Exercise builds brain health: key roles of growth factor cascades and inflammation

Human and other animal studies demonstrate that exercise targets many aspects of brain function and has broad effects on overall brain health. The benefits of exercise have been best defined for learning and memory, protection from neurodegeneration and alleviation of depression, particularly in elderly populations. Exercise increases synaptic plasticity by directly affecting synaptic structure and potentiating synaptic strength, and by strengthening the underlying systems that support plasticity including neurogenesis, metabolism and vascular function. Such exercise-induced structural and functional change has been documented in various brain regions but has been best-studied in the hippocampus – the focus of this review. A key mechanism mediating these broad benefits of exercise on the brain is induction of central and peripheral growth factors and growth factor cascades, which instruct downstream structural and functional change. In addition, exercise reduces peripheral risk factors such as diabetes, hypertension and cardiovascular disease, which converge to cause brain dysfunction and neurodegeneration. A common mechanism underlying the central and peripheral effects of exercise might be related to inflammation, which can impair growth factor signaling both systemically and in the brain. Thus, through regulation of growth factors and reduction of peripheral and central risk factors, exercise ensures successful brain function.

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.