On the Run for Hippocampal Plasticity

Abstract

Accumulating research in rodents and humans indicates that exercise benefits brain function and may prevent or delay onset of neurodegenerative conditions. In particular, exercise modifies the structure and function of the hippocampus, a brain area important for learning and memory. This review addresses the central and peripheral mechanisms underlying the beneficial effects of exercise on the hippocampus. We focus on running-induced changes in adult hippocampal neurogenesis, neural circuitry, neurotrophins, synaptic plasticity, neurotransmitters, and vasculature. The role of peripheral factors in hippocampal plasticity is also highlighted. We discuss recent evidence that systemic factors released from peripheral organs such as muscle (myokines), liver (hepatokines), and adipose tissue (adipokines) during exercise contribute to hippocampal neurotrophin and neurogenesis levels, and memory function. A comprehensive understanding of the body-brain axis is needed to elucidate how exercise improves hippocampal plasticity and cognition.

Figure 1.

Running induces structural and functional plasticity in the hippocampus. Illustration summarizing how running enhances neurogenesis, accelerates new neuron maturation, augments hippocampal volume (in humans), and promotes angiogenesis. Enhanced neural plasticity and improved memory function may be supported by central and peripheral factors. Increased levels of growth factors in the brain may result, in part, from systemic factors secreted by muscle (myokines), liver (hepatokines), and fat cells (adipokines). BHA, β-Hydroxybutyrate; BDNF, brain-derived neurotrophic factor; FGF-2, fibroblast growth factor 2; IGF-1, insulin-like growth factor 1; IL-6, interleukin 6; IL-10, interleukin 10; L&M, learning and memory; VEGF, vascular endothelial growth factor.

Figure 2.

Neurogenesis in the adult mouse dentate gyrus (DG) of the hippocampus and a diagram of modification of new neuron network by running. (A) Photomicrographs of new neurons (green) in a coronal mouse brain section; a mouse 2 months after injection with retrovirus-expressing green fluorescent protein (GFP) in the DG. Section was stained for GFP (green) and GABAergic inhibitory interneuron marker parvalbumin (red), and nuclei were labeled with 4′,6-diamidino-2-phenylindole (DAPI, blue). (B) Diagram illustrating how running reorganizes the network of new hippocampal neurons (Vivar et al. 2016). One month of running in male C57Bl/6 mice enhanced DG neurogenesis (threefold). Afferent input (squares) was also increased, but less so (twofold). The resulting change in new neuron connectivity may promote sparse encoding of information and result in a more robust memory-processing system. The expansion of the neural network and enhanced distribution of information over new DG cells may provide more structural redundancy in which failure of one pathway can be compensated for by another.