voluntary access to running wheels (animals run ~3 miles/day)
• Short-term running- start at 6 weeks of age- sacrifice four weeks later
• Long-term running- start at 6 weeks of age- sacrifice 5 months later
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Exercise improves the performance of TgCRND8 animals in the Morris water maze
Ave
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Long-term running reduces ß-amyloid load in TgCRND8 animals
(by immunohistochemistry)
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Long-term running reduces ß-amyloid in TgCRND8 animals (by ELISA)
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Long-term running enhances neurogenesis in TgCRND8 animals
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Can exercise improve learning in late stage AD?
???????????
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Pre- fibrilar β-amyloid is decreased by 3 wks running in 18m old
Tg2576 miceC
TGrun0%
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Inflammation
• Is a common component of the metabolic syndrome
• IL-1 and TNF impair insulin/IGF-1 signaling (insulin resistance) and increase the risk for progression (various refs)
• IL-1 impairs BDNF and neurotrophin signaling (“neurotrophin resistance”) (Tong, 2007)
• Can exercise reduce inflammation????
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IL-1IL-1 0
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IFN-IFN-
Exercise reverses the effects of Exercise reverses the effects of “AD” on inflammatory system“AD” on inflammatory system
Pro-inflammatory: BAD Anti-inflammatory: GOOD
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Inflammation
• Impairs insulin/IGF-1 signaling, e.g., IL-1β, TGFα (insulin resistance)
• Impairs BDNF signaling, e.g., IL-1β (neurotrophin resistance)
• Exercise thus acts via growth factor cascades at multiple levels. Induction and relief from suppression.
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BDNF signal transduction: IL-1β impairs IRS coupling similar to its effect on IGF-1
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BDNF
• BDNF and mood (Martinowich, etal, Nature Neuroscience, 2007)
• Hipocampal neurogenesis in depression (Sahay and Hen, Nature Neuroscience 2007)
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Part III: Environmental enrichment/exercise and Diet: multi-factorial interventions
• Supplements/Nutrients
• Some dietary factors may regulate brain health and cognitive performance
• Interact with environmental enrichment and exercise
• Can control the metabolic syndrome
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Can antioxidants and/or Exercise/Environmental Enrichment
Delay the Development of Age Dependent Cognitive Dysfunction and Neuropathology in Canines?
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Spatial Memory and Treatment
Year of Study
Year 1 Year 2 Year 3
Err
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C/C C/E A/C A/E
P<.09
P<.05
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Cognition, Mood and Motor control?
• Growth factor cascades and their regulation underlie aspects of enhancing brain function and structure and protecting from pathology (Cotman, 2007, Trends in NS)
• Growth factor signaling can be impaired by inflammation
• Growth factor cascades may be a common denominator for cognitive impairment, depression and some aspects of motor control??
• Exercise accesses these mechanisms
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Acknowledgments
• Nicole Berchtold
• Liz Head
• Paul Adlard
• Liqi Tong
• Robert Balazs
• Kate Nicole
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Canine Antioxidant Diet
• Antioxidants• dl-alpha tocopherol acetate-
1050 ppm (20 mg/kg - 800 IU
• Stay-C (ascorbyl monophosphate)-100 ppm
• Spinach, carrot granules, tomato pomace, citrus pulp, grape pomace - 1% each in exchange for corn (Increased ORAC by 50%)
Mitochondrial cofactors
• dl-Lipoic acid - 135 ppm (2.7 mg/kg)
• l-carnitine,Acetyl-car-300 ppm (6 mg/kg)
ROS
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Enrichment Protocol
• Play toys• Kennelmate• 3x20 min walks• Additional cognitive
experience
Controls
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6 months
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Effect of diet on oddity discrimination in aged beagles
Oddity task
0 1 2 3 4 5
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Diet fortified animals make few mistakes as task difficulty increases
Effect of diet on oddity discrimination in aged beagles
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Is the intervention able to “reverse” age related
cognitive dysfunction?
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Summary
• Part I: Exercise access brain learning mechanisms and regulates growth factors
• Part II: Exercise can delay onset of age-related pathology and improve learning even once pathology has evolved
• Part III: Exercise and environmental enrichment with an antioxidant diet can improve learning