Sound body, Sound mind

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

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

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

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

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)

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

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

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

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

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

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

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

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)

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

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

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%

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)

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%

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

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???

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

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

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

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

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

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

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

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

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

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

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

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

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)

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

So don’t stop exercising! https://www.youtube.com/watch?v=9CaXvv7GwCM

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

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

Shock avoidance