Genetic influences on exercise-induced adult hippocampal neurogenesis across 12 divergent mouse strains

Abstract

New neurons are continuously born in the hippocampus of several mammalian species throughout adulthood. Adult neurogenesis represents a natural model for understanding how to grow and incorporate new nerve cells into preexisting circuits in the brain. Finding molecules or biological pathways that increase neurogenesis has broad potential for regenerative medicine. One strategy is to identify mouse strains that display large vs. small increases in neurogenesis in response to wheel running so that the strains can be contrasted to find common genes or biological pathways associated with enhanced neuron formation. Therefore, mice from 12 different isogenic strains were housed with or without running wheels for 43 days to measure the genetic regulation of exercise-induced neurogenesis. During the first 10 days mice received daily injections of 5-bromo-2'-deoxyuridine (BrdU) to label dividing cells. Neurogenesis was measured as the total number of BrdU cells co-expressing NeuN mature neuronal marker in the hippocampal granule cell layer by immunohistochemistry. Exercise increased neurogenesis in all strains, but the magnitude significantly depended on genotype. Strain means for distance run on wheels, but not distance traveled in cages without wheels, were significantly correlated with strain mean level of neurogenesis. Furthermore, certain strains displayed greater neurogenesis than others for a fixed level of running. Strain means for neurogenesis under sedentary conditions were not correlated with neurogenesis under runner conditions suggesting that different genes influence baseline vs. exercise-induced neurogenesis. Genetic contributions to exercise-induced hippocampal neurogenesis suggest that it may be possible to identify genes and pathways associated with enhanced neuroplastic responses to exercise.

Figure 1

Genetic differences in home cage activity and wheel running behavior. A) Mean distance traveled per day (±SE) in the custom-made home cages without wheels plotted separately for each strain. B) Mean distance traveled per day on running wheels (±SE) plotted for each strain. The means are collapsed across sex (n=8 animals per bar). The bars are sorted from least active to the most active strain.

Figure 2

Genetic differences in exercise-induced adult hippocampal neurogenesis. Top, representative sections through the dentate gyrus of a sedentary mouse and a runner stained for BrdU with A) DAB as the chromogen and B) triple fluorescent stained BrdU red, NeuN (mature neuronal marker) green and S100β (astrocyte marker) blue. C) Mean number of BrdU positive cells per volume granule layer of the dentate gyrus multiplied by the proportion of BrdU cells expressing NeuN (±SE) plotted separately for each strain and treatment group (sedentary versus runner), collapsed across sex (n=8 animals per bar). The bars are sorted from least to most neurogenesis in the runner condition.

Figure 3

Analysis of covariance. A) Individual levels of neurogenesis (i.e., number of BrdU positive cells per volume granule layer of the dentate gyrus multiplied by the proportion of BrdU cells expressing NeuN) plotted against distance traveled in cages without wheels. B) Individual levels of neurogenesis plotted against distance run on wheels.

Figure 4

Genetic correlations. A) Strain mean distance (km/day) accumulated on running wheels plotted against strain mean distance (km/day) traveled in sedentary cages without wheels. B) Strain mean level of neurogenesis under sedentary conditions (i.e., mean number of BrdU positive cells per volume granule layer of the dentate gyrus multiplied by the proportion of BrdU cells expressing NeuN) plotted against strain mean distance traveled in cages without wheels. C) Strain mean level of neurogenesis in runners plotted against strain mean distance run on wheels. D) Strain mean level of neurogenesis in runners plotted against strain mean level of neurogenesis under sedentary conditions.