Sound body, Sound mind

1. Sound body, Sound mind

2. Roadmap • Effects of exercise on brain-derived neurotrophic (BDNF) • BDNF regulation and function in the hippocampus • Short term effects of exercise on BDNF • How exercise, BDNF, and LTP all come together • Benefits of exercise

3. More than just a hot bod Studies have shown exercise: • Improves depressive symptoms • Enhances coping capacity in response to stress • Decreases anxiety • Improves learning, memory, cognition • Enhances mood

4. Brain-derived neurotrophic factor • Most abundant neurotrophic factor in the brain • Has a role in: • Cell survival • Neurogenesis • Neuroplasticity • Neuroprotection • Enhanced BDNF in hippocampus improves both short-term and long-term memory

5. H.S. Oliff (1998) Exercise-induced regulation of brain-derived neurotrophic factor (BDNF) transcripts in rat hippocampus

6. What’s the relationship? • Pervious results: two nights of voluntary wheel running upregulates BDNF mRNA expression in the hippocampus • Oliff studied the effects of shorter exercise bursts on BDNF expression • 0, 6, and 12 hours of running wheel exercise for rats • Investigated the possible preferred transcriptional pathways involved in the short-term exercise (not talking about those today)

7. Materials and Methods • Male Fisher rats were trained on a running wheel for 3 nights • Then given 10 nights to attenuate any effects of running • Zero hour group sacrificed immediately after 10 night attenuation • Remaining rats were given 6 or 12 hours of voluntary running before they were sacrificed • Controls were sacrificed at the same time, but were never exposed to the wheel

8. Results • BDNF mRNA levels were significantly increased in the CA1 region of the hippocampus • At zero hours

9. Results • BDNF mRNA levels were significantly increased in all hippocampal areas, except DG • At 6 hours

10. Results • Exon I mRNA levels follows what has been observed in previous tests • Expression of all hippocampal areas significantly increased, except CA1 • Only CA1 shows a significant increase in Exon II mRNA level

12. Running wheel exercise increased BDNF mRNA levels in the hippocampus nearly as a whole during short bursts of exercise • Positive correlation between distance ran and BDNF expression

13. Z.H. Fang (2013) Effect of treadmill exercise on the BDNF-mediated pathway in the hippocampus of stressed rats

14. BDNF and Exercise • Reduction in BDNF is associated with depression • Physical activity increases BDNF in the hippocampus • To levels near that of antidepressants

15. Pathway of BDNF  Depression relief GSK-3B  antidepressant action BDNF TrkB PI3K/Akt mTOR p70S6K  antidepressant action • Ketamine activates mTOR (promotes antidepressant action) • Rapamycin inhibits mTOR (blocks antidepressant action)

21. Pathway of BDNF  Depression relief • mTOR increases synapse formation in the hippocampus via: • Cell-adhesion molecules • Neuroligin 1 (NLG 1) • B-neurexin • Scaffolding proteins • Postsynaptic density protein-95 (PSD-95) • Synaptic vesicle machinery proteins • Synaptophysin (SYP) • Loss of SYP is associated with Alzheimer’s disease

22. Materials and Methods • 8 week old Sprague-Dawley rats • 4 groups: • Control sedentary • Control exercise • Stressed sedentary • Stressed exercise • Stressed groups were given 2h/day immobilization stress for 7 days • Exercise groups were ran on treadmills after 2h of stress for 5 days

23. Results • Immobilization decreased levels BDNF and Trk receptor in the hippocampus • BDNF 51% / Trk 48% • Treadmill exercise reversed stress induced decreases • BDNF 141% / Trk 90% • Treadmill exercise increased BDNF and Trk levels in the absence of stress • BDNF 170% / Trk 131%

25. Results • Immobilization decreases levels of Akt, GSK-3B, mTOR, and p70S6K • 65% / 54% / 39% / 56% (respectively) • Treadmill exercise reversed the reduction of these proteins • 109% / 74% / 94% / 132% (respectively) • Treadmill exercise alone increased levels of these proteins in the absence of stress • 153% / 141% / 120% / 159% (respectively)

27. Results • Immobilization decreased pre/postsynaptic protein expression • SYP 44% / PSD-95 52% / B-neurexin 57% / NLG 1 51% • Treadmill exercise rescued protein expression • SYP 98% / PSD-95 124% / B-neurexin 112% / NLG 1 118% • Treadmill exercise increased protein expression in the absence of stress • SYP 152% / PSD-95 153% / B-neurexin 133% / NLG 1 134%

29. Treadmill exercise increased BDNF levels • Activating Akt and mTOR, while inhibiting GSK-3B via TrkB receptor signaling • Increasing levels of synaptic protein levels via activation of mTOR

30. Previous Studies • Found that disruption in the HPA axis lead to excessive levels of glucocorticoids (corticosterone), associated with depression • Repeated immobilization stress lead to increased levels of corticosterone and a reduction in hippocampal BDNF • Changes were prevented by antidepressant administration • Could exercise replace/suppliment the antidepressants???

32. What could start this? • Serotonin (5-HT) and/or norepinephrine (NE) could be increasing BDNF levels during exercise • 5-HT/NE  cAMP/PKA  CREB  BDNF • 5-HT/NE increases after antidepressant administration • But… therapeutic effects begin 3-4 weeks after • Maybe mTOR or GSK-3B is responsible for the rapid antidepressant action of exercise

33. More than just another Prozac • BDNF inhibits GSK-3B promoting synaptic plasticity and neuroprotection • Neuroprotection believed to be needed for antidepressant action • BDNF = Good, because activation of GSK-3B leads to apoptosis • BDNF and PSD-95 may influence synaptogenesis • Increasing the number/size of dendrite spines in hippocampus • BDNF and PSD-95 KO mice show altered long-term memory and impaired learning

36. S.E. Kim (2013) Treadmill exercise and wheel exercise enhances expression of neurotrophic factors in the hippocampus of lipopolysaccharide-injected rats

37. Putting our money where our tropin is! • Induced brain inflammation similar to what is seen in chronic neurodegenerative disorders via Lipopolysaccharide (LPS) • Alzheimer’s disease • Parkinson’s disease • LPS degenerates learning ability and memory • Suppresses long term potentiation (LTP) • LTP – The process by which a junction increases its strength • Increased synaptic plasticity

39. Coming back to CREB • BDNF work through its receptor TrkB to enhance LTP in the hippocampus • Modulates neural growth and memory processing • Positive correlation – the more learning/memory tasks the greater the concentration of BDNF in the hippocampus • Before BDNF, cyclic AMP response element biding protein (CREB) regulates expression of BDNF • Decreases in CREB are seen in deterioration of the hippocampus • E.g.: Age-induced memory impairment

40. Materials and Methods • Six week old Spargue-Dawley rats • Separated into 4 groups: • Sham-operation • Brain inflammation-induced • Brain inflammation-induced and treadmill exercise • Brain inflammation-induced and wheel exercise • Brain inflammation was induced via LPS

41. Materials and Methods • Exercise began one day after LPS injections • Treadmill exercise group was forced to run for 30 min/day for 6 weeks • Wheel exercise group was placed in cages with a running wheel • Allowed to exercise voluntarily

42. Materials and Methods • Spatial learning ability was determined using a Morris water maze • Data was measured via: • Western blot analysis • Electrophysiological recordings

43. Results • Injection of LPS increased swim path distance and the latency to escape when compared to the sham group • Treadmill and wheel exercise significantly decreased both the swim distance and latency to escape • Both exercise group had similar recovering effects on spatial learning

45. Results • BDNF, TrkB, and CREB all showed significantly reduced levels in the LPS induced brain inflammation group • Both treadmill and running wheel exercise significantly enhanced levels of BDNF, TrkB, and CREB in the exercise groups

47. Results • Synaptic signals potentiated by a 25 mM TEA application for 10 minutes • Brain inflammation significantly inhibited TEA-induced LTP in CA3 mossy fibers of hippocampus • Treadmill and wheel exercise groups recovered TEA-induced LTP previously suppressed by brain inflammation • Recovery effects of exercise were similar for treadmill and wheel groups

50. Bringing it all together! • LPS induced brain inflammation impairs memory and learning ability • Changes to memory/learning associated with BDNF, TrkB, and CREB • Activation of the immune system down regulates neurotrophic factors and impairs LTP • LPS suppresses LTP in CA3 region of the hippocampus • Exercise reverses memory/learning impairments due to LSP • Regardless of type of exercise, and possibly the means (forced vs volunteer)