A major sex difference in Alzheimer’s disease (AD) is that men with the disease die earlier than do women. In aging and preclinical AD, men also show more cognitive deficits. Here, we show that the X chromosome affects AD-related vulnerability in mice expressing the human amyloid precursor protein (hAPP), a model of AD. XY-hAPP mice genetically modified to develop testicles or ovaries showed worse mortality and deficits than did XX-hAPP mice with either gonad, indicating a sex chromosome effect. To dissect whether the absence of a second X chromosome or the presence of a Y chromosome conferred a disadvantage on male mice, we varied sex chromosome dosage. With or without a Y chromosome, hAPP mice with one X chromosome showed worse mortality and deficits than did those with two X chromosomes. Thus, adding a second X chromosome conferred resilience to XY males and XO females. In addition, the Y chromosome, its sex-determining region Y gene (Sry), or testicular development modified mortality in hAPP mice with one X chromosome such that XY males with testicles survived longer than did XY or XO females with ovaries. Furthermore, a second X chromosome conferred resilience potentially through the candidate gene Kdm6a, which does not undergo X-linked inactivation. In humans, genetic variation in KDM6A was linked to higher brain expression and associated with less cognitive decline in aging and preclinical AD, suggesting its relevance to human brain health. Our study suggests a potential role for sex chromosomes in modulating disease vulnerability related to AD.

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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.

Aversion to environmental cues of predators is an integral part of defensive behaviors in many prey animals. It enhances their survival and probability of future reproduction. At the same time, animals cannot be maximally defended because imperatives of defense usually trade-off with behaviors required for sexual reproduction like display of dominance and production of sexual pheromones. Here, we approach this trade-off through the lens of arginine vasopressin (AVP) neurons within the posterodorsal medial amygdala (MePD) of mice. This neuronal population is known to be involved in sexual behaviors like approach to sexually salient cues. We show that chemogenetic partial ablation of this neuronal population increases aversion to predator odors. Moreover, overexpression of AVP within this population is sufficient to reduce aversion to predator odors. The loss of fear of the predator odor occurs in parallel with increased recruitment of AVP neurons within the MePD. These observations suggest that AVP neurons in the medial aspect of the extended amygdala are a proximate locus for the reduction in innate fear during life stages dominated by reproductive efforts.

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Males exhibit shorter lifespan and more cognitive deficits, in the absence of dementia, 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 (XY). 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 transcript 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 aged 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, in the aging XY brain, without altering total activity or anxiety-like measures. Further understanding the demethylase-independent downstream mechanisms of Kdm6a may lead to novel therapies for treating age-induced cognitive deficits in both sexes.

Arginine vasopressin (AVP) is expressed in both hypothalamic and extra-hypothalamic neurons. The expression and role of AVP exhibit remarkable divergence between these two neuronal populations. Polysynaptic pathways enable these neuronal groups to regulate each other. AVP neurons in the paraventricular nucleus of the hypothalamus increase the production of adrenal stress hormones by stimulating the hypothalamic–pituitary–adrenal axis. Outside the hypothalamus, the medial amygdala also contains robust amounts of AVP. Contrary to the hypothalamic counterpart, the expression of extra-hypothalamic medial amygdala AVP is sexually dimorphic, in that it is preferentially transcribed in males in response to the continual presence of testosterone. Male gonadal hormones typically generate a negative feedback on the neuroendocrine stress axis. Here, we investigated whether testosterone-responsive medial amygdala AVP neurons provide negative feedback to hypothalamic AVP, thereby providing a feedback loop to suppress stress endocrine response during periods of high testosterone secretion. Contrary to our expectation, we found that AVP overexpression within the posterodorsal medial amygdala increased the recruitment of hypothalamic AVP neurons during stress, without affecting the total number of AVP neurons or the number of recently activated neurons following stress. These observations suggest that the effects of testosterone on extra-hypothalamic AVP facilitate stress responsiveness through permissive influence on the recruitment of hypothalamic AVP neurons.