Edited by: Arianna Maffei, SUNY Stony Brook, USA
Reviewed by: Mazahir T. Hasan, Charité-Universitätsmedizin-Berlin, Germany; Alexander K. Murashov, East Carolina University, USA
*Correspondence: Cristy Phillips, Department of Physical Therapy, Arkansas State University, PO Box 910, 2713 Pawnee, Jonesboro, AR 72401, USA e-mail:
This article was submitted to the journal Frontiers in Cellular Neuroscience.
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While the relationship between increased physical activity and cognitive ability has been conjectured for centuries, only recently have the mechanisms underlying this relationship began to emerge. Convergent evidence suggests that physical activity offers an affordable and effective method to improve cognitive function in all ages, particularly the elderly who are most vulnerable to neurodegenerative disorders. In addition to improving cardiac and immune function, physical activity alters trophic factor signaling and, in turn, neuronal function and structure in areas critical for cognition. Sustained exercise plays a role in modulating anti-inflammatory effects and may play a role in preserving cognitive function in aging and neuropathological conditions. Moreover, recent evidence suggests that myokines released by exercising muscles affect the expression of brain-derived neurotrophic factor synthesis in the dentate gyrus of the hippocampus, a finding that could lead to the identification of new and therapeutically important mediating factors. Given the growing number of individuals with cognitive impairments worldwide, a better understanding of how these factors contribute to cognition is imperative, and constitutes an important first step toward developing non-pharmacological therapeutic strategies to improve cognition in vulnerable populations.
Man has sought to better understand the relationship between a healthy body and mind for centuries. Exploring this relationship during the pre-Socratic era, the Greek philosopher Thales of Miletus (624–546 B.C.) declared that a happy man is one that possessed a healthy body, a resourceful mind, and a docile nature. Hippocrates (
Here we describe current knowledge on the effects of physical activity on cognitive function and the cellular and molecular mechanisms that underlie this relationship. Initially, an overview of the putative mechanisms linking physical activity, cognition, and the subsystems subserving cognitive function prefaces a more intense focus on the neurotrophin signaling hypothesis. This will be followed by a description of studies in both human and animal models that implicate brain-derived neurotrophic factors (BDNF) in these molecular and cellular processes. Finally, cautionary notes regarding the deleterious effects of extreme physical activity are proffered and suggestions for clinical intervention then flank the discussion.
Numerous studies have reported a robust relationship between high levels of physical activity, hippocampal size, and cognitive measures. Studies in the elderly have shown a direct correlation between increased levels of physical activity and improved cognition, with increases in hippocampal volume following exercise (Erickson and Kramer,
The cardiovascular benefits of sustained physical activity include improved exercise capacity, alterations in lipid profiles, reductions in obesity indices, increased rates of heart recovery and variability, reduced resting pulse, and improved blood rheology and hemodynamics (Vuori et al.,
Physical activity results in increased levels of pro-inflammatory, anti-inflammatory cytokines, cytokine inhibitors and chemokines depending upon the intensity and duration of such exercise. The immunological benefits of sustained physical activity include overall enhancement of immune function and anti-inflammatory processes. The importance of the role of exercise in inducing anti-inflammatory effects is underscored by the fact that chronic inflammation has been linked etiologically to cognitive impairment, cardiovascular diseases, and neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD; Gleeson et al.,
While chronic exercise leads to a reduction in chronic inflammation, acute exercise appears to promote a proinflammatory release of cytokines. Performing a meta-analysis, Ploeger et al. (
1) IL-6 is a pro-inflammatory cytokine released in the periphery by T-cells, macrophages, fibroblasts, endothelial cells, and osteoblasts (Burger,
While some studies report that moderate levels of aerobic exercise lead to release of IL-6 from muscle, with circulating levels increasing up to 100-fold for up to 1 h following participation (Pedersen and Fischer,
2) IL-8 or chemokine (CXC Motif) ligand 8 (CXCL8) belongs to CXC family of chemokines and affects many aspects of the immune system, including chemotactic effects on B and T lymphocytes. Additionally, IL-8 appears to promote local angiogenesis in muscle (Akerstrom et al.,
3) CXCL12 (formerly known as SDF-1) is a pleiotropic chemokine that participates in adaptive immune responses and angiogenesis by recruiting endothelial progenitor cells from the bone marrow (Salcedo and Oppenheim,
4) CRP is an acute-phase protein found in the blood, the levels of which play a crucial role in the human immune system. It has been shown that pyramidal neurons of the hippocampus cortical regions express CRP (Yasojima et al.,
5) TNF (formerly known as tumor necrosis factor-α) is monocyte-derived cytokine that performs a variety of functions in the neuroimmune system, including cell proliferation, differentiation, and cytolysis. It has been shown that elevated levels of TNF are a risk factor for AD in older adults (Tan et al.,
Together, the aforementioned studies reveal the presence of a link between exercise and the immune system and implicate this system in many neurobiological processes that underlie cognitive dysfunction, aging, and neurogeneration, extending well beyond classical chemotactic functioning. Among the processes implicated are neuromodulatory and neurotransmitter-like effects along with direct and indirect regulation of neurogenesis.
Improved trophic factor signaling has been considered as the most popular hypothesis to explain the positive effects of physical activity on cognition, with attention centering on the neurotrophins (NTs). NTs are comprised of a closely related family of polypeptides that regulate a variety of neuronal functions including proliferation, survival, migration, and differentiation (Salehi et al.,
Evolutionary studies suggest that early members of the NT family evolved approximately 600 million years ago from a common gene, resulting in the sharing of a highly conserved six-cysteine residue domain. Early duplications in the ancestral gene led to the formation of the four members of the NT family (NGF, BDNF, NT-3, and NT4/5). Comparative studies have revealed that while certain members of this NT family have shown extensive divergence (e.g., NGF), others remained largely conserved (e.g., BDNF). BDNF’s high rate of conservation suggests poor evolutionary tolerance for divergence (Götz et al.,
Among NTs, BDNF is the most widely expressed in the brain, affecting neuronal survival, differentiation, axonal path-finding (Reichardt,
The synthesis of BDNF occurs primarily in the CNS, initially as a precursor molecule consisting of 250 amino acid residues, a length twice the size of mature BDNF (Götz and Schartl,
BDNF is synthesized in the periphery by vascular endothelial cells, T-cells, B cells, monocytes (Kerschensteiner et al.,
NTs play a vital role in the maintenance of the structural and functional health of neurons that underlie cognition (including those of the hippocampal formation, basal forebrain cholinergic neurons, and NE-ergic neurons of the locus coeruleus). Evidence for this lies in the fact that BDNF is expressed pervasively throughout the brain, readily crosses the BBB, significantly impacts the structure and function of the hippocampal dentate gyrus (DG) via its widely expressed TrkB receptors, and imposes a negative feedback on FNDC5 synthesis (negative feedback). These facts suggest that NTs play a crucial role in cognition and, in conjunction with the evidence that links exercise with cognition, makes it seem plausible that NTs may be significantly involved in the mechanisms that underlie the positive effects of physical activity on cognitive function.
The most widely studied polymorphism in BDNF is the val66met substitution (Sanchez et al.,
In neurons, BDNF is not exclusively synthesized in the somata; rather, fragments of
Therefore, the incidence of SNPs should be taken into account when considering the effects of physical activity on BDNF levels and vice versa (Figure
Numerous studies in humans and animals have linked the modulation of BDNF with physical activity and cognition. Studies have demonstrated the intensity of exercise training is positively correlated with BDNF plasma levels in young, healthy individuals (Ferris et al.,
Insulin-like growth factor 1 (IGF-1) is an important trophic factor for growth and metabolic reactions. High concentrations of this 70 amino acid polypeptide chain are released by the liver (Clemmons et al.,
Peroxisome proliferator-activated receptor-gamma coactivator protein-1alpha (PGC-1α) is a transcriptional co-activator of mitochondrial biogenesis and oxidative metabolism in brown fat (Spiegelman,
Since PGC-1α is a transcription factor with no ability to bind to DNA, it has been suggested that it binds to nuclear receptor estrogen-related receptor α (ERRα). This is supported by the fact that physical activity leads to increased ERRα gene expression in the brain (Wende et al.,
Recent studies have shown that Pgc-1α is synthesized in muscle cells and induced by exercise and stimulates many of the known markers of exercise in muscles including mitochondrial biogenesis, angiogenesis and fiber-type switching. While chronic long-term treadmill running over 12 weeks leads to increase in Pgc-1α gene expression in muscles, sedentary lifestyle has been shown to be associated with reduced expression of this factor (Handschin and Spiegelman,
Fibronectin type III domain containing 5 (FNDC5) is a PGC-1α-dependent myokine that is released during exercise (Boström et al.,
In rodents’ brain,
Lecker et al. (
Recently, it was shown that exercise induces
The exact role of FNDC5 is yet to be fully understood, but it has been shown that it leads to a significant increase in
Despite the positive effects of moderate physical activity on the brain, a number of studies have linked extreme exercise to disruption of cellular, metabolic, and hormonal processes and, in turn, to adverse neurological sequelae and cognitive dysfunction. Here, we review cellular mechanisms by which extreme physical activity might interfere with normal neuronal function, particularly those involved in learning and memory.
The brain comprises approximately 2% of adult human body weight and yet consumes approximately 20% of oxygen at rest (Allaman,
Cortisol is a glucocorticoid (GC) that is released from the adrenal gland in response to stress (Kudielka et al.,
Historically, it has been assumed that physical activity lowers GC levels and attenuates the adverse effects of stress (Cornil et al.,
While the interactions between mind, brain, and body have been conjectured for centuries, only recently have we begun to understand the putative molecular mechanisms of such a relationship. Ratification of the positive benefits of physical activity are now evident in studies demonstrating that increased physical activity can significantly improve longevity (Bronnum-Hansen et al.,
Also drawing increased attention in recent years is the positive role that physical activity plays in increasing learning and memory (van Praag et al.,
In the CNS, exercise has been shown to increase adult neurogenesis in the DG of the hippocampus, improve dendritic complexity and synaptic plasticity in the perforant path that carries information from the entorhinal cortex to the DG (Eadie et al.,
At the interface of physical activity and enhanced cognitive function are NTs, particularly BDNF. BDNF is upregulated following physical activity, with approximately 70–80% of the additional expression derived centrally. Notably, activity-induced upregulation of BDNF has been found primarily in the hippocampus, a brain region critically important for learning and memory.
The questions that have been raised are on the nature of specificity and on the increase in
As we showed here (Sanchez et al.,
Moreover, a better understanding of the relationship between genetic profiles and distinct response to illness will permit health care professionals to prescribe individualized exercise regimens according to genetic profile. Such would enable the diagnosis and treatment of an individual’s personal response to aging and illness (Booth and Laye,
The identification of irisin suggests new avenues for pharmacological intervention. It has been shown that IV administration of irisin increases BDNF in mice, a potential treatment for improved BDNF levels in those individuals who because of physical impairments cannot participate in physical activity.
Plasma BDNF measures are highly variable between individuals. Thus, meaningful studies must account for age, gender, ethnicity, body weight (Komori et al.,
A key area of future research will be to refine cognitive studies so as to investigate the genetically determined personalized response to physical activity to increase relevance and translatability to humans. Uncovering the molecular and cellular linkages between physical activity and cognition is critical to advancements in studies of aging and neurodegeneration. A better understanding of these mechanisms will enable the development of pharmaceuticals, particularly for those who are activity limited (coma, spinal cord injury, etc.). Moreover, a better understanding will permit healthcare professionals to provide individualized prescriptions for patients after considering their genetic and proteomic profiles, both of which determine an individual’s personal response to aging and illness (Booth and Laye,
There is an urgent need to develop pharmacological and non-pharmacological methods to improve the status of neurons and their dendritic terminals given the increase in individuals affected by neurodegenerative disorders. Physical activity offers an affordable and effective method to improve cognitive function in all ages, particularly the elderly who are most vulnerable to neurodegenerative disorders. The dual effects of chronic and acute physical activity on inflammatory processes, particularly in those individuals with an underlying inflammatory condition, must be better understood such that the nature of physical activity and its inducing health benefits can be harnessed for therapeutic purposes in vulnerable populations.
Further refinement of the mechanisms by which myokines are released by peripheral muscles during exercise could improve our understanding of mechanisms of BDNF synthesis by the DG and could potentially lead to the identification of new and therapeutically-important factors that mediate these effects. Moreover, since the majority of BDNF synthesis occurs in the hippocampus, there might be new technologies developed in the future to quantify the release of BDNF from the brain and not in whole circulation. The availability of novel nanotechnological methods to collect blood samples locally at the cellular level would refine further knowledge about the type and intensity of physical activities that induce BDNF synthesis in the brain (Song et al.,
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Ahmad Salehi is supported by grants from Down syndrome Research Foundation (DSRTF), Research Down Syndrome (RDS), and Alzheimer’s Association. We would like to thank Ms. Persia Salehi for her professional graphic work. Cristy Phillips is partially supported by a Faculty Development Grant provided by the College of Nursing and Health Professions at Arkansas State University. Mehmet Akif Baktir is partially supported by a grant from Erciyes University Foundation, Kayseri, Turkey. Malathi Srivatsan is partially supported by a grant from Arkansas Biosciences Institute.
Alzheimer’s disease
blood brain barrier
brain-derived neurotrophic factor
C-reactive protein
central nervous system
cerebrospinal fluid
chemokine (CXC Motif) ligand 8
chemokine (CXC Motif) ligand 12
CXC chemokine receptor 1
CXC chemokine receptor 2
dentate gyrus
dentate granule cells
estrogen-related receptor α
fibronectin type III domain containing 5
glucocorticoids
Insulin-like growth factor 1
interleukin 6
interleukin 8
nerve growth factor
neurotrophin-3
neurotrophin-4/5
neurotrophins
peroxisome proliferator-activated receptor-gamma coactivator protein-1alpha
nor-epinephrinergic
Parkinson’s disease
peroxisome proliferator-activated receptor-gamma coactivator protein-1alpha
repetitive transcranial magnetic stimulation
reactive oxygen species
single nucleotide polymorphism
tropomyosin related kinase
tropomyosin related kinase B belonging to receptor tyrosine kinase family
tumor necrosis factor
uncoupling protein
untranslated region