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Can exercise help repair the FASD brain?. UBC Campus, Vancouver. UBC/UVIC Campus, Victoria. Brian Christie, Division of Medical Sciences. Department of Psychology. UBC - Cellular and Physiological Sciences UVIC - Division of Medical Sciences. Studying the brain. 100 billion neurons.

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can exercise help repair the fasd brain

Can exercise help repair the FASD brain?

UBC Campus, Vancouver

UBC/UVIC Campus, Victoria

Brian Christie,

Division of Medical Sciences

Department of Psychology

UBC - Cellular and Physiological Sciences

UVIC - Division of Medical Sciences

studying the brain
Studying the brain

100 billion neurons

Each neuron has 1000 to 10000 synapses

new neurons in an old brain
New Neurons in an Old Brain?

Human Cells

Rat Cells

2 3 times as many new neurons in animals that exercise
2-3 times as many new neurons in animals that exercise!

Basic Questions:

Do these new cells have a purpose?

Does prenatal ethanol exposure affect them?

exercise seems to enhance both the function and the structure of the brain
Exercise seems to enhance both the function and the structure of the brain:
  • Have more new neurons
  • Have more synapses and bigger dendrites
  • Have more “good chemicals” in their brains
  • Learn faster
  • Remember longer

Animals that exercise:

Can we use this knowledge to do something positive?

the fas fasd brain
The FAS/FASD Brain”

1. There is cell loss in the Hippocampus of offspring following prenatal ethanol exposure.

2. Hippocampal cells do not appear to be fully mature.

3. Animals (including humans) exposed to ethanol exhibit impaired learning.

4. Neurons in the brain do not communicate as well as they should.

Can exercise rescue animals from the deleterious effects of PNEE?

slide7

Brian Christie, DMS, UVIC

Ethanol exposure in the first two trimesters:

  • These experiments require 3 groups of animals
    • 1. Ad Libitum Controls (AL)
    • 2. PNEE (35.5% ethanol derived calories)
    • 3. Pair-fed (PF) get the same number of calories as PNEE animals but have maltose-dextrin substituted for ethanol.

Ethanol Diet

Pair-fed, No Ethanol

Ad Libitum (no diet, no alcohol)

slide8

Brian Christie, DMS, UVIC

Gestation Day 1

Female rats become

pregnant and

or

begin prenatal feeding

(ethanol, pair-fed,

or ad libitum diet).

23 days

Postnatal Day 1

Special diets end.

Pups are born.

Litters are culled to 10

(5 m and 5 f).

22 days

Female

Male

Postnatal Day 22

Offspring

Offspring

Pups are weaned

and housed individually in either normal cages

or cages containing an exercise wheel

according to sex and prenatal diet.

The offspring

Never drink themselves

* Note this is the equivalent of drinking in G1 and G2 only.

slide9

Brian Christie, DMS, UVIC

BehaviouralTesting in the offspring when they are adults (P50-60).

Reference memory

Working memory

slide10

Hippocampal Long-Term Potentiation:A Biological Mechanism for Learning and Memory.

Naïve Response

Conditioned Response

Increase in Slope

Path A

5 mV

10 msec

LTP Induced at Synapses in Conditioned Pathway only.

reading an ltp graph

LTP

LTD

Reading an LTP Graph

Response Size

Time

slide12

Brian Christie, DMS, UVIC

Normal adult animals show more LTP when they are allowed to exercise.

slide13

Brian Christie, DMS, UVIC

Pair-fed animals also show more LTP when they are allowed to exercise.

slide14

Brian Christie, DMS, UVIC

PNEE animals also show more LTP when they are allowed to exercise!

slide15

Brian Christie, DMS, UVIC

After exercising, PNEE animals do slightly better than normal “non-exercising” animals.

slide16

24 Hr

4 weeks

Cell Proliferation

Neurogenesis

BrdU Injection

slide18

Brian Christie, DMS, UVIC

1200

*

VE

Con

1000

*

*

800

Mean # BrdU cells/hpc

600

400

200

0

PNEE

Pair-fed

Ad-lib

DG Neurogenesis

exercise increases dendrite complexity and length

Brian Christie, DMS, UVIC

Exercise increases dendrite complexity and length.

Wang and Wojtowicz, 2000

Eadieet al., 2005

Redila et al., 2006

take home messages

Brian Christie, DMS, UVIC

Take Home Messages
  • Exercise enhances neurogenesis in the DG.
  • Exercise enhances synaptic plasticity in the DG.
  • Exercise increases dendritic complexity in the DG.
  • Exercise enhances learning in behaviors that seem to involve the DG.
  • Early teratogen exposure can reduce neurogenesis, synaptic plasticity, and learning.
  • Exercise may help to alleviate these deficits.
slide21

Brian Christie, DMS, UVIC

Acknowledgements

PDF

MD

PhD

MD

RNA

MD

MD

MD

PDF

  • Supported by:
  • Alcoholic Beverage Medical Research Foundation
  • Human Early Learning Partnership
  • CIHR

PhD

MSc

fasd and oxidative stress

ROS

Lipid peroxidation

FASD and Oxidative Stress

Impaired membrane fluidity

4HNE and MDA

production

Mitochondria damage

Protein and DNA adducts

CYP2E1

Alcohol

(CH3CH2OH)

Acetaldehyde

(CH3CHO)

ADH

Redox Modifications

Altered cell signalling

ALDH

Decreased glutathione

pool

Acetate

(CH3COO-)

Cell Death

Decreased antioxidant

protection

Krebs Cycle

Cognitive and Behavioural Problems

omega 3 fatty acids
Omega-3 fatty acids
  • Essential polyunsaturated fatty acids
  • Incorporated into membrane phospholipids
  • Α-linolenic acid (precursor)
  • EPA (20:5ω3)
  • DHA (22:6ω3)
rodent model of fasd
Rodent model of FASD
  • Liquid diet (1st and 2nd trimester equivalent)
  • Ethanol Treated Group
  • Pairfed Group (stress and nutrition control)
  • Ad Libitum Control Group

Average BAC Level in Ethanol exposed dams on GD15: 103g/dl

slide26

Glutathione helps remove alcohol from cells.

If the body is exposed to a toxin such as alcohol then GST can bind GSH to the toxin and create a detoxified compound that can then be excreted from the system

GSH

GST

X alcohol

GS-X

GSH: Glutathione

GST: Glutathione-S-Transferase

slide27

Glutathione helps reduce reactive oxygen species associated with Alcohol.

- Mitochondrial

Respiration

- Metabolism of alcohol

O2-

SOD

GPx

H2O2

H2O

CAT

H2O

GSSG

GSH

OH

GSH: Glutathione

GST: Glutathione-S-Transferase

GR: Glutathione Reductase

GPx: Glutathione Peroxidase

GSSG: Glutathione disulfide

GR

we need antioxidants to prevent cellular damage

Protein Carbonyl Formation

We need antioxidants to prevent cellular damage.

Protein

Fe+2

Arg

Lipid Peroxidation

Thr

Pro

H202

Disrupted membrane fluidity

Protein Carbonyl

Cellular Dysfunction

Cell Death

Malondialdehyde (MDA) release

Protein and DNA Adducts

fasd reduces brain glutathione levels
FASD reduces Brain Glutathione Levels

**

**

**

**

**

**

**

Ad Libitum control

Ethanol

Pairfed

** = p < 0.001

fasd does not change the availability of antioxidant enzymes
FASD does not change the availability of antioxidant Enzymes

GPx

H2O2

H2O

GSH

GSSG

GST

GS-X

X

GR

CAT

SOD

2H2O2

2H2O

O2

H2O2

O2

O2-

slide32

**

**

**

**

**

**

**

**

Solid = Regular Diet

Stripes = Omega-3

* = p < 0.05

** = p < 0.001

*

*

*

*

*

omega 3 reduces oxidative damage
Omega-3 reduces oxidative damage

MDA = malondialdehyde (lipid peroxidation product)

slide34

Synaptic Plasticity

EPSP

TBS

Theta burst stimulation (TBS)

fEPSP slope (% change)

synaptic plasticity is impaired by pnee
Synaptic Plasticity is Impaired By PNEE

Ethanol, n=11

Pair-fed, n=12

Ad Libitum control, n=17

TBS

*

omega 3 supplementation restores synaptic plasticity
Omega-3 Supplementation Restores Synaptic Plasticity.

TBS

*

Ethanol n=11

Ad libitum control, n=17

Ethanol+ omega-3, n=17

link between gsh and ltp
Link between GSH and LTP?
  • Oxidative stress can decrease LTP

(Serrano and Klann, 2004; Auerbach and Segal 1997; Pellmaret al., 1991)

  • Depleting GSH also decreases LTP

(Almaguer-Milan et al., 2000; Steulletet al., 2006)

  • GSH Supplementation to slices increases LTP

(Robillardet al., 2011)

  • GSH can affect the redox state of the NMDA receptor

(Janaky 1999; Tan and Aizermann 1993; Ogita 1995)