Samira Abdulai-Saiku

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.

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.

Males exhibit shorter lifespan and more cognitive deficits in aging human populations. In mammals, the X chromosome is enriched for neural genes and is a major source of biologic sex difference, in part, because males show decreased expression of select X factors. While each sex (XX and XY) harbors one active X due to X chromosome inactivation in females, some genes, such as Kdm6a , transcriptionally escape silencing in females – resulting in lower levels in males. Kdm6a is a known histone demethylase (H3K27me2/3) with multiple functional domains that is linked with synaptic plasticity and cognition. Whether elevating Kdm6a could benefit the aging male brain and whether this requires its demethylase function remains unknown. We used lentiviral-mediated overexpression of the X factor in the hippocampus of aging male mice and tested their cognition and behavior in the Morris water maze. We found that acutely increasing Kdm6a – in a form without demethylase function – selectively improved learning and memory, without altering total activity or anxiety-like measures, in the aging XY brain. Further understanding the demethylase-independent downstream mechanisms of Kdm6a may lead to novel therapies for treating age-induced cognitive deficits in both sexes.

Summary: Female mammalian cells harbor two X chromosomes, one of maternal and one of paternal origin. During development, one X randomly inactivates ^1–4 . This renders either the maternal or paternal X active, causing X mosaicism that varies among individual females, with some showing considerable or complete skew in the general female population ^5–7 . Parent-of-X-origin can modify epigenetics via DNA methylation ^{8, 9} and possibly gene expression; thus, mosaicism could buffer dysregulated processes in aging and disease. However, whether X skewing – or its mosaicism – alters functions in females is largely unknown. Here we tested whether skew toward the maternal X (Xm) influences key functions of the body. Among cardiac, bone, metabolic, and brain functions, Xm selectively impaired cognition in female mice throughout the lifespan. Cognitive deficits were accompanied by Xm-mediated acceleration of biologic or epigenetic aging of the female hippocampus, a key center for learning and memory. Xm showed epigenetic imprinting of several genes within hippocampal neurons, suggesting silenced cognitive loci. Thus, the maternal X chromosome impaired cognition, accelerated brain aging, and silenced genes. Understanding how the maternal X impairs brain function could lead to new understanding of female heterogeneity in cognitive heath and to X chromosome-derived pathways against cognitive deficits and brain aging.

Infection with the protozoan Toxoplasma gondii causes loss of innate fear of cat odors in both male and female rats. This behavioral change is presumed to reflect a parasitic manipulation that increases transmission of the parasite from its intermediate to definitive host. The host behavioral change in male rats is dependent on gonadal steroids. In contrast, the loss of fear in female rats is not accompanied by greater gonadal steroids and cannot be rescued by gonadectomy. This disparity suggests that proximate mechanisms of the post infection host behavioral change in rats are sexually dimorphic. Here, we report that female rats infected with Toxoplasma gondii exhibit greater abundance of messenger RNA for oxytocin and oxytocin receptors in the paraventricular nucleus of the hypothalamus and posterodorsal medial amygdala, respectively. Brain oxytocin is critical for sex-typical social and sexual behaviors in female rodents. The change in oxytocin and its receptor could potentially alter activity in the social salience circuits, leading to a reduction in defensive behaviors and an increase in approach to ambivalent environmental cues. Our results argue that sexually dimorphic neural substrates underpin sexually monomorphic host behavioral change in this host–parasite association.

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

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.

Background: The behavior of animals is intricately linked to the environment; a relationship that is often studied in laboratory conditions by using environmental perturbations to study biological mechanisms underlying the behavioral change. Methods: This study pertains to two such well-studied and well-replicated perturbations, i.e., stress-induced anxiogenesis and Toxoplasmagondii -induced loss of innate fear. Here, we demonstrate that behavioral outcomes of these experimental manipulations are contingent upon the ambient quality of the wider environment where animal facilities are situated. Results: During late 2014 and early 2015, a building construction project started adjacent to our animal facility. During this phase, we observed that maternal separation stress caused anxiolysis, rather than historically observed anxiogenesis, in laboratory rats. We also found that Toxoplasma gondii infection caused an increase, rather than historically observed decrease, in innate aversion to predator odors in rats. Conclusion: These observations suggest that effects of stress and Toxoplasma gondii are dependent on variables in the environment that often go unreported in the published literature.