Shoshanna Vaynman

Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition

We found that a short exercise period enhanced cognitive function on the Morris water maze (MWM), such that exercised animals were significantly better than sedentary controls at learning and recalling the location of the platform. The finding that exercise increased brain‐derived neurotrophic factor (BDNF), a molecule important for synaptic plasticity and learning and memory, impelled us to examine whether a BDNF‐mediated mechanism subserves the capacity of exercise to improve hippocampal‐dependent learning. A specific immunoadhesin chimera (TrkB‐IgG), that mimics the BDNF receptor, TrkB, to selectively bind BDNF molecules, was used to block BDNF in the hippocampus during a 1‐week voluntary exercise period. After this, a 2‐trial‐per‐day MWM was performed for 5 consecutive days, succeeded by a probe trial 2 days later. By inhibiting BDNF action we blocked the benefit of exercise on cognitive function, such that the learning and recall abilities of exercising animals receiving the BDNF blocker were reduced to sedentary control levels. Inhibiting BDNF action also blocked the effect of exercise on downstream systems regulated by BDNF and important for synaptic plasticity, cAMP response‐element‐binding protein (CREB) and synapsin I. Specific to exercise, we found an association between CREB and BDNF expression and cognitive function, such that animals who were the fastest learners and had the best recall showed the highest expression of BDNF and associated CREB mRNA levels. These findings suggest a functional role for CREB under the control of BDNF in mediating the exercise‐induced enhancement in learning and memory. Our results indicate that synapsin I might also contribute to this BDNF‐mediated mechanism.

Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function

The ability of exercise to benefit neuronal and cognitive plasticity is well recognized. This study reveals that the effects of exercise on brain neuronal and cognitive plasticity are in part modulated by a central source of insulin-like growth factor-I. Exercise selectively increased insulin-like growth factor-I expression without affecting insulin-like growth factor-II expression in the rat hippocampus. To determine the role that insulin-like growth factor-I holds in mediating exercise-induced neuronal and cognitive enhancement, a specific antibody against the insulin-like growth factor-I receptor was used to block the action of insulin-like growth factor-I in the hippocampus during a 5-day voluntary exercise period. A two-trial-per-day Morris water maze was performed for five consecutive days, succeeded by a probe trial 2 days later. Blocking hippocampal insulin-like growth factor-I receptors did not significantly attenuate the ability of exercise to enhance learning acquisition, but abolished the effect of exercise on augmenting recall. Blocking the insulin-like growth factor-I receptor significantly reversed the exercise-induced increase in the levels of brain-derived neurotrophic factor mRNA and protein and pro-brain-derived neurotrophic factor protein, suggesting that the effects of insulin-like growth factor-I may be partially accomplished by modulating the precursor to the mature brain-derived neurotrophic factor. A molecular analysis revealed that exercise significantly elevated proteins downstream to brain-derived neurotrophic factor activation important for synaptic function, i.e. synapsin I, and signal transduction cascades associated with memory processes, i.e. phosphorylated calcium/calmodulin protein kinase II and phosphorylated mitogen-activated protein kinase II. Blocking the insulin-like growth factor-I receptor abolished these exercise-induced increases. Our results illustrate a possible mechanism by which insulin-like growth factor-I interfaces with the brain-derived neurotrophic factor system to mediate exercise-induced synaptic and cognitive plasticity.

License to run: exercise impacts functional plasticity in the intact and injured central nervous system by using neurotrophins.

Exercise has been found to impact molecular systems important for maintaining neural function and plasticity. A characteristic finding for the effects of exercise in the brain and spinal cord has been the up-regulation of brain-derived neurotrophic factor (BDNF). This review focuses on the ability of exercise to impact brain circuitry by promoting neuronal repair and enhance learning and memory by increasing neurotrophic support. A paragon for the role of activity-dependent neurotrophins in the CNS is the capacity of BDNF to facilitate synaptic function and neuronal excitability. The authors discuss the effects of exercise in the intact and injured brain and spinal cord injury and the implementation of exercise preinjury and postinjury. As the CNS displays a capacity for plasticity throughout one’s lifespan, exercise may be a powerful lifestyle implementation that could be used to augment synaptic plasticity, promote behavioral rehabilitation, and counteract the deleterious effects of aging.

Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity.

This study was designed to identify molecular mechanisms by which exercise affects synaptic-plasticity in the hippocampus, a brain area whose function, learning and memory, depends on this capability. We have focused on the central role that brain-derived neurotrophic factor (BDNF) may play in mediating the effects of exercise on synaptic-plasticity. In fact, this impact of exercise is exemplified by our finding that BDNF regulates the mRNA levels of two end products important for neural function, i.e. cAMP-response-element binding (CREB) protein and synapsin I. CREB and synapsin I have the ability to modify neuronal function by regulating gene-transcription and affecting synaptic transmission, respectively. Furthermore, we show that BDNF is capable of concurrently increasing the mRNA levels of both itself and its tyrosine kinaseB (TrkB) receptor, suggesting that exercise may employ a feedback loop to augment the effects of BDNF on synaptic-plasticity. The use of a novel microbead injection method in our blocking experiments and Taqman reverse transcription polymerase reaction (RT-PCR) for RNA quantification, have enabled us to evaluate the contribution of different pathways to the exercise-induced increases in the mRNA levels of BDNF, TrkB, CREB, and synapsin I. We found that although BDNF mediates exercise-induced hippocampal plasticity, additional molecules, i.e. the N-methyl-D-aspartate receptor, calcium/calmodulin protein kinase II and the mitogen-activated protein kinase cascade, modulate its effects. Since these molecules have a well-described association to BDNF action, our results illustrate a basic mechanism through which exercise may promote synaptic-plasticity in the adult brain.

Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor.

A diet high in total fat (HF) reduces hippocampal levels of brain-derived neurotrophic factor (BDNF), a crucial modulator of synaptic plasticity, and a predictor of learning efficacy. We have evaluated the capacity of voluntary exercise to interact with the effects of diet at the molecular level. Animal groups were exposed to the HF diet for 2 months with and without access to voluntary wheel running. Exercise reversed the decrease in BDNF and its downstream effectors on plasticity such as synapsin I, a molecule with a key role in the modulation of neurotransmitter release by BDNF, and the transcription factor cyclic AMP response element binding protein (CREB), important for learning and memory. Furthermore, we found that exercise influenced the activational state of synapsin as well as of CREB, by increasing the phosphorylation of these molecules. In addition, exercise prevented the deficit in spatial learning induced by the diet, tested in the Morris water maze. Furthermore, levels of reactive oxygen species increased by the effects of the diet were decreased by exercise. Results indicate that exercise interacts with the same molecular systems disrupted by the HF diet, reversing their effects on neural function. Reactive oxygen species, and BDNF in conjunction with its downstream effectors on synaptic and neuronal plasticity, are common molecular targets for the action of the diet and exercise. Results unveil a possible molecular mechanism by which lifestyle factors can interact at a molecular level, and provide information for potential therapeutic applications to decrease the risk imposed by certain lifestyles.

Brain-derived neurotrophic factor functions as a metabotrophin to mediate the effects of exercise on cognition

Brain‐derived neurotrophic factor (BDNF) has been shown to mediate the effects of exercise on synaptic plasticity and cognitive function, in a process in which energy metabolism probably plays an important role. The purpose of the present study was to examine the influence of exercise on rat hippocampal expression of molecules involved in the regulation of energy management and cognitive function, and to determine the role of BDNF in these events. One week of voluntary exercise that enhanced learning and memory performance elevated the expression of molecular systems involved in the metabolism of energy [AMP‐activated protein kinase (AMPK), ubiquitous mitochondrial creatine kinase (uMtCK) and uncoupling protein 2] and molecules that work at the interface of energy and synaptic plasticity [BDNF, insulin‐like growth factor I (IGF‐I) and ghrelin]. The levels of BDNF mRNA were associated with the mRNA levels of AMPK, uMtCK, IGF‐I and ghrelin. Inhibiting the action of BDNF during exercise abolished an exercise‐mediated enhancement in spatial learning and increased the expression of all of the molecular systems studied. BDNF blocking also disrupted the association between learning speed and levels of AMPK, uMtCK, ghrelin and IGF‐I mRNAs. These findings suggest that the effects of exercise on synaptic plasticity and cognitive function involve elements of energy metabolism, and that BDNF seems to work at the interface between the two processes as a metabotrophin.

Revenge of the “Sit”: How lifestyle impacts neuronal and cognitive health through molecular systems that interface energy metabolism with neuronal plasticity

Exercise, a behavior that is inherently associated with energy metabolism, impacts the molecular systems important for synaptic plasticity and learning and memory. This implies that a close association must exist between these systems to ensure proper neuronal function. This review emphasizes the ability of exercise and other lifestyle implementations that modulate energy metabolism, such as diet, to impact brain function. Mechanisms believed to interface metabolism and cognition seem to play a critical role with the brain derived neurotrophic factor (BDNF) system. Behaviors concerned with activity and metabolism may have developed simultaneously and interdependently during evolution to determine the influence of exercise and diet on cognition. Alook into our evolutionary past indicates that our genome remains unchanged from the times of our hunter‐gatherer ancestors, whose active lifestyle predominated throughout almost 100% of humankinds existence. Consequently, the sedentary lifestyle and eating behaviors enabled by the comforts of technologic progress may be reaping “revenge” on the health of both our bodies and brains. In the 21st century we are confronted by the ever‐increasing incidence of metabolic disorders in both the adult and child population. The ability of exercise and diet to impact systems that promote cell survival and plasticity may be applicable for combating the deleterious effects of disease and ageing on brain health and cognition.

Exercise differentially regulates synaptic proteins associated to the function of BDNF

We explored the capacity of exercise to impact select events comprising synaptic transmission under the direction of brain-derived neurotrophic factor (BDNF), which may be central to the events by which exercise potentiates synaptic function. We used a specific immunoadhesin chimera (TrkB-IgG) that mimics the BDNF receptor, TrkB, to selectively block BDNF in the hippocampus during 3 days of voluntary wheel running. We measured resultant synapsin I, synaptophysin, and syntaxin levels involved in vesicular pool formation, endocytosis, and exocytosis, respectively. Synapsin I is involved in vesicle pool formation and neurotransmitter release, synaptophysin, in the biogenesis of synaptic vesicles and budding, and syntaxin, in vesicle docking and fusion. Exercise preferentially increased synapsin I and synaptophysin levels, without affecting syntaxin. There was a positive correlation between synapsin I and synaptophysin in exercising rats and synapsin I with the amount of exercise. Blocking BDNF abrogated the exercise-induced increases in synapsin I and synatophysin, revealing that exercise regulates select properties of synaptic transmission under the direction of BDNF.

Exercise induces BDNF and synapsin I to specific hippocampal subfields

To assess the relationship between brain‐derived neurotrophic factor (BDNF) and synapsin I in the hippocampus during exercise, we employed a novel microsphere injection method to block the action of BDNF through its tyrosine kinase (Trk) receptor and subsequently measure the mRNA levels of synapsin I, using real‐time TaqMan RT‐PCR for RNA quantification. After establishing a causal link between BDNF and exercise‐induced synapsin I mRNA levels, we studied the exercise‐induced distribution of BDNF and synapsin I in the rodent hippocampus. Quantitative immunohistochemical analysis revealed increases of BDNF and synapsin I in CA3 stratum lucidum and dentate gyrus, and synapsin I alone in CA1 stratum radiatum and stratum laconosum moleculare. These results indicate that exercise induces plasticity of select hippocampal transsynaptic circuitry, possibly comprising a spatial restriction on synapsin I regulation by BDNF.

Exercise affects energy metabolism and neural plasticity-related proteins in the hippocampus as revealed by proteomic analysis

Studies were conducted to evaluate the effect of a brief voluntary exercise period on the expression pattern and post‐translational modification of multiple protein classes in the rat hippocampus using proteomics. An analysis of 80 protein spots of relative high abundance on two‐dimensional gels revealed that approximately 90% of the proteins identified were associated with energy metabolism and synaptic plasticity. Exercise up‐regulated proteins involved in four aspects of energy metabolism, i.e. glycolysis, ATP synthesis, ATP transduction and glutamate turnover. Specifically, we found increases in fructose‐bisphosphate aldolase C, phosphoglycerate kinase 1, mitochondrial ATP synthase, ubiquitous mitochondrial creatine kinase and glutamate dehydrogenase 1. Exercise also up‐regulated specific synaptic‐plasticity‐related proteins, the cytoskeletal protein α‐internexin and molecular chaperones (chaperonin‐containing TCP‐1, neuronal protein 22, heat shock 60‐kDa protein 1 and heat shock protein 8). Western blot was used to confirm the direction and magnitude of change in ubiquitous mitochondrial creatine kinase, an enzyme essential for transducing mitochondrial‐derived ATP to sites of high‐energy demand such as the synapse. Protein phosphorylation visualized by Pro‐Q Diamond fluorescent staining showed that neurofilament light polypeptide, glial fibrillary acidic protein, heat shock protein 8 and transcriptional activator protein pur‐alpha were more intensely phosphorylated with exercise as compared with sedentary control levels. Our results, together with the fact that most of the proteins that we found to be up‐regulated have been implicated in cognitive function, support a mechanism by which exercise uses processes of energy metabolism and synaptic plasticity to promote brain health.