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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. 100 billion neurons.

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Can exercise help repair the FASD brain?

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  1. 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

  2. Studying the brain 100 billion neurons Each neuron has 1000 to 10000 synapses

  3. New Neurons in an Old Brain? Human Cells Rat Cells

  4. 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?

  5. 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?

  6. 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?

  7. 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)

  8. 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.

  9. Brian Christie, DMS, UVIC BehaviouralTesting in the offspring when they are adults (P50-60). Reference memory Working memory

  10. 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.

  11. LTP LTD Reading an LTP Graph Response Size Time

  12. Brian Christie, DMS, UVIC Normal adult animals show more LTP when they are allowed to exercise.

  13. Brian Christie, DMS, UVIC Pair-fed animals also show more LTP when they are allowed to exercise.

  14. Brian Christie, DMS, UVIC PNEE animals also show more LTP when they are allowed to exercise!

  15. Brian Christie, DMS, UVIC After exercising, PNEE animals do slightly better than normal “non-exercising” animals.

  16. 24 Hr 4 weeks Cell Proliferation Neurogenesis BrdU Injection

  17. Brian Christie, DMS, UVC

  18. Brian Christie, DMS, UVIC 1200 * VE Con 1000 * * 800 Mean # BrdU cells/hpc 600 400 200 0 PNEE Pair-fed Ad-lib DG Neurogenesis

  19. Brian Christie, DMS, UVIC Exercise increases dendrite complexity and length. Wang and Wojtowicz, 2000 Eadieet al., 2005 Redila et al., 2006

  20. 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.

  21. 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

  22. 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

  23. Omega-3 fatty acids • Essential polyunsaturated fatty acids • Incorporated into membrane phospholipids • Α-linolenic acid (precursor) • EPA (20:5ω3) • DHA (22:6ω3)

  24. 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

  25. Does prenatal ethanol exposure alter the capacity of the brain to handle oxidative stress?

  26. 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

  27. 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

  28. 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

  29. FASD reduces Brain Glutathione Levels ** ** ** ** ** ** ** Ad Libitum control Ethanol Pairfed ** = p < 0.001

  30. 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-

  31. Does Omega-3 fatty acid supplementation enhance glutathione levels and reduce oxidative stress?

  32. ** ** ** ** ** ** ** ** Solid = Regular Diet Stripes = Omega-3 * = p < 0.05 ** = p < 0.001 * * * * *

  33. Omega-3 reduces oxidative damage MDA = malondialdehyde (lipid peroxidation product)

  34. Synaptic Plasticity EPSP TBS Theta burst stimulation (TBS) fEPSP slope (% change)

  35. Synaptic Plasticity is Impaired By PNEE Ethanol, n=11 Pair-fed, n=12 Ad Libitum control, n=17 TBS *

  36. Omega-3 Supplementation Restores Synaptic Plasticity. TBS * Ethanol n=11 Ad libitum control, n=17 Ethanol+ omega-3, n=17

  37. 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)

  38. GSH Depletion Impairs Synaptic Plasticity

  39. Acknowledgements

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