Antidepressant effects of exercise: evidence for an adult-neurogenesis hypothesis?

Abstract

It has been hypothesized that a decrease in the synthesis of new neurons in the adult hippocampus might be linked to major depressive disorder (MDD). This hypothesis arose after it was discovered that antidepressant medications increased the synthesis of new neurons in the brain, and it was noted that the therapeutic effects of antidepressants occurred over a time span that approximates the time taken for the new neurons to become functional. Like antidepressants, exercise also increases the synthesis of new neurons in the adult brain: a 2-3-fold increase in hippocampal neurogenesis has been observed in rats with regular access to a running wheel when they are compared with control animals. We hypothesized, based on the adult-neurogenesis hypothesis of MDD, that exercise should alleviate the symptoms of MDD and that potential mechanisms should exist to explain this therapeutic effect. Accordingly, we evaluated studies that suggest that exercise is an effective treatment for MDD, and we explored potential mechanisms that could link adult neurogenesis, exercise and MDD. We conclude that there is evidence to support the hypothesis that exercise alleviates MDD and that several mechanisms exist that could mediate this effect through adult neurogenesis.

Fig. 1: Hippocampal neurogenesis. (A) Schematic of the hippocampus illustrating the relation between granule cells in the dentate gyrus (DG) and pyramidal cells in the cornu Ammonis (CA1, CA3). DG granule cells extend axons from the inner granule zone that project onto dendrites of pyramidal cells in the CA3 layer of the cornu Ammonis (pink). CA3 pyramidal neurons extend axons to CA1 dendrites (black); CA1 cells then extend axons to multiple neural areas, in particular to the cortex. (Bi) Progenitor cells (blue) in the subgranular zone of the DG give way to immature neurons (yellow with extension) that initially extend a proboscis (primary dendrite) through the granular cell layer as well as an axon toward the CA3 region. (Bii) Dendritic complexity increases as neurons mature and migrate into the granule cell layer. (Biii) Some new neurons migrate to the outer granular zone and have dendrites that no longer possess a primary dendrite but, rather, have a more bush-like appearance.

Fig. 2: Exercise increases neurogenesis in adult rats. (Ai–Aiii) Images of 42-day-old cells from a control animal (Ai) and an animal given free access to an exercise wheel (Aii). New neurons are shown in red, whereas mature granule cells are green, and astrocytes are blue. (Aiii) Confocal image of boxed area outlined in red from Ai. For new cells to be considered neurons, they must stain red (bromodeoxyuridine [BrdU], a marker of new cells) and green (Neuronal Nuclei [NeuN], a mature neuronal marker), but not blue (glial fibrillary acidic protein [GFAP], a marker of mature astrocytes). The cell at the centre of the white crosshairs is flipped 90° in both the x and y planes to ensure that the cell is co-labelled for both BrdU and NeuN. (B) Figure shows that exercise (black bars) increases the number of BrdU-positive cells in animals compared with controls (white bars), irrespective of the dose of BrdU administered to the animal (data adapted from Eadie et al, J Comp Neurol 2005;486:39-4747).