Exercise improves cognitive function, both in the short term immediately following exercise, and in the long term as a result of increased physical fitness. These effects appear to be mediated by increased neurogenesis in the brain, the production of new neurons and their incorporation into neural circuits. This is particularly important in learning and memory, with most research focused on the hippocampus. Here, researchers dig in deeper to better understand how neurogenesis improves these aspects of cognitive function following exercise.
The incidence of cognitive decline increases with age, especially for impairments in episodic memory and spatial memory, which are typically associated with the hippocampus. Deterioration in the morphometry of the hippocampus, as well as the integrity of its circuitry, are thought to be critical in the progression of these deficits. There is increasing evidence that some forms of physical exercise protect against spatial memory decline; however, the results have been inconsistent in both humans and animals. Although several explanations have been proposed, the precise mechanisms by which exercise improves brain health remain unclear. We recently demonstrated that an optimal period of exercise in aged mice is required to activate neurogenesis in a growth hormone-dependent manner, resulting in the restoration of hippocampal-dependent spatial learning. What remains elusive, however, is how the structure and functional circuitry of the hippocampus is remodeled and what drives these connectivity changes following exercise in the aged brain.
In studies showing that adult hippocampal neurogenesis (AHN) leads to cognitive changes during aging, little has been reported about how exercise affects the structure and functional circuitry responsible for behavioral changes, and whether any circuitry changes are dependent on the level of neurogenesis. Magnetic resonance imaging (MRI) studies in humans have revealed that older adults show significant increases in hippocampal volume and functional connectivity after aerobic exercise intervention. Similarly, rodent MRI studies have demonstrated that running increases hippocampal volume and blood flow. However, the specific circuitry related to improved cognition and whether this is directly regulated by neurogenesis remain unknown.
To address these issues, we applied structural, diffusion, and functional MRI (fMRI) longitudinally following different periods of exercise in mouse models. We hypothesized that behavioral performance in aged mice depends on dentate gyrus (DG) connectivity driven by exercise-induced neurogenesis. To determine the contribution of AHN to this process, we specifically ablated doublecortin (DCX)-positive newborn neurons using our novel knockin DCXDTR mouse line. Our results reveal that improved spatial learning in aged mice after exercise is due to enhanced DG connectivity, particularly the strengthening of the DG-Cornu Ammonis 3 (CA3) and the DG-medial entorhinal cortex (MEC) connections in the dorsal hippocampus. Moreover, we provide evidence that this change in circuitry is dependent on the activation of neurogenesis.