Physical exercise increases adult hippocampal neurogenesis in male rats provided it is aerobic and sustained

Abstract

Key points: Aerobic exercise, such as running, enhances adult hippocampal neurogenesis (AHN) in rodents. Little is known about the effects of high-intensity interval training (HIT) or of purely anaerobic resistance training on AHN. Here, compared with a sedentary lifestyle, we report a very modest effect of HIT and no effect of resistance training on AHN in adult male rats. We found the most AHN in rats that were selectively bred for an innately high response to aerobic exercise that also run voluntarily and increase maximal running capacity. Our results confirm that sustained aerobic exercise is key in improving AHN.

Abstract: Aerobic exercise, such as running, has positive effects on brain structure and function, such as adult hippocampal neurogenesis (AHN) and learning. Whether high-intensity interval training (HIT), referring to alternating short bouts of very intense anaerobic exercise with recovery periods, or anaerobic resistance training (RT) has similar effects on AHN is unclear. In addition, individual genetic variation in the overall response to physical exercise is likely to play a part in the effects of exercise on AHN but is less well studied. Recently, we developed polygenic rat models that gain differentially for running capacity in response to aerobic treadmill training. Here, we subjected these low-response trainer (LRT) and high-response trainer (HRT) adult male rats to various forms of physical exercise for 6-8 weeks and examined the effects on AHN. Compared with sedentary animals, the highest number of doublecortin-positive hippocampal cells was observed in HRT rats that ran voluntarily on a running wheel, whereas HIT on the treadmill had a smaller, statistically non-significant effect on AHN. Adult hippocampal neurogenesis was elevated in both LRT and HRT rats that underwent endurance training on a treadmill compared with those that performed RT by climbing a vertical ladder with weights, despite their significant gain in strength. Furthermore, RT had no effect on proliferation (Ki67), maturation (doublecortin) or survival (bromodeoxyuridine) of new adult-born hippocampal neurons in adult male Sprague-Dawley rats. Our results suggest that physical exercise promotes AHN most effectively if the exercise is aerobic and sustained, especially when accompanied by a heightened genetic predisposition for response to physical exercise.

Figure 1. Experiment 1 indicated that the number of doublecortin‐positive new neurons was highest in rats genetically predisposed to a high response to training and in which aerobic fitness consequently increased significantly in response to voluntary wheel running

Abbreviations: C, control; gcl, granule cell layer; HIT, high‐intensity interval training; HRT, high‐response trainer; IHC, immunohistochemistry; LRT, low‐response trainer; mo, months old; RW, running wheel; and Sed, sedentary. A, outline of the experiment. B, running in rats allowed access to running wheels throughout the first 7 days. The HRT rats increased running more compared with LRT rats. C, throughout the whole 7 week training period, the running distance was comparable in both rat lines and changed in a quadratic manner. D, running speed increased in both LRT and HRT rats in response to either HIT or RW. The biggest improvement was seen in HRT rats voluntarily training on a running wheel. E, there was no baseline difference in adult hippocampal neurogenesis in the two rat lines. F, however, when allowed to run freely on a wheel in the home cage for 7 weeks, the HRT rats showed a higher number of new neurons in the hippocampus compared with rats of the same rat line either not trained at all (Sed) or subjected to HIT three times a week. G, representative examples of doublecortin‐positive cells (brown) in the dentate gyrus in each group of rats are illustrated. The background stain (Cresyl Violet) shows cell bodies of mature neurons in light blue. The hilus and the granule cell layer are indicated in the top left panel. The scale bar length is 50 μm, and the scale is the same in all panels (original magnification, ×400). Insets depict cell groups positive for doublecortin at ×1000 magnification, and arrows point to these cells in the ×400 photos. In B–F, vertical lines depict the SEM. Asterisks refer to statistically significant effects/differences, as follows: *P < 0.05, **P < 0.01 and ***P < 0.001.

Figure 2. Experiment 2 indicated more doublecortin‐positive new hippocampal neurons in rats subjected to endurance training on a treadmill compared with rats subjected to resistance training on a vertical ladder

Abbreviations: End, endurance training; Res, resistance training; other abbreviations are as in the legend to Fig. 1. A, outline of the experiment. B, HRT rats showed a greater adaptive response to aerobic training, i.e. their percentage change in maximal running speed increased more than the LRT rats. C, subsequent endurance training on a treadmill resulted in a comparable increase in maximal running speed in both rat lines, but HRT rats outperformed LRT rats overall. D, resistance training led to a bigger improvement in strength in HRT compared with LRT rats. E, rats subjected to endurance training (regardless of rat line) had a greater number of new neurons in the hippocampus. F, representative examples of doublecortin‐positive cells (brown) in the tip of the dentate gyrus in each group of rats. The background stain (Cresyl Violet) shows cell bodies of mature neurons in light blue. The hilus and the granule cell layer are indicated in the top left panel. The scale bar length is 50 μm, and the scale is the same in all panels (original magnification, ×400). Insets illustrate the doublecortin‐positive cells at ×1000 magnifcation. In B–E, vertical lines depict the SEM. Asterisks refer to statistically significant differences, as follows: *P < 0.05 and ***P < 0.001.

Figure 3. Experiment 3 indicated no effect of 8 weeks of resistance training on a vertical ladder on adult hippocampal neurogenesis in male Sprague–Dawley rats

Abbreviations: BrdU, bromodeoxyuridine; End, endurance training; Res, resistance training; other abbreviations are as in the legend to Fig. 1. A, outline of the experiment. B, strength increased in all rats subjected to resistance training. Asterisks refer to a significant difference (***P < 0.001). Vertical lines depict the SEM. C, the proliferation of cells in the hippocampus was similar in the resistance training and sedentary groups. Black arrows mark the locations of clusters of Ki67‐positive cells (×400 magnification) illustrated in the insets (×1000 magnification). The background stain (Cresyl Violet) shows cell bodies of mature neurons in light blue. The hilus and the granule cell layer are indicated in the top panel. The scale bar length is 50 μm, and it applies to all the ×400 photomicrographs. D, animals subjected to resistance training and those kept sedentary had a similar number of immature adult‐born new neurons in the hippocampus. Doublecortin‐positive cells in brown; mature neurons in light blue. E, the survival of adult‐born neurons in the hippocampus was also not affected by resistance training. Bromodeoxyuridine‐positive cells in brown; mature neurons in light blue.

Figure 4. Post‐training maximal running capacity and total running distance are correlated with adult hippocampal neurogenesis in adult male rats

Abbreviations are as in the legend to Fig. 1. All data in this figure are from experiment 1. A, the greater the distance an animal ran during HIT training on the treadmill across 7 weeks of training, the more doublecortin‐positive new neurons were present in the hippocampus at the end of the experiment. B, the higher the maximal running capacity of a given rat subjected to voluntary running on a running wheel was at the end of the training period, the more new neurons were found in the hippocampus. C, the greater the distance an animal ran voluntarily in the running wheel throughout the 7 weeks of training, the more doublecortin‐positive new neurons were present in the hippocampus at the end of the experiment.