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 % / B-neurexin 112% / NLG 1 118%
Treadmill exercise increased protein expression in the absence of stress
SYP 152% / PSD % / 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 Data was measured via:
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

49. Black square = Sham operation group
Black circle = brain inflammation group
White square = brain inflammation + treadmill group
White circle = brain inflammation + wheel group
Observe the end pattern of each signal (white shapes trend together, aka exercise groups, and black box has a greater amplitude than black cicle

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)

51. Conclusion
CREB activation promotes production of BDNF in the hippocampus
BDNF in the hippocampus improves memory/learning function in aging rats
BDNF has neuroprotective properties that can reverse memory/learning impairment due to damaging inflammation
Exercise (both voluntary and forced) upregulates levels of CREB, BDNF, and their associated pathways
Activation of this system lead to neuroplasticity (LTP) and neurogenesis
Suppression can lead to apoptosis

52. So don’t stop exercising!

53. Long story short, work out and one day you can be the president!

54. A bit of extra info K.C. Wang (2013)
Chronic inflammation (by LPS) in neonatal rats did not cause actual cell death of dopaminergic neurons in SN
Recoverable by adult ages
LPS exposure and subsequent inflammation lead to learning/memory deficits
Tested using risk avoidance task
Less “anxiety-like” responses in the EPM
Axonal injury in the CA1 region of hippocampus

55. Shock avoidance