Effects of physical exercise on memory

Physical exercise, particularly continuous aerobic exercises such as running, cycling and swimming, has many cognitive benefits and effects on the brain. Influences on the brain include increases in neurotransmitter levels, improved oxygen and nutrient delivery, and increased neurogenesis in the hippocampus. The effects of exercise on memory have important implications for improving children's academic performance, maintaining mental abilities in old age, and the prevention and potential cure of neurological diseases.

Exercise has many physiological benefits, including advantageous effects on learning and memory. Gene expression associated with brain plasticity increases with exercise, which enhances neurogenesis, blood flow, and neuronal resistance to injury, specifically in the hippocampus. The hippocampus is crucial for learning and memory storage. Neuroimaging techniques also show changes in brain structure and function with regular exercise in human studies. Increases in cerebral blood volume in the dentate gyrus of the hippocampus are associated with verbal learning and memory improvements, with cerebral blood volume possibly indicating neurogenesis. Animal research has shown that exercise increases neuronal growth, cognitive function, and positively impacts neural systems associated with learning and memory.

The type of exercise is also related to the neurological improvements seen. Aerobic exercise (also known as "cardio") is physical exercise of relatively low intensity. People that regularly participate in aerobic exercise have greater neuropsychological test scores compared to people that participate in strength and flexibility training. This trend has been demonstrated in elderly individuals. Types of aerobic exercise include:
 * Brisk walking
 * Running / jogging
 * Swimming
 * Cycling

Physical activity benefits cognition as a whole. Specifically, however, executive control processes (such as working memory, multitasking or planning) are more positively affected in comparison to other regions of the brain. This demonstrates the direct link between the improvement in memory processes and aerobic exercise. The prefrontal cortex is primarily responsible for supporting executive control processes, and studies suggest exercise may be used as an intervention to prevent age-related decline in executive control and memory.

Increased oxygenation
One of the immediate effects of exercise is the increased flow of oxygen and rapid delivery of nutrients to the brain. Regular exercise increases the supply of tiny blood vessels that bring oxygen-rich blood to brain regions involved in cognitive functioning. Evidence suggests that aerobic exercises that allow you to breathe at a steady rate and carry on a conversation may be more beneficial to the brain than anaerobic exercises such as sprinting. In strenuous exercise, the muscles require more oxygen and glucose to continue working, which leaves less oxygen available for the brain. Continuous activities such as brisk walking are a much more effective means of increasing brain circulation, and may consequently produce more cognitive and memory benefits. This increased brain oxygenation caused by exercise is the reason why people find it easier to focus and sustain attention after going for a walk or jog. When walking, leg muscles do not utilize as much oxygen as they do with other more strenuous exercises. This increases oxygenation, glucose, and circulation in the brain leading to elevated oxygen delivery and improved brain performance.

Reduced stress
Stress has many physiological effects and pathological impacts on the body. It inhibits the growth of new brain cells through the release of the hormone cortisol. Significant stress-related decreases in the volume of the hippocampus can be seen in rats, and longer depression duration is also linked to hippocampal atrophy. When exposed to a psychosocial laboratory stress, subjects with high stress-induced cortisol levels showed poorer memory performance, specifically in declarative memory. If a patient is administered cortisol, independent of the psychological stress, they show impaired performance in declarative memory as well as spatial tasks. The negative impact of stress can also be seen at the genetic level. Physiologically, stress exposure induces a decrease in BDNF mRNA levels which can lead to depression. Exercise can treat or prevent the stress-induced decrease in BDNF expression associated with acute stress exposure.To combat these detrimental effects on the body, exercise is a natural way of relieving everyday stress.

There are a number of ways in which exercise may serve to reduce stress and consequently free up one's attentional resources and improve memory:
 * Exercise relaxes muscles: Being stressed causes the muscles in the body to become tense and stiff. Physical activity improves oxygen delivery to the muscles, removing tension and muscle soreness.
 * Exercise produces feeling of happiness: Through the production of endorphins, exercise removes stress by creating a peaceful feeling of euphoria.
 * Exercise reduces feelings of frustration: A good way to relieve yourself of stressful thoughts is to go for a walk or jog. Performing physical activity forces the brain to concentrate on your body and its surroundings, giving the mind a break from focusing solely on frustrations.
 * Exercise improves stress resiliency: People who exercise are more likely to have less of a stress reaction to adverse situations.

Cortisol
Cortisol is a glucocorticoid that is released from the adrenal gland in response to stressful situations. Studies have shown that excessive cortisol interferes with the function of neurotransmitters and impairs the ability to retrieve long term memories. Rats stressed by an electrical shock thirty minutes before navigating through a familiar maze show significantly lowered performance. This same result occurs in rats injected with cortisol directly, confirming its role in memory impairment. A study at the University of Zurich also demonstrated the detrimental effects of cortisol on memory. Healthy adults were asked to memorize a series of unrelated nouns presented on a screen for four seconds each, and were then required to recall the words immediately after the learning trial, and one day after. Subjects who took a tablet of cortisone (a precursor of cortisol) one hour before the recall test administered the day after showed impaired memory performance. Memory was not affected when subjects took the cortisone one hour before the initial word presentation, or immediately after the word presentation. This suggests that cortisol impairs the ability to retrieve older memories (long term memory), but not the ability to encode or retrieve short term memories.

The primary effect of cortisol on memory function is its negative influence on the hippocampus. The natural stress response is mediated by the Hypothalamic-pituitary-adrenal axis. When a stressor is present, the hypothalamus releases corticotropin-releasing hormone (CRF), which stimulates the anterior pituitary gland to release adrenocorticotropic hormone (ACTH). This hormone travels to the adrenal glands, which are signalled to release cortisol. This cortisol is released into the body and travels to the hippocampus, which acts as a negative feedback mechanism. When cortisol reaches the hippocampus, it signals the hypothalamus to shut off CRF release, thereby shutting off the release of cortisol as well. Cortisol has been found to accelerate the degeneration of the hippocampus. Since aging naturally results in hippocampal atrophy, this presents an even larger problem. As the hippocampus shrinks over time, it loses its ability to provide proper feedback to the hypothalamus during the stress response, causing cortisol release to occur for longer periods of time. This, in turn, leads to further hippocampal decay due to the greater amounts of cortisol

Moderate-intense exercise produces stress on the body, and therefore releases cortisol. However exercise training increases the threshold for cortisol release, making the body more resilient to the effects of stress. The more physical activity you do, the more efficient the body becomes at dealing with both physical and mental stressors. Engaging in regular exercise therefore serves a protective function, warding off hippocampal atrophy by cortisol. This has serious implications for the prevention of neurological diseases such as Alzheimer's, since individuals with smaller hippocampi have been found to be at increased risk.

Endorphins
Endorphins are endogenous opioid polypeptides containing thirty amino acid units, that are released by the pituitary gland during periods of stress to produce analgesia by binding to the same receptors in the brain as opioids such as morphine. Engaging in continuous aerobic exercise for thirty minutes at a time or longer results in a large production of endorphins, creating the euphoric phenomenon known as "runner's high." The three main endorphins released by the pituitary during exercise are Alpha-Endorphin, Beta-Endorphin, and Gamma-Endorphin. Beta-Endorphin, formed mainly by the amino acid tyrosine, has the strongest impact on the brain and body during exercise due to its analgesic effects.

The role of endorphins in memory is not yet certain. Microinjections of posttraining Beta-Endorphin into the medial septal area of rats results in impaired spatial learning in a novel environment, but has no effect on working memory in a familiar environment. Administration of Naloxone(an opioid antagonist drug) into the medial septal area facilitates spatial learning in new environments. These results suggest that endorphins may impair a person's ability to acquire new memories. Other research has indicated that people with higher levels of endorphins have retained memories for a longer period of time and have shown improvements in learning. More research needs to be done to determine the exact mechanism by which endorphins impact learning and memory processes.

Brain Plasticity and Neurogenesis
Brain plasticity is essentially the ability of the brain to develop new neuronal connections. It is demonstrated often after injury or environmental changes. Exercise increases neurotrophic factors such as BDNF and IGF-1 which are necessary for survival of neurons, neuronal differentiation, and synaptic plasticity. Evidence supports that voluntary exercise leads to increased axon regeneration and neurite outgrowth compared to sedentary animals. The growth directly correlated with the amount of exercise the animal participated in, specifically the total distance the animal had run. The animals in the exercise condition showed an increased level of axonal regrowth after neural injury, due to higher neurotrophin levels such as BDNF. This shows how behaviours such as voluntary exercise can impact neurotrophin levels and neurogenesis, inducing activity-dependent plasticity. Exercise increases the expression of genes that are required for this rapid neural growth in the brain. Neurogenesis in the hypothalamus is linked to improvements in learning as well as in memory. For example, one study demonstrated exercise-induced neurogenesis in the hippocampus improved spatial memory.

BDNF
One of the most significant effects of exercise on the brain is the increased expression of BDNF (Brain-Derived Neurotrophic Factor) and its receptor TrkB (Tyrosine Kinase Receptor). BDNF is a secreted protein encoded by the BDNF gene, with highest levels of expression found within the cerebral cortex, hippocampus, thalamus, hypothalamus and cerebellum. Research has provided a great deal of support for the role of BDNF in hippocampal neurogenesis, synaptic plasticity, and neural repair. Engaging in moderate-high intensity aerobic exercise such as running, swimming and cycling, stimulates greater expression of BDNF and TrkB receptor. Animal studies have shown that mice forced to run on a treadmill show greater concentration of serum BDNF and enhanced performance on the Morris Water Maze than sedentary mice. Exercising mice that are given a specific protein to prevent the binding of BDNF to the TrkB receptor show no difference in spatial memory performance on the Morris Water Maze when compared to the sedentary control group. Exercise has also been shown to have a protective effect on BDNF, preventing a decrease in hippocampal BDNF proteins typically brought on by acute immobilization stress. Exercise negates the effects of stress on BDNF proteins, which in turn benefits the hippocampus by maintaining levels of neurotrophins in the brain.

IGF-1
IGF-1 (Insulin Growth Factor-1) is a single chain protein consisting of 70 amino acids with a similar chemical structure to insulin. It is produced primarily by the liver and functions to control body growth and tissue remodeling. Studies have shown that IGF-1 also plays a role in brain neurogenesis, angiogenesis and neural plasticity. Mice with low serum IGF-1 levels due to disruption of the IGF-1 gene within the liver showed impaired performance on spatial recognition tasks requiring the hippocampus. These deficits were removed by synaptic administration of IGF-1.

Physical activity is associated with increased IGF-1 activity within the brain, as well as enhanced cognitive abilities. Rats forced to run on treadmills over a two-week period showed higher levels of circulating IGF-1 accompanied by an increase in cell proliferation in the dentate gyrus and dendritic spine density of CA1 pyramidal cells. IGF-1 knockout mice who completed the same exercise program did not show these effects. The decline in neurogenesis typically associated with old age was slowed by exercise combined with IGF-1 treatment in rats.

Dopamine
Dopamine is a neurotransmitter produced in several areas in the brain, acting as a chemical messenger between neurons. It is important in the reward or pleasure signalling pathway, memory and motor control. However, the effects of dopamine are complicated and not very well understood. Low levels of dopamine are associated with depression, whereas high levels of dopamine are experienced when participating in pleasurable activities such as eating, exercise or sex. Addictive drugs such as cocaine or nicotine mimic the effects of dopamine in the brain. Dopamine is a precursor to norepinephrine and epinephrine, and levels of dopamine are responsive to levels in serotonin. These neurotransmitters are also involved in the effects of exercise on memory and cognitive processes.

Exercise increases dopamine levels in the brain through a calcium-dependent process that regulates numerous brain functions. Dopamine levels were regulated by exercise in epileptic and spontaneously hypertensive rats; demonstrating the possibility that exercise can be used to improve symptoms of Parkinson’s Disease or dementia (which are associated with low dopamine levels). Regular aerobic exercise has a protective effect on D2 dopamine receptor levels, also preventing any modifications in dopamine metabolism due to the aging process. The release of dopamine by neurons is necessary for sustaining neural activity and working memory. The main purpose and effects of dopamine are evasive because dopamine alters neuronal responses to other neurons that are connected by synapses. Results after an experiment that varies dopamine levels depend on how the cell is stimulated, inhibited or excited.

One experiment showed the impact of administration of a dopaminergic antagonist which inhibited D1/D5 dopamine receptors in the hippocampus. The reduction in dopamine levels caused impaired memory for encoding of new memories in an episodic-like memory task, but did not affect previous memories that had already been encoded. D1/D5 receptor activation is required while encoding in order to ensure the memory lasts. Dopamine is released in the hippocampus when attention is diverted to novel stimuli, perhaps to aid in memory encoding.

Serotonin
Serotonin (5-hydroxytryptamine: 5-HT) is a monoamine neurotransmitter derived from the amino acid tryptophan. It is found mainly within the gastrointestinal tract, but can also be found in the brain. Brain serotonin levels are elevated following physical activity through two mechanisms: It has been found that at least thirty minutes of daily aerobic activity such as running, biking or walking is needed to elevate serotonin synthesis in the brain. Weight lifting and stretching exercises have not been associated with increased serotonin levels.
 * 1) Motor activity increases both the release and synthesis of serotonin
 * 2) Exercise increases levels of tryptophan in the brain, which is then used to manufacture greater amounts of serotonin

Serotonin plays an important role in learning and memory, particularly in the acquisition and retrieval of short term memories. The receptor subtypes of serotonin that have been found within brain regions involved in memory function include the 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT6, and 5-HT7 classes. Agonists at the 5-HT2A, 5-HT2C and 5-HT4 receptor have produced improvements in memory. Intracerebroventricular injection of the selective serotonergic neurotoxin 5,7-dihydroxytryptamine impaired the creation of short term aversive odor-taste associations in the terrestrial slug Limax, and lowered the performance of rats in the Radial Arm Maze task. Rats with serotonin transporter (SERT) knockout show impaired object memory possibly due to lower intracellular serotonin levels. There is also evidence to suggest that serotonin may have a reciprocal relationship with BDNF, the neurotrophic factor strongly implicated in hippocampal neurogenesis and long term potentiation (LTP). BDNF elevates serotonin production and serotonergic signalling stimulates BDNF expression. Since exercise is known to substantially increase BDNF expression, this may be another mechanism through which physical activity increases brain levels of serotonin.

Serotonin is the primary neurotransmitter involved in depression. Depressed individuals have lower levels of serotonin than nondepressed individuals, and antidepressant medications such as SSRIs (Selective serotonin reuptake inhibitor) are often prescribed in an attempt to elevate serotonin activity. Neuroimaging has revealed reduced brain activity in the frontal lobes of depressed patients, and tests have shown that depression impairs the ability to create long term memories due to lack of concentration. Physical activity has been proposed as a possible remedy for depression due to its ability to increase levels of brain serotonin. In this way, exercise may help prevent memory impairment through combating depression with heightened serotonin levels.

Norepinephrine
Norepinephrine has several roles as a hormone and as a neurotransmitter. Synthesized from dopamine, it acts in the central and sympathetic nervous systems by binding to adrenergic receptors. Packaged into vesicles, it is released into the synaptic cleft, transmitting signals by acting on adrenergic receptors. Norepinephrine is later degraded or taken up by other cells. The effect of norepinephrine depends on the expression of the receptors on the different cell types. It impacts the environment surrounding neurons, glial cells, neocortex, and hippocampus through its anti-inflammatory properties. Stressful events result in physiological changes that lead to the release of norepinephrine. It is released from the locus ceruleus, which is associated with most norepinephrine pathways in the central nervous system. Norepinephrine, as well as epinephrine, are responsible for the “fight or flight” response, increasing heart rate, glucose levels and blood flow which enhances alertness and arousal. Tyrosine is a precursor to dopamine, which is a precursor to norepinephrine and epinephrine. It is an amino acid found in meat, cheese, nuts and eggs. Norepinephrine has therapeutic uses. If not present in sufficient amounts it negatively impacts physiological and cognitive processes. Deficiencies in norepinephrine can lead to: Attention and focus are largely influenced by norepinephrine and dopamine concentrations. Norepinephrine has a stimulating effect that promotes long-term memory. It also prolongs the euphoric effect stimulated by endorphins by protecting them from being degraded prematurely. Psycho-stimulating drugs are prescribed in order to increase levels of norepinephrine and dopamine in patients with ADHD (Attention Deficit Hyperactivity Disorder). In Alzheimer’s Disease most norepinephrine projecting cells are lost. Norepinephrine is prescribed to people with severe hypertension, or to patients as an anti-depressant in serotonin-norepinephrine reuptake inhibitors. Levels of norepinephrine increase through exercise and through increased consumption of foods high in tyrosine in the diet. Exercise improves depression by increasing galinin, which is a neurotransmitter that controls norepinephrine production.
 * lack of motivation
 * lack of energy
 * depression

Emotional memory consolidation has been shown to be amplified by norepinephrine concentrations. The higher the noradrenergic activation is when presented emotion-evoking material, the greater the memory consolidation. Exercise directly post-learning increased norepinephrine levels that improved retrograde memory. The study independently separated the effects of norepinephrine on men and women, and found norepinephrine increased emotional memory consolidation regardless of age. An animal model demonstrating high levels of running activity was used in another study contrasting levels of norepinephrine in these active rats versus control rats. Results showed norepinephrine transmission in the hippocampus of active rats was higher than controls even when sedentary. Hippocampal norepinephrine levels play a role in memory and are elevated with regular exercise.

Glutamate
Glutamate, the most common neurotransmitter in the brain, is also the major excitatory neurotransmitter involved in many aspects of brain function including learning and memory. Animal studies have shown that treadmill running significantly increases glutamate levels during and for a short while following exercise in rats. The major role of Glutamate in memory is through its activation of NMDA receptors within the hippocampus.
 * NMDA Receptor
 * The NMDA (N-methyl-D-aspartate) receptor is a type of glutamate receptor found mainly in the CA1 (Cornu Ammonis area 1) region of the hippocampus, that plays a key role in spatial memory function and long term potentiation (LTP). Evidence for the role of NMDA in spatial learning has been shown through various animal studies in which NMDA receptor antagonists such as MK-801, ketamine and phencyclidine have been shown to significantly decrease performance on tasks such as passive avoidance and the Morris Water Maze. Mutant mice lacking the NMDA receptor subunit NR2A and NMDA receptor 1 knockout mice both show reduced hippocampal LTP and selectively impaired performance on spatial learning tasks. Studies have suggested that the NMDA receptor system may be important in the formation of new memories, but not in memory maintenance. This has been demonstrated by the fact that blocking the NMDA receptor after learning a task has no effect on memory performance in humans, whereas blocking these receptors before learning results in memory impairment. The positive effects of physical activity on the expression of NMDA receptors and glutamate activity is still being investigated, however a few studies provide support for this hypothesis. Synaptic plasticity in the dentate gyrus of the hippocampus shows increased LTP for mice who have access to an exercise wheel, compared to a control group who engage in no physical activity.

Structural Changes
Neuroimaging studies have revealed that physical activity is correlated with an increase in gray matter volume in several cortical regions associated with memory and encoding processes. Research on healthy adults engaging in medium intensity exercise has shown that the greatest changes in gray matter takes place within the cingulate cortex, prefrontal cortex, sections of the dorsal anterior cingulate cortex, supplementary motor area, and middle frontal gyrus. Areas implicated in memory and cognition that show increased gray matter volume in response to exercise include: Slight increases in gray matter volume following exercise has also been seen in the parietal cortex, specifically in the precuneus, that plays a role in episodic memory retrieval.
 * Dorsolateral Prefrontal Cortex: promotes long-term memory formation.
 * Anterior Prefrontal Cortex: involved in monitoring and verification of memory searches.
 * Anterior Cingulate Cortex: involved in early learning and problem solving
 * Ventral Anterior Cingulate Cortex: processes emotional content
 * Dorsal Anterior Cingulate Cortex: processes cognitive information.
 * Posterior Cingulate Cortex: shows activation in episodic recognition of previously encountered information.

The brain structure most highly affected by physical activity is the hippocampus. Regular exercise has been shown to counter the shrinking of the hippocampus that naturally occurs in late adulthood. A study conducted with 120 older adults revealed that participating in regular aerobic exercise increased the volume of the left hippocampus by 2.12% and the right hippocampus by 1.97% over a one year period. Adults who only engaged in low intensity stretching exercises showed a 1.40% and 1.43% decline in the left and right hippocampus respectively. Neuroimaging also revealed that exercise increases the volume of the anterior hippocampus but not the posterior hippocampus. Regions in the anterior hippocampus such as the dentate gyrus have been shown to be most involved in cell proliferation and spatial memory acquisition. Subjects in the study who underwent the greatest improvement in aerobic fitness level over the one year period as determined by VO2 max showed greater increases in hippocampal volume. Subjects in the low intensity stretching group who had higher fitness levels at baseline showed less hippocampal volume loss, providing evidence for exercise being protective against age-related cognitive decline.

Spatial Memory
Spatial memory is the part of memory responsible for regulating and encoding information about the surroundings and orientation in space. This type of memory is primarily controlled by the hippocampus. Since exercise has such a large impact on hippocampal growth and neurogenesis, it is not much of a surprise that spatial memory is one of the main types of memory affected by physical activity. Neuroimaging has provided evidence for larger hippocampi in physically fit adults. These people also show better performance on various spatial memory tasks than adults low in physical fitness. Animal studies have provided substantial evidence for the role of exercise in spatial memory. Healthy adolescent rats submitted to daily sessions of treadmill running show increased hippocampal mossy fiber density in adulthood, and improved performance in the Morris Water Maze (when placed in a large pool of water, the time it took for rats to swim to a submerged platform on successive trials decreased at a greater rate than rats who had not run on the treadmills). Rats given lesions to the hippocampus show impaired spatial memory in the Morris Water Maze compared to healthy controls. A recent study subjected lesioned rats to treadmill running at 17 meters per minute for 1 hour per day, 7 days a week for 60 days in total. Results showed that, compared to the lesioned rats who had not participated in exercise, the treadmill running lesioned rats demonstrated improved Morris Water Maze performance. This has implications for neurological diseases such as Alzheimer's, since it is clear that physical activity can improve spatial memory even in the presence of hippocampal damage.

Learning and Consolidation
Most of the research done concerning the impact of physical activity on learning has been conducted through classical conditioning animal studies using rats and mice. However there is also evidence for exercise improving memory consolidation and learning performance in humans. One study assessed the ability of 27 healthy adult subjects to learn a novel vocabulary either directly after high intensity anaerobic sprints, low intensity aerobic running, or a period of rest. Results revealed that vocabulary learning was 20% faster when it took place after the high intensity exercise compared to the low intensity and sedentary conditions. Learning was slowest during the rest condition, confirming the hypothesis that any level of exercise may have an impact on memory compared to remaining sedentary. Levels of BDNF and catecholamines (dopamine, epinephrine and norepinephrine) were also assessed prior to and after the interventions and after learning took place. High intensity exercise led to the strongest increases in both BDNF and catecholamine levels. This suggests that the mechanism through which physical activity improves memory may in fact be through these chemical mediators. These findings concerning the ability for physical activity to facilitate learning has implications for helping students of all ages to improve their efficiency and capacity to absorb information when studying.

Classical Conditioning
Animal studies in conditioned fear conditioning have provided evidence that physical activity is involved in learning, particularly learning consolidation. Mice given 2 weeks of access to a running wheel prior to experiencing paired tone and foot shock conditioned faster (as indicated by the startle response) than mice who underwent conditioning with no prior exercise. Subsequent experiments gave the mice access to wheel running either immediately before fear conditioning (acquisition), immediately after conditioning (consolidation), or 2 weeks after conditioning had taken place, prior to a test (retrieval). Results revealed that fear conditioning was enhanced in the mice that exercised immediately prior and after conditioning, but showed no difference compared to sedentary mice when the exercise had taken place 2 weeks after the initial learning. This suggests that exercise improves learning acquisition and consolidation, but may not have an impact on memory retrieval. Studies seem to suggest that aerobic exercise has the greatest impact on improving learning and memory consolidation. Rats who exercised on a running wheel for 17 days prior to eye-blink conditioning learned the association between a tone and an air puff faster, and showed a larger reflexive eye-blink response than rats who did not exercise. Rats who participated in 17 days of acrobatic training (navigating through an elevated obstacle course) showed no difference in eye-blink conditioning compared to sedentary rats.

Retrieval
Enhanced physical activity is associated with improved cognitive function in both rodent and human models. While the Morris water maze is used to test spatial memory in rats, it has been used to test memory retrieval as well. Van Praag and colleagues (1999) performed a study where mice had one month of voluntary running before performing the Morris water maze, compared to control mice who were sedentary during that time. The authors found that the exercise mice group mastered the Morris water maze faster than the control group that did not have any physical activity. They attributed this difference to an increase in hippocampus size and neurogenesis from physical activity. Similarly, rats that were provided a running wheel for 4–8 weeks would show increased freezing behaviour in the fear conditioning task. An increase in freezing behaviour meant that once rats experienced the fear conditioning task once, they were more capable of retrieving the memory of the first unpleasant event, and better able to prepare when they recognize the same situation.

State-dependent Learning
State-dependent learning is a phenomenon where retrieval of previously learned material is best when the internal physiological state of the person or organism matches the state they were in during learning. Studies have shown that learning while performing aerobic physical activity shows this state-dependent learning effect during retrieval. Participants learned lists of words either at rest or while riding a stationary bicycle, and were later tested for their memory of the words either in the same state as they were in during learning (learning at rest - retrieval at rest; learning while exercising - retrieval while exercising) or in the opposite state (learning at rest - retrieval while exercising; learning while exercising - retrieval at rest). Words learned during aerobic exercise were better recalled when retrieved during exercise, while words learned at rest were better recalled at rest. This has implications for students who like to study while working out at the gym. Although the increased oxygenation caused by exercise will certainly help students sustain attention while learning the material, state-dependent learning suggests that recall during the actual exam may not be the best (assuming that the exam is given in the conventional, classroom setting with students seated at their desks). It may therefore be better for students to study at a desk after having exercised so that they will reap the benefits of brain circulation, but not be in the state of exercising (increased heart rate, physical exertion) that later may influence retrieval.

Education and Learning Implications
Physical activity has contributed to reducing childhood obesity and the incidences of cardiovascular disease, colon & breast cancer, and depression & anxiety across the adult lifespan. The connection between physical activity and cognitive performance has been investigated in a number of studies, many of which observed a positive correlation between the two. Sibley and Etnier (2003) performed a meta-analysis that looked at the relationship in children. They reported a beneficial relationship in the categories of perceptual skills, intelligence quotient, achievement, verbal tests, mathematic tests, developmental level/academic readiness and other, with the exception of memory, that was found to be unrelated to physical activity. The correlation was strongest for the age ranges of 4-7 and 11–13 years. On the other hand, Chaddock and colleagues (2011) found results that contrasted Sibley and Etnier's meta-analysis. In their study, the hypothesis was that lower-fit children would perform poorly in executive control of memory and have smaller hippocampal volumes compared to higher-fit children. Instead of physical activity being unrelated to memory in children between 4 and 18 years of age, it may be that preadolescents of higher fitness have larger hippocampal volumes, than preadolescents of lower fitness. According to a previous study done by Chaddock and colleagues (Chaddock et al. 2010), a larger hippocampal volume would result in better executive control of memory. Other studies have suggested that exercise is unrelated to academic performance, perhaps due to the parameters used to determine exactly what academic achievement is. This area of study has been a focus for education boards that make decisions on whether physical education should be implemented in the school curriculum, how much time should be dedicated to physical education, and its impact on other academic subjects.

Animal studies have also shown that exercise can impact brain development early on in life. Mice that had access to running wheels and other such exercise equipment had better neuronal growth in the neural systems involved in learning and memory. Neuroimaging of the human brain has yielded similar results, where exercise leads to changes in brain structure and function. Some investigations have linked low levels of aerobic fitness in children with impaired executive function in older adults, but there is mounting evidence it may also be associated with a lack of selective attention, response inhibition, and interference control.

Physical Activity and the Elderly
Signs of cognitive decline become more evident with age. Cross-sectional studies have shown a positive link between exercise and general cognitive function in older individuals. However, such a correlation varies when a neurodegenerative disorder is taken into account. Below are three memory-related diseases, Alzheimer's disease, Huntington's disease and Parkinson's disease, that usually manifest in mid to late adulthood, and the effects that physical activity has been thought to have for each.

Alzheimer's Disease
Alzheimer's Disease (AD) is a cortical neurodegenerative disorder that progresses over time. It represents the eighth leading cause of death in people over the age of 65, and is the most common form of dementia. AD is characterized by the destruction of specific cortical nerve cells, neuritic plaques, and neurofibrillary tangles. Symptoms of AD can be divided into stages. Early, pre-dementia stages of the disease involve mild cognitive impairment (MCI), where minor memory problems and complex mental tasks may not affect an individual's daily routine, but may become clinical signs for the onset of AD. The mild to moderate stages include a decline in independence, where normal activities such as getting dressed, and judgment and organization ability is impaired. Late stage AD can be characterized by a loss of biographical memories, a reduction in language, and overall cognitive function is severely impaired. Death in AD is most frequently caused by pneumonia that leads to myocardial infarction and septicaemia. There is no cure for AD, only means of slowing down the progression and improving the condition of symptoms, but no treatment targets the underlying mechanism of disease. Many studies have been done to see if exercise preserves cognitive function, though results have varied. Exercise has been shown to play a role in decreasing the risk of developing AD, and may be protective against the development of cognitive impairment.

Current literature focuses on how physical activity can reduce the chance of onset of AD, and what it can do to slow down symptom progression when the patient is already diagnosed. A study by Friedland and colleagues (2001) surveyed 193 AD patients and 358 healthy participants 20–60 years of age. They collected data based on 26 activities in passive, intellectual, and physical categories in early adulthood (20–39 years) and middle adulthood (40–59 years). It was observed that people who developed AD were those who participated in less intellectual, passive, and physically activities in their midlife. A literature review by Rolland and colleagues (2008) found that AD individuals who incorporated physical activity in their daily lives would reduce cognitive decline and improve psychological and/or physical performance, as well as mobility, balance, and strength. Reasons physical activity leads to a reduced risk of AD include lowering body weight, as obesity is a risk factor for AD, a healthier diet, and improved blood pressure & cardiovascular health. Depression, malnutrition and behaviour disturbances, which can lead to faster cognitive decline, are also held off with exercise.

Huntington's Disease
Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder where protein aggregates in neurons, destroying them, leading to a decline in motor skills, chorea, subcortical dementia, and other psychiatric symptoms. These symptoms include mood change, impaired memory formation, information-processing deficits and a disruption in spatial working memory. Neurological alterations occur in the caudate nucleus, hippocampus, and in the putamen and globus pallidus to a lesser degree. The onset of the disease is related to the CAG trinucleotide expansion in the Huntingtin gene that codes for the amino acid glutamine. The normal range is 10-35 repeats, while diseased individuals will generally have 36 or more repeats, although the excessive repeats do not necessarily mean symptoms will develop. Environmental factors also have an impact on disease onset and progression. Each generation, the number of repeats increases, thus the age of onset decreases every generation. As with AD, there is no cure for HD, only treatment to improve the various conditions associated with it. Patients generally die within 10–20 years of disease onset.

Physical therapy can be sought to help improve the motor impairments of the disease. The conclusions about the effects of exercise on cognitive function in HD patients have varied across the literature. Pang and colleagues (2006) studied R6/1 transgenic mice models of HD, with results that showed exercise delayed the onset of symptoms and slowed cognitive decline. On the other hand, another study by Kohl and colleagues (2007) used the R6/2 transgenic mouse model of HDstrain to see if physical activity could stimulate hippocampal neurogenesis from neural stem cells. Their study found that physical exercise did stimulate cell proliferation and survival in normal healthy mice, but did not enhance hippocampal neurogenesis in the transgenic mice. They speculated that this result may be due to an effect the mutated Huntingtin gene, and by extension the mutated Huntingtin protein, has on the mechanisms needed for successful hippocampal neurogenesis in HD patients. Further research needs to be done before a solid conclusion can be reached about the effects of exercise on HD cognitive function, specifically in human models.

Parkinson's Disease
Parkinson's disease (PD) is a neurodegenerative disorder. It is generally recognized as a movement disorder that produces symptoms such as bradykinesia, rigidity, shaking, and impaired gait. It affects about 1 million people in the United States. Motor symptoms of PD are caused by the death of dopamine-containing neurons in the substantia nigra pars compacta, which is located in the mesencephalon (midbrain), and the accumulation of Lewy bodies and neurites.

While PD is classified as a disorder that leads to a deterioration of motor skill, progression of the disease will eventually result in cognitive and behavioural deficits. Psychosocial well-being is thought to be a contributing factor to the quality of life of PD patients, and has become a key focus of research in recent years. Cognitive dysfunction will impair normal everyday activities of life. These disturbances mainly disrupt executive functions, such as multitasking, driving, and situations that require planning. Certain methods to improve motor functions of PD patients do not generally impact the cognitive deficits. For instance, dopamine replacement therapy, which releases the dopamine precursor L-DOPA within the brain and allows it to cross the blood-brain barrier, will improve motor ability but has no association with cognitive function. Deep brain stimulation that may result in improved motor function, may in turn have negative effects on cognitive function.

A review by Kramer and colleagues (2006) found that some neurotransmitter systems are affected by exercise in a positive way. A few studies reported seeing an improvement in brain health and cognitive function due to exercise. One particular study by Kramer and colleagues (1999) found that aerobic training improved executive control processes supported by frontal and prefrontal regions of the brain. These regions are responsible for the cognitive deficits in PD patients, however there was speculation that the difference in the neurochemical environment in the frontal lobes of PD patients may inhibit the benefit of aerobic exercise. Nocera and colleagues (2010) performed a case study based on this literature where they gave participants with early-to mid-staged PD, and the control group cognitive/language assessments with exercise regimens. Individuals performed 20 minutes of aerobic exercise three times a week for 8 weeks on a stationary exercise cycle. It was found that aerobic exercise improved several measures of cognitive function, providing evidence that such exercise regimens may be beneficial to patients with PD.

Future research
There are many unexplored fields or concepts in this area, and many unanswered questions. Memory is a very broad cognitive concept with a variety of factors interacting to affect it in different ways. A few areas of possible future research include:
 * Impact of exercise throughout child development, how it impacts cortical development and neural organization
 * Are the mechanisms for memory improvement different in children versus adults?
 * Examine ways that schools can utilize the findings concerning physical activity and memory to help children reach their highest learning potential
 * Determine the exact mechanism by which endorphins impact learning and memory processes
 * Determine which types of exercise produce the best benefits for the brain (most studies have shown that aerobic exercise is preferable, however several findings provide evidence for higher intensity anaerobic exercise also having an impact)