Jacob Trotter and Dr. Jeffrey Edwards, Department of Physiology and Developmental Biology
Introduction
The hippocampus is an area of the brain that mediates learning and memory by changing the properties of synapses between its neurons. This ability of synapses to change is known as synaptic plasticity. Long-term potentiation (LTP), a long-lasting increase in signal transmission between two neurons, is one of several phenomena underlying synaptic plasticity and is the cellular correlate of memory and learning. Several studies of LTP in mice show that there is a marked impairment of LTP in hippocampal slices taken from rodents exposed to stress. Their data suggests that stress may lead to deficits in learning and memory. In fact, behavioral studies in mice show a significant decrease in performance on memory tasks. Although stress has been shown to be detrimental to our ability to acquire and store new information, there has been increasing evidence that exercise has profound benefits for learning and memory. Exercise enhances LTP in the hippocampus and also improves results on memory tasks. These results suggest that exercise might be able to serve as a defense against the effects of stress on learning and memory. Despite this possibility, there has yet to be a study incorporating both stress and exercise in hippocampal mediated learning and memory. For this reason, we conducted an experiment to investigate this possibility.
Methods
All subjects were male mice from our colony maintained at the Life Sciences Laboratory Animal Facility at Brigham Young University. All experimental procedures were approved by the Institutional Animal Care and Use Committee of Brigham Young University. Mice were separated randomly after infancy into cages with or without exercise wheels. Mice in exercise cages were allowed to exercise ad libitum (voluntarily) for at least a month prior to experimentation. Exercise was quantified using odometers on the running wheels to measure the distances ran by the mice. Mice were separated into four groups: control mice (no-stress-no-exercise), stress-no-exercise mice, exercise-no-stress mice, and stress-exercise mice. Stress mice underwent a three-day stress protocol prior to experimentation. On the first day, mice underwent a cold-swim stress in which they were required to swim for five minutes in 5-10°C water. On the second day, mice were placed on a high platform with no sidewalls for 25 minutes. On the final day, the mice were placed in a restraining tube and shocks were administered to their tails every minute for an hour. Mice were anesthetized using Isoflourane and immediately decapitated. Coronal brain slices were cut using a vibratome with a thickness of 400 μm. Slices were transferred to a recording chamber held at ~30°C and perfused with artificial cerebrospinal fluid. Cellular electrical activity was recorded as fEPSPs (field excitatory postsynaptic potentials) in the stratum radiatum of the CA1 region of the hippocampus. Using a bipolar stimulating electrode the brain slices were stimulated with a precise current and following a 15-minute baseline, a theta stimulus (two bursts of 5 pulses at 100 Hz, repeated at 200 μsec intervals ten times) at 1½ times baseline current was used to induce LTP. Recordings were digitized and analyzed using laboratory software (Clampex, Clampfit, Excel, Origin). Multiple experiments were averaged to determine the net effect of each group.
Results
The differences in LTP levels were compared between the various experimental groups using a Student’s t-Test. We found the sedentary-stress mice to have significantly decreased LTP when compared to the control mice (p=.03). While we anticipated enhanced LTP in our exercise-no-stress group, we did not observe a significant difference between the control mice and exercise-no-stress mice (p=.13). The exercisestress mice exhibited LTP levels similar to the control mice (p=.47) and LTP levels that were significantly greater than the exercise-no-stress mice (p=.04). (See Figure 1)
Discussion
Since memory and learning are vital components of everyday life, it is important to recognize the influence of stress on memory and to be aware of possible ways to counter its negative effects. From our results it appears that exercise may be an effective way to counter the effects stress has on cognitive functions such as memory and learning. The mechanism through which exercise improves memory and learning is still unknown; however studies involving exercise suggest that Brain Derived Neurotrophic Factor (BDNF) may play a critical role. For example, one study showed that animals that exercised regularly prior to a forced swim stress were protected from normal reductions in BDNF and that animals that were depleted of BNDF exhibited anxiety-like behaviors1. Further investigation of BDNF mechanisms is still needed and perhaps could help in the development of therapies for various cognitive impairments.
Conclusion
In conclusion, it appears exercise can help counter the reduction of LTP due to stress and help preserve the associative learning pathways in the mouse hippocampus. By inference, it is likely that exercise also plays a significant role in human hippocampal health. Taking this into consideration, exercise may serve as a safe and cost-effective therapy to combat the harmful effects of stress on cognitive health, particularly learning and memory. Our results contribute to the continually growing body of literature demonstrating the benefits exercise has on not only physical health, but also cognitive function and overall quality of life. The physiological effects of exercise deserve further investigation and may contribute to our understanding of neurodegenerative disease and treatment.
Figure 1 – Comparison of the averaged fEPSPs between experimental groups. Baseline cellular electrical activity was established the first 15 minutes. The arrow marks the induction of LTP using Theta Burst stimulation. After the arrow we see the differing levels of LTP achieved by each experimental group.
1Russo-Neustadt A, Ha T, Ramirez R, Kesslak JP. Physical activity–antidepressant treatment combination: Impact on brain-derived neurotrophic factor and behavior in an animal model. Behavioral Brain Research. 2001;120(1):87- 95.