Cotman - Ppt

8/3/2019 Cotman - Ppt

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Exercise induces BDNF,

improves learning and reduces

-amyloid

Carl W. Cotman

Institute for Brain AgingUniversity of California, Irvine


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Behavioral Interventions:

The New Direction

Exercise

MentalActivity

Diet


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Outline

Part 1. Can exercise induce neurotrophic

factors and improve learning?Part 2. Can exercise reduce pathology in a

AD transgenic mouse and improvelearning?


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BDNF (Brain Derived Neurotrophic

Factor) is a Synaptic Modulator:


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BDNF Brain Derived

Neurotrophic Factor Necessary for learning and long term

synaptic change Stimulates synaptic growth and

neurogenesis Protects neurons from injury

How to get more? Simple - exercise


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Is BDNF increased by

exercise in the brain ?

Where? And how fast and long

lasting?

How much exercise?


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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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Time course of BDNF Protein

Induction

0

2550

75

100

125150

175

200

225

250

0

2550

75

100

125

150

175

200

225

250

20 4 7 14 28 72

DAILY EXERCISE

***

***

***

0 7 14 28

*

**

ALTERNATING DAYS

BDNFProtein

(%S

eden

tary)

Days Days

Berchtold, et al., submitted


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So..what is the functional

significance?

Learning?

Stress Relief?


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Exercise Enhances

Learning in the Morris Water Maze

0

20

40

60

80

100

120

Timetoreachplatform(

sec

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6

Days of training

Sedentary

Exercising

* p < 0.05*

*

*

*


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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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Can exercise prevent the stress

induced reduction in BDNF? Animals given 3 wks. of voluntary running

Subjected to acute immobilization stress Circulating corticosterone and brain BDNF

measured

Hypothesis: Exercise will offset the effect of

acute stress, possibly via a reduction inlevels of circulating corticosterone.


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At 10 hours post-stress, BDNF is decreased in stressed animals,

but remains elevated in animals that had prior exercise

0

20

40

60

80

100

120

140

160

180

200

Normalisedlevel

ofBDNFprot

ein(%o

f

sedentary)standarderrorattenhours

ControlSedentary

ControlExercising

StressedSedentary

StressedExercising

*

*

*

* Significantly different (p


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Many plasticity genes are regulated

by BDNF,e.g., Synapsin: Regulates presynaptic vesicle availability

Modulates neurotransmitter release into synapse Block TrkB in vivo suppresses exercise-induction of synapsin mRNA (Gomez-Pinilla,

2003)

CREB: Transcription factor, drives downstream gene expressionImportant in LTP, learning and memory

Block TrkB in vivo suppresses exercise-induction of CREB (Gomez-Pinilla, 2003)

NR2b: subunit of glutamate receptor (NMDA)Overexpression enhances LTP and improves learning Slice culture: BDNF increases NR2b protein

NARP: Trafficking/insertion of glutamate receptors in PSD,critical to LTP and learning Slice culture: BDNF increases NARP protein

COX-2: traditionally known for immune functionRole in plasticity: localized to dendrites

Slice culture: BDNF increases COX-2 protein


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Practical Questions

How long lasting is the increase after

stopping exercise? How frequent is necessary

Can the increase be recoveredrapidly if exercise is stopped for a

peroid?


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Is there a molecular memory

for exercise?

Many of the gene changes including CREB arelinked to learning and memory

Is the experience of exercise encoded so toallow the brain to learn to respond?

Thus, if so exercise may prime the brain to

respond to experiences, and induce a state ofreadiness.

How Often to Exercise?: Is there a


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How Often to Exercise?: Is there a

Molecular Memory Exercise

Paradigm:

14 days of exercise:

- Daily (during 2 weeks)- Alternating (during 4 weeks)

Wheels locked:

- 1 week, 2 weeks

Second short run period (2 days)

Note: 2 days exercise alone isnot sufficient to increase BDNF

0

2550

75

100

125

150

175

200

1 wk delay2 wk delay

Daily Alternating DaysSED

*** *** ******

roten

(%s

edentary)

Prior Exercise Primes subsequent BDNFResponsiveness

Priming effect endures at least 2 weeks

Equivalent Secondary Responsiveness if prior

exercise is Daily Regime or Alternating Days ofExercise


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HIPPOCAMPUSGenomic regulationStructural change

- vascular- neuronal- neurogenesis

Increased neuronal health

EXERCISE

PeripheralFactors

Blood Brain Barrier

EstrogenIGF-1

Raphe (5-HT)Locus coeruleus (NE)

BDNF

Glucocorticoids

Medial Septum

other plasticity genes

(ACh/GABA)

Cotman & BerchtoldCotman & Berchtold

20022002

E t d i ti d b li


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Estrogen-deprivation reduces baseline

BDNF gene expression (Berchtold, etal., E.J.of Neurosc., 2001)

Intact

OVX-3

OVX-7

100

125

150

DG hilus CA3 CA1

0

25

50

75

***

*

*T*

*T

B

DNFmRNAex

pression

(%I

ntact)

* p


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xerc se- n uceincrease is lost after 7 weeks of

estrogen deprivation

0

25

50

75

100

125

150

175INTACT OVX-3 wk OVX-7 wk

BDNFm

RNAexpress

ion

(%s

ed

entaryIntact)

***

***

SedentaryExercise

*** significantly different from sedentary p


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Estrogen-replacement

increases BDNF mRNA level

B

DNFmRNAexp

ression

(%s

edentaryIn

tact)

200

0

25

50

75

100

125

150

175

225

DG hilus CA3 CA1

OVX-7

OVX-7/E

T

***

***

*** p


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Exercise Further Increases

BDNF, Specifically in the DG

DG hilus CA3 CA1

0

50

100

150

200

**T

SED

EX

BDNFmRNAexpression

(

%s

edentaryInta

ct)

** p


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ormone rep acemen(17-beta Estradiol)

Restores Running Behavior

0

500

1000

1500

2000

2500

3000

3500

1 2 3 4 5

OVX

OVX/Ebeta

INTACT

*

**

**

*

T

Days

nigh

tlyrunningdist

ance

(meters)

* p


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ESTROGENPHYSICALACTIVITY

BDNF

I i ff ti i AD


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Is exercise effective in AD

transgenic models ?

Will voluntary running improve learningand memory?

Stimulate neurogenesis? Reduce -amyloid in the brain?


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Animal model

Widespread plaque deposition, including the hippocampus and

cortex

Chishti et al., JBC 276: 21562-21570, 2001.

V l t E i P di


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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

E i i h f f


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Exercise improves the performance of

TgCRND8 animals in the Morris water maze

0

5

10

15

20

25

30

35

40

45

50

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6Averageescapelatency(seconds)

standard

er

ror

Sedentary

Exercise

*

*

*

* p


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Long-term running reduces -amyloid

load in TgCRND8 animals(by immunohistochemistry)



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Long term running reduces amyloid

load in TgCRND8 animals(by ELISA)

0

20

40

60

80

100

120

140

A1-40 A1-42Formic-acidextractablecor

ticalamyloid

(%

ofsedentary

)

SedentaryExercise

* *

L t i h


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Long-term running enhances

neurogenesis in TgCRND8 animals


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Mechanism: Long-term running had -

no effect on steady-state levels of the amyloidprecursor protein, APP

no effect on secretase activity levels (, , )

Does short term running affect APP

processing?

Short-term running mediates APP


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Short term running mediates APP

processing

0

20

40

60

80

100

120

A1-40 A1-42

P

ercentage

of

sedent

ary

Sedentary

Exercise

0

20

40

60

80

100

120

alpha-CTF beta-CTF

P

ercentage

of

sedent

ary

Sedentary

Exercise

no effect on total APP

no effect on secretase activity (, , )

no effect on neprilysin or IDE


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Summary

BDNF increases with exercise in the

hippocampus within a few days and lasts BDNF induction can be rapidly restored bya brief period of exercise even after

exercise is stopped for weeks Exercise improves the rate of learning

Exercise reduces -amyloid in thehippocampus and cortex

Exercise alters APP processing


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Summary Part 2

Exercise in a transgenic AD mouse

improves learning Exercise reduces -amyloid in the

hippocampus and cortex

Exercise alters APP processing


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Diet? What effect

does an antioxidant

diet have on

cognition?

Can antioxidants and/or


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Exercise/Environmental Enrichment

Delay the Development of Age

Dependent Cognitive Dysfunction

and Neuropathology in Canines?

Canine Antioxidant


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Canine Antioxidant

Diet Antioxidants

dl-alpha tocopherol acetate-1050 ppm (20 mg/kg - 800IU

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 (2.7mg/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

Learning Is Impaired in Old


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Oddity Discrimination Learning as a Function of Age

Task

Oddity -1 Oddity -2 Oddity -3 Oddity -4

ErrorstoCriterion(Mean)

0

20

40

60

80

100

120

140

Young Dogs

Old Dogs

Aged dogs make

more mistakes astask complexity

increases .

Canines


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E ffec t o f d ie t on od d i ty d isc r im ina tion in a ge d b ea g les

O dd ity task

0 1 2 3 4 5

Errorstocriterion

0

5 0

1 0 0

1 5 0

2 0 0C o n t r o lA n t i o x i d a n t

*

*

Diet fortified animals make few mistakes as task difficulty increases


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Is the intervention able to

reverse age relatedcognitive dysfunction?

Spatial Memory and


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p y

TreatmentP


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What effect, if any, do thetreatments have on brain

pathology?

Effect of Antioxidant Diet on


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Total Amyloid Load (6E10)By Brain Region

Brain Region

Prefrontal Entohrinal Parietal Occipital

AmyloidLoad(%

)

0

2

4

6

8

Control Diet

Antioxidant Diet

Entorhinal

Conclusion


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Conclusion

A growing clinical literature suggests that

exercise and diet can delay the onset ofcognitive decline and AD

Animal models show that exercise induces

BDNF, a key plasticity and neuroprotecive

factor

Animal models show that exercise and dietcan reduce -amyloid levels

Summary Part 3


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Summary Part 3

A diet enriched in mitochondrialantioxidants improves learning in aged

dogs Reduces -amyloid accumulation

Diet plus environmental enrichment is

better than either alone

Reduced reactive oxygen species(ROS) production by mitochondria in


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(ROS) production by mitochondria in

treated aged dogs

Time5 min 10 min 15 min

%I

ncreaseinReactiveOxygenSp

eciesProduction

0

200

400

600

800

1000

1200

1400YoungOld Control

Old Antioxidant

ROS


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g g


Is there a molecular memory for


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exercise? Exercise may prime the brain for learning

and induces a state of readiness?


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exercise seems to prime the brain to respond to

experiences, induce a state of readiness.

Is there a molecular memory for

exercise?

BDNF is a Synaptic


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BDNF is a Synaptic

Modulator

Is BDNF induced by exerciseand where in brain?

How much exercise?


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Exercise increases BDNF mRNAHIPPOCAMPUS:

Rats: 1 week exercise (male sprague-dawley, 3 months)

Berchtold et al., 2002

Exercise increases BDNF protein


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Exercise increases BDNF protein

Distance (meters/night)

500040003000200010000

60

120

180

240300

360

BDNF(pg/ml)

R2 = 0.771

D.

EX SED0

100

200

300

BDNF(pg/ml)

*C.

Group

Many plasticity genes are regulated


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by BDNF,e.g., Synapsin: Regulates presynaptic vesicle availability

Modulates neurotransmitter release into synapse

Block TrkB in vivo suppresses exercise-induction of synapsin mRNA (Gomez-Pinilla,2003)

CREB: Transcription factor, drives downstream gene expressionImportant in LTP, learning and memory

Block TrkB in vivo suppresses exercise-induction of CREB (Gomez-Pinilla, 2003)

NR2b: subunit of glutamate receptor (NMDA)Overexpression enhances LTP and improves learning Slice culture: BDNF increases NR2b protein

NARP: Trafficking/insertion of glutamate receptors in PSD,

critical to LTP and learning Slice culture: BDNF increases NARP protein

COX-2: traditionally known for immune functionRole in plasticity: localized to dendrites Slice culture: BDNF increases COX-2 protein

Exercise restores some of theage-related losses in synaptic


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age related losses in synaptic

proteins

50

75

100

125

150

PSD-95 VESL/homer COX-2 Synapsin

%

YoungSe

dentary

CNS and Peripheral FactorsInteract with Exercise to Regulate


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Interact with Exercise to Regulate

BDNF

Exercise Hippocampus DownstreamfunctionalchangesBDNF

Medial Septum(ACh/GABA)

Locus Coeruleus (NE)

Raphe (5-HT)

Peripheral Factors

Blood-Brain Barrier

IGF-1EstrogenGlucocorticoids

Cotman and Berchtold (2002), TINS

Practical Questions


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Practical Questions

How long lasting is the increase after

stopping exercise? How frequent is necessary

Can the increase be recoveredrapidly if exercise is stopped for a

peroid?

BDNF Protein Stability


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After Exercise Ends


0

20

40

60

80

100

120

140

160

180

SED

BDNFprotein(%s

edentary)

0 1 3 7 14

Days after end of exercise(4 weeks Daily Exercise)

*** ***

* *Paradigm: 4 weeks daily voluntaryexercise

Day 0 - end of exercise

period,- wheels locked

Sacrifice on days 0,1,3,7,14

after end of exercise

Protein levels assessed

Time course of BDNF Protein


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Induction

0

25

50

75

100

125

150

175

200

225

250

0

25

50

75

100

125

150

175

200

225

250

20 4 7 14 28 72

DAILY EXERCISE

***

***

***

0 7 14 28

*

**

ALTERNATING DAYS

BDNFP

rotein

(%S

edentary)

Days Days


Is there a molecular memory


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for exercise?

Many of the gene changes including CREB arelinked to learning and memory

Is the experience of exercise encoded so to

allow the brain to learn to respond?

Thus, if so exercise may prime the brain to

respond to experiences, and induce a state ofreadiness.

Once exercise stops is the induction stored in

molecular memory?!


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molecular memory?!

0

25

50

75

100

125

150

175

200

1 wk delay2 wk delay

Daily Alternating DaysSED

*** *** *** ***

roten

(%s

edentary)

Paradigm:

14 days of exercise:- Daily (during 2 weeks)

- Alternating (during 4 weeks)

Wheels locked:- 1 week, 2 weeks

Second short run period (2 days)

Note: 2 days exercise alone isnot sufficient to increase BDNF

Prior Exercise Primes subsequent BDNFResponsiveness

Priming effect endures at least 2 weeks

Equivalent Secondary Responsiveness ifprior exercise is Daily Regime or

Alternating Days of Exercise

So What is the


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functional significance

of brain changes

induced by exercise? Learning? Stress relief?

Exercise Enhances


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Learning in the Morris Water Maze

0

20

40

60

80

100

120

Timetoreachplatform(

sec

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6

Days of training

Sedentary

Exercising

* p < 0.05*

*

**


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Is exercise an effective intervention


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in AD transgenic models ?

Will voluntary running improve learningand memory?

Reduce -amyloid in the brain?

Stimulate neurogenesis?

Voluntary Exercise Paradigm


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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

Long-term running enhances the rate


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of learning in TgCRND8 animals


load in TgCRND8 animals


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g(by immunohistochemistry)

Short-term running mediates APP

processing


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0

20

40

60

80

100

120

A1-40 A1-42

P

ercentage

of

seden

tary

Sedentary

Exercise

0

20

40

60

80

100

120

alpha-CTF beta-CTF

P

ercentage

of

sede

ntary

Sedentary

Exercise

no effect on total APP

no effect on secretase activity (, , )

no effect on neprilysin or IDE

Why is learning and memory


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improved?

Hypothesis Neurogenesis? Hypothesis A may impair CREB and

Elk transcriptional activity essential forlearning and memory, e.g., induced by

BDNF



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Recent clinical/ epidemiological


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findings Exercise and intellectual activities in mid life delay ADonset (Friedland, 2001)

TV is associated with an increased risk of AD, 1.3Xrisk/hr of TV/day (Friedland, 2005)

Exercise increases brain volume in select areas andlarger brains are associated with those most fit (Kramer,2004,2005)

Women who get the most exercise show less cognitivedecline (Yaffe, 2005;Grodstein, 2004)

Those engaged in 4 or more physical activities have halfthe risk for AD, but mainly for ApoE4 carriers (Lyketsos,2005)

Exercise


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Functional changes:

Exercise

? -Increase BDNF-synaptic plasticity

-Increased neuron

number

-Improve learning

Documents

Cotman - Ppt