Growth Factor (GF) Cascades and exercise and the regulation of cognition, mood and motor control:...
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Transcript of Growth Factor (GF) Cascades and exercise and the regulation of cognition, mood and motor control:...
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
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
Exercise induces growth factor cascades and regulates peripheral risk factors for brain dysfunction
BDNF (Brain Derived Neurotrophic Factor) is necessary for learning:
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?
Is BDNF increased with exercise in brain?
Exercise increases BDNF mRNAHIPPOCAMPUS:
Rats: 1 week exercise (male sprague-dawley, 3 months)
Berchtold et al., 2002
0
20
40
60
80
100
120
Tim
e to
rea
ch p
latf
orm
(se
c)
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
Days of training
Sedentary
Exercising
* p < 0.05
*
**
*
Exercise Enhances Learning in the Morris Water Maze
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)
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.
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
Other targets of exercise
Neurogenesis, Angiogenesis
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)
(van Praag, 2005)
Neurogenesis in the young and aged dentate gyrus.
New neurons?
• Exercise can increase brain vessels and the generation of new neurons in brain.
• Humans?
Pereira et al., 2007
Exercise selectively increases dentate gyrus cerebral blood volume in mice.
Pereira et al., 2007
Exercise-induced increases cerebral blood volume and correlates with neurogenesis in mouse
hippocampus
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).
Growth factor cascades regulate learning, neurogenesis, and angiogenesis (Cotman,2007, Trends in
NS).
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
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?
Animal model
• Widespread plaque deposition, including the hippocampus andcortex
Chishti et al., JBC 276: 21562-21570, 2001.
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
Exercise improves the performance of TgCRND8 animals in the Morris water maze
Ave
rage
esc
ape
late
ncy
(sec
onds
) ±
stan
dard
er
ror
0
5
10
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20
25
30
35
40
45
50
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
SedentaryExercise*
* *
*p<0.02
Long-term running reduces ß-amyloid load in TgCRND8 animals
(by immunohistochemistry)
0
20
40
60
80
100
120
140
Aß1-40 Aß1-42For
mic
-aci
d e
xtra
ctab
le c
orti
cal a
myl
oid
(%
of
sed
enta
ry)
SedentaryExercise
* *
Long-term running reduces ß-amyloid in TgCRND8 animals (by ELISA)
Long-term running enhances neurogenesis in TgCRND8 animals
Can exercise improve learning in late stage AD?
???????????
0
10
20
30
40
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60
70
Tg2576 sed
Tg2576 run
avg
ref
eren
ce t
rial
late
ncy
Reference memory improves in Tg2576 run
0
10
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30
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60
1.1 2.1
trial
late
ncy
(se
c) WTtc
TGtc
TGrun
*
*
*
Pre- fibrilar β-amyloid is decreased by 3 wks running in 18m old
Tg2576 miceC
TGrun0%
20%
40%
60%
80%
100%
120%
140%
TGsed
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????
IL-1IL-1 0
20
40
60
80
100
120
140
160
180
200
WT sed
WT run
Tg sed
Tg2576 run
pg
/mL
WT sed
WT run
Tg sed
Tg2576 run
0
5
10
15
20
25
30
WT sed
WT run
Tg2576 sed
Tg2576 run
pg
/mL
WT sed
WT run
Tg2576 sed
Tg2576 run
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
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.
BDNF signal transduction: IL-1β impairs IRS coupling similar to its effect on IGF-1
BDNF
• BDNF and mood (Martinowich, etal, Nature Neuroscience, 2007)
• Hipocampal neurogenesis in depression (Sahay and Hen, Nature Neuroscience 2007)
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
Can antioxidants and/or Exercise/Environmental Enrichment
Delay the Development of Age Dependent Cognitive Dysfunction and Neuropathology in Canines?
Spatial Memory and Treatment
Year of Study
Year 1 Year 2 Year 3
Err
ros
to C
rite
rio
n
0
50
100
150
200
250
300
C/C C/E A/C A/E
P<.09
P<.05
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
Acknowledgments
• Nicole Berchtold
• Liz Head
• Paul Adlard
• Liqi Tong
• Robert Balazs
• Kate Nicole
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
Enrichment Protocol
• Play toys• Kennelmate• 3x20 min walks• Additional cognitive
experience
Controls
6 months
Effect of diet on oddity discrimination in aged beagles
Oddity task
0 1 2 3 4 5
Err
ors
to
cri
teri
on
0
50
100
150
200 Control Antioxidant
*
*
Diet fortified animals make few mistakes as task difficulty increases
Effect of diet on oddity discrimination in aged beagles
Is the intervention able to “reverse” age related
cognitive dysfunction?
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