Trends in Neurosciences
ReviewExercise builds brain health: key roles of growth factor cascades and inflammation
Introduction
Much evidence is converging on the concept that lifestyle factors such as exercise can improve learning and memory, delay age-related cognitive decline, reduce risk of neurodegeneration, and play a part in alleviating depression. As we delineate in the first part of this review, the evidence that exercise can affect these endpoints has become better established in the past few years, and provides a foundation for elucidating more precisely the mechanisms through which exercise modulates brain function. In the subsequent two sections, by focusing primarily on the hippocampus, we discuss how exercise can affect brain structure, from increased neurogenesis and angiogenesis to greater dendritic complexity, and we define the underlying mechanisms. It is increasingly clear that a central mechanism is exercise-dependent peripheral and central regulation of growth factors, which operate in unique cascades to orchestrate structural and functional change. In turn, mechanisms that interfere with growth factor signaling – specifically inflammation – are modulated by exercise in the periphery and in the central nervous system (CNS), as outlined in the last section. We propose that reduction of inflammation by exercise is a common means by which exercise reduces peripheral risk factors for cognitive decline and neurodegeneration. We conclude with a brief analysis of future directions and approaches to optimize the impact of exercise on brain function.
Section snippets
Exercise enhances learning and plasticity
In humans, robust effects of exercise have been most clearly demonstrated in aging populations, where sustained exercise participation enhances learning and memory, improves executive function, counteracts age-related and disease-related mental decline, and protects against age-related atrophy in brain areas crucial for higher cognitive processes 1, 2, 3. Interestingly, a dose–response relationship between exercise duration/intensity and health-related quality of life has been reported, whereby
Mechanisms of exercise effects on brain health
In parallel with its benefits in learning and depression, exercise modulates a range of supporting systems for brain maintenance and plasticity including neurogenesis, enhanced CNS metabolism and angiogenesis. Neurogenesis and other exercise-induced alterations in neuronal circuitry and function must be met by an adequate nutrient and energy supply, which in turn is supported by changes in metabolic function and blood flow.
Enhanced hippocampal neurogenesis is one of the most reproducible
Growth factors are central to the benefits of exercise for the brain
Exercise modulates both plasticity and various supporting systems that participate in maintaining brain function and health. To understand how exercise achieves these effects, the regulatory mechanisms underlying these changes need to be defined. At first glance, it would seem unlikely that common mechanisms could mediate the varied effects of exercise on learning, depression, neurogenesis, angiogenesis and overall brain health. An emerging overarching concept, however, is that exercise
Systemic mechanisms: exercise reduces peripheral risk factors
An emerging fundamental concept is that brain health and cognitive function are modulated by the interplay of various central and peripheral factors. Specifically, brain function is compromised by the presence of peripheral risk factors for cognitive decline, including hypertension, hyperglycemia, insulin insensitivity and dyslipidemia – a cluster of features that have been conceptualized as the ‘metabolic syndrome’ [73]. Of the various aspects of the metabolic syndrome, the most crucial for
Conclusion and future directions
Human and animal studies indicate that exercise targets many aspects of brain function and has broad effects on overall brain health, resilience, learning and memory, and depression, particularly in elderly populations. Exercise sets into motion an interactive cascade of growth factor signaling that has the net effect of stimulating plasticity, enhancing cognitive function, attenuating the mechanisms driving depression, stimulating neurogenesis and improving cerebrovascular perfusion. IGF-1
Acknowledgements
Support provided in part by grant NIA AG00538 and a donation from Rich Muth.
References (92)
The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis
Arch. Phys. Med. Rehabil.
(2004)Exercise-induced changes in cardiac gene expression and its relation to spatial maze performance
Neurochem. Int.
(2006)The effects of training and detraining on memory, neurotrophins and oxidative stress markers in rat brain
Neurochem. Int.
(2006)The effects of forced exercise on hippocampal plasticity in the rat: a comparison of LTP, spatial- and non-spatial learning
Behav. Brain Res.
(2007)The select action of hippocampal calcium calmodulin protein kinase II in mediating exercise-enhanced cognitive function
Neuroscience
(2007)Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague–Dawley rats in vivo
Neuroscience
(2004)Exercise differentially regulates synaptic proteins associated to the function of BDNF
Brain Res.
(2006)Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus
Neuroscience
(2005)Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease
Lancet Neurol.
(2005)Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in Huntington's disease transgenic mice
Neuroscience
(2006)