Fig. 2: The Xm chromosome impairs cognition across the lifespan and accelerates epigenetic brain ageing in female mice.
From: The maternal X chromosome affects cognition and brain ageing in female mice
a, Diagram of the open-field apparatus to test context-dependent spatial learning and memory18. Mice were tested for 10 min on three consecutive days across the lifespan during young (age: 4–8 months), middle-aged (age: 9–11 months) and old (age: 20–24 months) life stages in the same cohort; day 1 is the first day of open-field testing in young mice. b, Xm skew increasingly impaired spatial habituation and dishabituation across the lifespan. *Significant or trending to significant (unpaired t-test). Two-way mixed-model ANOVA: time, P ≤ 0.0001; genotype, P = 0.0056 (Xm+Xp young mice: n = 10; Xm+Xp middle-aged mice: n = 10; Xm+Xp old mice: n = 9; Xm young mice: n = 19; Xm middle-aged mice: n = 18–19; Xm old mice: n = 14–15). c, Xm skew accelerated age-dependent forgetfulness by middle age (day 80 versus day 3 (80 vs 3)) (unpaired two-tailed t-test, *P = 0.0231; Xm+Xp middle-aged mice: n = 11; Xm middle-aged mice: n = 18). In the old mice (day 486 versus day 82 (486 vs 82)), Xm skew further worsened forgetfulness (unpaired two-tailed t-test, *P = 0.0522; Xm+Xp old mice: n = 9; Xm old mice: n = 15). d, Diagram of the two-trial large Y maze for testing spatial and working memory in young mice (age: 2–5 months) and old mice (age: 20–24 months). e, In old mice, but not young mice, Xm skew impaired spatial and working memory, measured by ratio of the time spent in the novel or familiar arm. Two-way ANOVA: age by genotype interaction; P = 0.0011. Bonferroni-corrected unpaired two-tailed t-test for old mice, *P = 0.0473 (Xm+Xp young mice: n = 19; Xm+Xp old mice: n = 8; Xm young mice: n = 22; Xm old mice; n = 12). f, Diagram of experimental process for assaying epigenetic age in young mice (age: 6 months) and old mice (age: 25 months). g, Epigenetic age of blood did not differ between young mice or old mice (Xm+Xp young mice: n = 8; Xm+Xp old mice: n = 6; Xm young mice: n = 10; Xm old mice: n = 7). h, Xm increased epigenetic age of the hippocampus in the old mice. *P = 0.0443 (unpaired two-tailed t-test; Xm+Xp old hippocampi: n = 6; Xm old hippocampi: n = 10), but not in young mice (Xm+Xp young hippocampi: n = 10; Xm young hippocampi: n = 10). i, The experimental process for assaying epigenetic DNA age in young mice (age: 6 months) and old mice (age: 25 months). Diagram of mouse in i is adapted from AnaitSmi/Shutterstock (https://www.shutterstock.com/). j, In old hippocampal and cortical neurons, Xm increased epigenetic age compared with Xp. *P = 0.0068 (paired two-tailed t-test; Xp old: n = 4 mice; Xm old: n = 4 mice). Epigenetic age was similar between young neurons expressing Xm and Xp (Xp young: n = 10 mice; Xm young: n = 10 mice). Each open symbol (c,e,g,h,j) represents an individual mouse. Data represent mean ± s.e.m.
