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Alzheimer’s disease (AD) disproportionately affects females and the progression from cognitively normal to mild cognitive impairment (MCI) and to AD may be sex-specific. Using the ADNI database, we analysed the effect of sex and APOE genotype and sex and diagnosis (cognitively normal (CN), MCI, AD) on: AD-related endpoints (cognition, hippocampal volume, amyloid beta, tau-pathology), immune, neuroplasticity, and stress markers, and blood epigenetic age. More males were diagnosed with MCI but there was no sex difference in those diagnosed with AD, suggesting the progression from CN, MCI to AD may be sex-specific. Several biomarkers may influence sex differences in incidence and progression of MCI and AD. We found that females had higher levels of plasma CRP and lower levels of CSF IL-8, IL-16, IgA, and ICAM1 than males. Increasing number of APOE ε4 alleles and diagnosis also decreased plasma CRP in both sexes. Sex, diagnosis, or APOE genotype did not affect epigenetic age acceleration. We found, consistent with other studies, that females had higher levels of CSF tau-pathology that was disproportionately affected by APOE genotype compared to males. Females also had better memory (including verbal) scores than males, which may suggest a delay in the onset of cognitive decline or diagnosis. Sex differences in immune biomarkers and hippocampal volume (direction was dependent on method of correction) indicate that the underlying physiology during aging may be sex-dependent.

Sex differences exist in the regulation of adult neurogenesis in the hippocampus in response to hormones and cognitive training. Here we investigated the trajectory and maturation rate of adult-born neurons in the dentate gyrus (DG) of male and female rats. Sprague-Dawley rats were perfused one, two or three weeks after BrdU injection, marking newly dividing cells. Adult-born neurons (BrdU/NeuN-ir) matured faster in males compared to females. Males had a greater density of neural stem cells (Sox2-ir) in the dorsal, but not in the ventral, DG and had higher levels of cell proliferation (Ki67-ir) than females. Males had a greater reduction in neurogenesis between one and two weeks after mitosis, while females showed similar levels of neurogenesis throughout. The faster maturation and attrition of new neurons suggests greater potential for neurogenesis to respond to external stimuli in males compared to females and emphasizes the importance of studying sex on adult hippocampal neurogenesis.

Postpartum depression affects approximately 15% of mothers. Unfortunately, treatment options for postpartum depression are limited. Pharmacological antidepressants such as fluoxetine (FLX) can be controversial due to inconclusive evidence of efficacy during the postpartum and concerns of neonatal exposure to antidepressants. Alternatively, non-pharmacological antidepressants such as exercise may be less controversial but its efficacy in postpartum depression is unclear. To investigate this, we treated rat dams daily with high levels of corticosterone (CORT; 40 mg/kg), to induce a depressive-like phenotype, or oil (vehicle for CORT) during the postpartum period. Within the oil and CORT conditions, four additional antidepressant conditions were created: 1. FLX (10 mg/kg) + exercise (voluntary access to running wheel); 2. FLX + no exercise; 3. Saline (vehicle for FLX) + exercise; 4. Saline + No exercise. We examined maternal care, depressive-like and anxiety-like behavior, stress reactivity, and hippocampal neurogenesis and dams were categorized as “high running” or “low running.” FLX treatment, alone or with high running, prevented CORT-induced disruptions in maternal care. As expected, CORT increased depressive-like behavior but exercise, regardless of running amount, reduced depressive-like behavior. Intriguingly, FLX, but not CORT, increased anxiety-like behavior, which was not mitigated by concurrent exercise. FLX treatment slightly but significantly facilitated serum CORT recovery after forced swim stress. CORT and FLX alone reduced neurogenesis, while exercise coupled with FLX increased density of doublecortin-expressing cells. High running increased density of doublecortin-expressing cells (immature neurons) in comparison to controls. Collectively, these findings indicate that FLX and exercise reverse different endophenotypes of depression in dams, which has translational implications for surveying treatment options of postpartum depression.

Sex differences exist in the vulnerability, incidence, manifestation, and treatment of numerous neurological and psychiatric diseases. Despite this prominent observation in the literature, there has been little consideration given to possible sex differences in outcome in both preclinical and clinical research. This review highlights evidence supporting why studying sex differences matter for advances in brain health as well as improving treatment for neurological and psychiatric disease. Additionally, we discuss some statistical and methodological considerations in evaluating sex differences, as well as, how differences in the physiology of the sexes can contribute to sex difference in disease incidence and manifestation. Furthermore, we review literature demonstrating that the reproductive experience in the female can render the female brain differentially vulnerable to disease across age. Finally, we discuss how genes interact with sex to influence disease risk and treatment and argue that sex must be considered in precision medicine. Together, the evidence reviewed here supports the inclusion of males and females at all levels of neuroscience research.

Adult hippocampal neurogenesis is often associated with hippocampus-dependent learning and memory. Throughout a new neuron’s development, it is differentially sensitive to factors that can influence its survival and functionality. Previous research shows that, spatial training that occurred 6 to 10 days after an injection of the DNA synthesis marker, bromodeoxyuridine (BrdU), increased cell survival in male rats. Because sex differences in spatial cognition and hippocampal neurogenesis have been reported, it is unclear whether spatial training would influence hippocampal neurogenesis in the same way in males and females. Therefore, this study examined sex differences in hippocampal neurogenesis following training in a spatial task. Male and female rats were trained in the spatial or cued version of the Morris water maze task 6 to 10 days after one injection of BrdU (200mg/kg). Twenty days following BrdU injection, all animals were given a probe trial and perfused. Males performed better in the spatial, but not cue, task than females. Spatial training increased BrdU-labeled cells relative to cue training only in males, but both males and females showed greater activation of new cells (BrdU co-labeled with immediate early gene product zif268) after spatial training compared to cue training. Furthermore, performance during spatial training was positively correlated with cell activation in females but not males. This study shows that while spatial training differentially regulates hippocampal neurogenesis in males and females, the activity of new neurons in response to spatial memory retrieval is similar. These findings highlight the importance of sex on neural plasticity and cognition.

Adult neurogenesis in the dentate gyrus (DG) plays a crucial role for pattern separation and there are sex differences in the regulation of neurogenesis. Although sex differences, favoring males, in spatial navigation have been reported, it is not known whether there are sex differences in pattern separation. The current study was designed to determine whether there are sex differences in the ability for separating similar or distinct patterns, learning strategy choice, adult neurogenesis and immediate early gene (IEG) expression in the DG in response to pattern separation training. Male and female Sprague-Dawley rats received a single injection of the DNA synthesis marker, bromodeoxyuridine (BrdU) and were tested for the ability of separating spatial patterns in a spatial pattern separation version of delayed nonmatching to place task using the 8-arm radial arm maze. Twenty eight days following BrdU injection, rats received a probe trial to determine whether they were idiothetic or spatial strategy users. We found that male spatial strategy users outperformed female spatial strategy users only when separating similar, but not distinct, patterns. Furthermore male spatial strategy users had greater neurogenesis in response to pattern separation training than all other groups. Interestingly neurogenesis was positively correlated with performance on similar pattern trials during pattern separation in female spatial strategy users but negatively correlated with performance in male idiothetic strategy users. These results suggest that the survival of new neurons may play an important positive role for pattern separation of similar patterns in females. Furthermore, we found sex and strategy differences in IEG expression in the CA1 and CA3 regions in response to pattern separation. These findings emphasize the importance of studying biological sex on hippocampal function and neural plasticity.

Both natural estrogens and progesterone influence synaptic plasticity and neurogenesis within the female hippocampus. However, less is known of the impact of synthetic hormones on hippocampus structure and function. There is some evidence that administration of the synthetic progestin, medroxyprogesterone acetate (MPA) is not as beneficial as natural progesterone and can attenuate estrogen-induced neuroprotection. Although estradiol’s effects have been well studied, little is known about the effects of natural and synthetic progestins alone and in combination with estradiol on adult neurogenesis in the female. In the present study, we investigated the effects of chronic estradiol, progesterone, MPA, and a co-administration of each progestin with estradiol on neurogenesis within the dentate gyrus of adult ovariectomized female rats. Twenty-four hours following a bromodeoxyuridine (BrdU; 200mg/kg) injection, female rats were repeatedly administered with either progesterone (1 or 4 mg), MPA (1 or 4 mg), estradiol benzoate (EB), progesterone or MPA in combination with EB (10