The Effects of Exercise on Synaptic Plasticity in Individuals With Mild Cognitive Impairment and in Healthy Aging.

Background: The proposed research will investigate the hypothesis that exercise improves cognition by enhancing synaptic plasticity in individuals with MCI and in aging. Synaptic plasticity refers to changes in synaptic efficacy that are the consequence of the inherent activity of a neuron. Synaptic plasticity is fundamental to preserving and creating memories and at the level of the synapse, is the result of a high influx of postsynaptic Ca2+ that yields long-term potentiation (LTP) (7,8,9). The proposed research is the first to assess whether synaptic plasticity is enhanced after exercise training in individuals with MCI. If confirmed, future work will identify substitutes for exercise that alter synaptic plasticity since not all individuals are capable of exercise.

Mild cognitive impairment (MCI) is the stage before the more serious decline of dementia. MCI affects an estimated 15% to 20% of people over age 65 with ~10%-15% of those progressing to dementia each year (1, 2). Amidst ongoing challenges in developing disease-modifying drugs, non-pharmacological interventions including exercise are recommended as part of overall MCI management (3) based on the positive effects of exercise on cognitive performance (4-6).

In humans, synaptic plasticity can be assessed in vivo by delivery of two forms of Transcranial magnetic stimulation (TMS). These are called intermittent theta-burst stimulation (iTBS) and 5Hz repetitive TMS (5Hz rTMS). Both forms delivered over the motor cortex induce synaptic plasticity as measured by short-term increases in the efficacy of the corticospinal pathway from cortex to muscle (10, 11). These effects are analogous to animal models of LTP, since they are mediated by glutamate and require glutamate binding at NMDA receptors (11). Thus, in humans, iTBS and 5Hz rTMS are non-invasive tools to assess whether 1) aging and MCI populations demonstrate synaptic plasticity and 2) interventions such as exercise can enhance the magnitude of synaptic plasticity. Compared to controls, individuals with MCI demonstrate blunted synaptic plasticity as indicated by a reduced response to 5Hz rTMS (12) and iTBS (13). The question posed herein is whether synaptic plasticity can be enhanced by exercise in individuals with MCI and in the aging population.

Many studies have investigated the impact of acute exercise on neurobiology. Brain-derived neurotrophic factor (BDNF) is a key regulator of processes crucial for cognition, learning and memory (14 -16). Similarly, a bone-derived hormone called osteocalcin (OCN) increases following exercise (17, 18) and increases the number of BDNF vesicles transported to the synapse (19 - 21). Osteocalcin is found in several different isoforms in serum, and the form involved in exercise effects is not known (22, 23). The proposed research will also test the hypothesis that exercise training increases serum BDNF and OCN in MCI and the aging population and that these changes will correlate with increases in synaptic plasticity. If true, this would suggest that exercise-induced increases in BDNF and OCN are a consequence of altering synaptic efficacy.

Self-Determined Intensity Interval training involves intermittent bouts of challenging exercise interspersed with short recovery intervals (24,25). This training is unique in that intensity is determined by the participants themselves. They are required to identify a pace that is a physical challenging and rate their perceived exertion. This type of training can be achieved by participants of all ages with various underlying conditions such as Type 2 Diabetes (38,39,40) and coronary artery disease (41,42) and obesity (43). Exercise promotes cognitive improvement (26) and can be performed in individuals with MCI (27). In a case study, twelve weeks of interval training improved cognition in one female living with MCI (28).