The second X chromosome confers resilience in a mouse model of Alzheimer’s disease potentially through the X-linked gene Kdm6a .

Women live longer than men and exhibit less cognitive aging. The X chromosome contributes to sex differences, as females harbor an inactive X (Xi) and active X (Xa), in contrast to males with only an Xa. Thus, reactivation of silent Xi genes may contribute to sex differences. We use allele-specific, single-nucleus RNA sequencing to show that aging remodels transcription of the Xi and Xa across hippocampal cell types. Aging preferentially changed gene expression on the X’s relative to autosomes. Select genes on the Xi underwent activation, with new escape across cells including in the dentate gyrus, critical to learning and memory. Expression of the Xi escapee Plp1 , a myelin component, was increased in the aging hippocampus of female mice and parahippocampus of women. AAV-mediated Plp1 elevation in the dentate gyrus of aging male and female mice improved cognition. Understanding how the Xi may confer female advantage could lead to novel targets that counter brain aging and disease in both sexes.

Testosterone reduces anxiety-like behaviors in rodents and increases exploration of anxiogenic parts of the environment. Effects of testosterone on innate defensive behaviors remain understudied. Here, we demonstrate that exogenous testosterone reduces aversion to cat odor in male mice. This is reflected as increased exploration of area containing cat urine when castrated male mice are supplied with exogenous testosterone. We also report that exogenous testosterone leads to DNA hypomethylation of arginine vasopressin (AVP) promoter in posterodorsal medial amygdala (MePD) and medial bed nucleus of stria terminalis (BNST). Our observations suggest that testosterone acting on AVP system within extended medial amygdala might regulate defensive behaviors in mice.

Female mammalian cells have two X chromosomes, one of maternal origin and one of paternal origin. During development, one X chromosome randomly becomes inactivated^1–4. This renders either the maternal X (X_m) chromosome or the paternal X (X_p) chromosome inactive, causing X mosaicism that varies between female individuals, with some showing considerable or complete skew of the X chromosome that remains active^5–7. Parent-of-X origin can modify epigenetics through DNA methylation^8,9 and possibly gene expression; thus, mosaicism could buffer dysregulated processes in ageing and disease. However, whether X skew or its mosaicism alters functions in female individuals is largely unknown. Here we tested whether skew towards an active X_m chromosome influences the brain and body—and then delineated unique features of X_m neurons and X_p neurons. An active X_m chromosome impaired cognition in female mice throughout the lifespan and led to worsened cognition with age. Cognitive deficits were accompanied by X_m-mediated acceleration of biological or epigenetic ageing of the hippocampus, a key centre for learning and memory, in female mice. Several genes were imprinted on the X_m chromosome of hippocampal neurons, suggesting silenced cognitive loci. CRISPR-mediated activation of X_m-imprinted genes improved cognition in ageing female mice. Thus, the X_m chromosome impaired cognition, accelerated brain ageing and silenced genes that contribute to cognition in ageing. Understanding how X_m impairs brain function could lead to an improved understanding of heterogeneity in cognitive health in female individuals and to X-chromosome-derived pathways that protect against cognitive deficits and brain ageing.