Sex influences cognitive aging and dementia, yet research on the impact of female-specific factors, such as parity and fetal sex, on later-life cognition remains limited and equivocal. Inconsistencies in the literature may reflect varying effects across cognitive domains and dementia status. This study reviewed data from female participants of the University of British Columbia Hospital Clinic for Alzheimer and Related Dementias (UBCH CARD) to examine how parity and son-to-daughter ratio affect performance on medial temporal lobe-dependent (episodic memory) and prefrontal lobe-dependent (executive function) tasks depending on dementia status. Among females with dementia, higher parity was associated with reduced episodic memory but enhanced executive function performance, whereas a greater son-to-daughter ratio was associated with reduced executive function performance. These relationships were not observed in cognitively normal females or those diagnosed with mild cognitive impairment. These results emphasize the importance of integrating sex-specific factors into research and the development of precision therapeutics.

Sex differences, driven in part by steroid hormones, shape the structure and function of the brain throughout the lifespan and manifest across brain health and disease. The influence of steroid hormones on neuroplasticity, particularly in the adult hippocampus, differs between the sexes, which has important implications for disorders and diseases that compromise hippocampus integrity, such as depression and Alzheimer disease. This Review outlines the intricate relationship between steroid hormones and hippocampal neuroplasticity across the adult lifespan and explores how the unique physiology of male and female individuals can affect health and disease. Despite calls to include sex and gender in research, only 5% of neuroscience studies published in 2019 directly investigated the influence of sex. Drawing on insights from depression, Alzheimer disease and relevant hippocampal plasticity, this Review underscores the importance of considering sex and steroid hormones to achieve a comprehensive understanding of disease susceptibility and mechanisms. Such consideration will enable the discovery of personalized treatments, ultimately leading to improved health outcomes for all.

During pregnancy and the postpartum, there are dynamic fluctuations in steroid and peptide hormone levels as well as inflammatory signalling. These changes are required for a healthy pregnancy and can persist well beyond the postpartum. Many of the same hormone and inflammatory signalling changes observed during the perinatal period also play a role in symptoms related to autoimmune disorders, psychiatric disorders, and perhaps neurodegenerative disease later in life. In this review, we outline hormonal and immunological shifts linked to pregnancy and the postpartum and discuss the possible role of these shifts in increasing psychiatric, neurodegenerative disease risk and autoimmune symptoms during and following pregnancy. Furthermore, we discuss how key variables such as the number of births (parity) and sex of the fetus can influence inflammatory signalling, and possibly future disease risk, but are not often studied. We conclude by discussing the importance of studying female experiences such as pregnancy and parenting on physiology and disease.

Hippocampal neurogenesis persists across the lifespan in many species, including rodents and humans, and is associated with cognitive performance and the pathogenesis of neurodegenerative disease and psychiatric disorders. Neurogenesis is modulated by steroid hormones that change across development and differ between the sexes in rodents and humans. Here, we discuss the effects of stress and glucocorticoid exposure from gestation to adulthood as well as the effects of androgens and estrogens in adulthood on neurogenesis in the hippocampus. Throughout the review we highlight sex differences in the effects of steroid hormones on neurogenesis and how they may relate to hippocampal function and disease. These data highlight the importance of examining age and sex when evaluating the effects of steroid hormones on hippocampal neurogenesis.

Sex differences exist in many neurological and psychiatric diseases, but these have not always been addressed adequately in research. In order to address this, it is necessary to consider how sex is incorporated into the design (e.g. using a balanced design) and into the analyses (e.g. using sex as a covariate) in the published literature. We surveyed papers published in 2009 and 2019 across six journals in neuroscience and psychiatry. In this sample, we find a 30% increase in the percentage of papers reporting studies that included both sexes in 2019 compared with 2009. Despite this increase, in 2019 only 19% of papers in the sample reported using an optimal design for discovery of possible sex differences, and only 5% of the papers reported studies that analysed sex as a discovery variable. We conclude that progress to date has not been sufficient to address the importance of sex differences in research for discovery and therapeutic potential for neurological and psychiatric disease.

BACKGROUND:Cognitive symptoms of major depressive disorder, such as negative cognitive bias, are more prevalent in women than in men. Cognitive bias involves pattern separation which requires hippocampal neurogenesis and is modulated by inflammation in the brain. Previously, we found sex differences in the activation of the amygdala and the hippocampus in response to negative cognitive bias in rats that varied with age. Given the association of cognitive bias to neurogenesis and inflammation, we examined associations between cognitive bias, neurogenesis in the hippocampus, and cytokine and chemokine levels in the ventral hippocampus (HPC) and basolateral amygdala (BLA) of male and female rats across the lifespan.RESULTS:After cognitive bias testing, males had more IFN-γ, IL-1β, IL-4, IL-5, and IL-10 in the ventral HPC than females in adolescence. In young adulthood, females had more IFN-γ, IL-1β, IL-6, and IL-10 in the BLA than males. Middle-aged rats had more IL-13, TNF-α, and CXCL1 in both regions than younger groups. Adolescent male rats had higher hippocampal neurogenesis than adolescent females after cognitive bias testing and young rats that underwent cognitive bias testing had higher levels of hippocampal neurogenesis than controls. Neurogenesis in the dorsal hippocampus was negatively associated with negative cognitive bias in young adult males.CONCLUSIONS:Overall, the association between negative cognitive bias, hippocampal neurogenesis, and inflammation in the brain differs by age and sex. Hippocampal neurogenesis and inflammation may play greater role in the cognitive bias of young males compared to a greater role of BLA inflammation in adult females. These findings lay the groundwork for the discovery of sex-specific novel therapeutics that target region-specific inflammation in the brain and hippocampal neurogenesis.

The rodent estrous cycle modulates a range of biological functions, from gene expression to behavior. The cycle is typically divided into four stages, each characterized by distinct hormone concentration profiles. Given the difficulty of repeatedly sampling plasma steroid hormones from rodents, the primary method for classifying estrous stage is by identifying vaginal epithelial cell types. However, manual classification of epithelial cell samples is time-intensive and variable, even amongst expert investigators. Here, we use a deep learning approach to achieve classification accuracy at expert level. Due to the heterogeneity and breadth of our input dataset, our deep learning approach ("EstrousNet") is highly generalizable across rodent species, stains, and subjects. The EstrousNet algorithm exploits the temporal dimension of the hormonal cycle by fitting classifications to an archetypal cycle, highlighting possible misclassifications and flagging anestrus phases (e.g., pseudopregnancy). EstrousNet allows for rapid estrous cycle staging, improving the ability of investigators to consider endocrine state in their rodent studies.

Sex differences in motivation for food rewards, gambling, and drugs of abuse are modulated by multiple factors, including sensory stimuli, gonadal hormones, and cognitive bias. Cues, drugs of abuse, and a high-fat diet can significantly impact neural signaling in the reward system and functioning of neural systems that regulate executive functions differentially in males and females. Additionally, sex differences in risky decision-making, cognitive bias, and motivation for food and drugs of abuse are mediated by gonadal hormones in both sexes. As neuroscientists analyze data from both sexes, it is becoming apparent that these differences are not simply mediated by hormones in females, but involve sex differences in the specific neural responses to stimuli, including both external stimuli and internal hormonal signals. Understanding sex differences in the mechanisms underlying reward-seeking behaviors and the development of substance use disorders will help uncover potential therapies and treatments that will benefit both men and women. Based on these observations, it is essential that females are included in neuroscience research.

Cognitive symptoms of depression, including negative cognitive bias, are more severe in women than in men. Current treatments to reduce negative cognitive bias are not effective and sex differences in the neural activity underlying cognitive bias may play a role. Here we examined sex and age differences in cognitive bias and functional connectivity in a novel paradigm. Male and female rats underwent an 18-day cognitive bias procedure, in which they learned to discriminate between two contexts (shock paired context A, no-shock paired context B), during either adolescence (postnatal day (PD 40)), young adulthood (PD 100), or middle-age (PD 210). Cognitive bias was measured as freezing behaviour in response to an ambiguous context (context C), with freezing levels akin to the shock paired context coded as negative bias. All animals learned to discriminate between the two contexts, regardless of sex or age. However, adults (young adults, middle-aged) displayed a greater negative cognitive bias compared to adolescents, and middle-aged males had a greater negative cognitive bias than middle-aged females. Females had greater neural activation of the nucleus accumbens, amygdala, and hippocampal regions to the ambiguous context compared to males, and young rats (adolescent, young adults) had greater neural activation in these regions compared to middle-aged rats. Functional connectivity between regions involved in cognitive bias differed by age and sex, and only adult males had negative correlations between the frontal regions and hippocampal regions. These findings highlight the importance of examining age and sex when investigating the underpinnings of negative cognitive bias and lay the groundwork for determining what age- and sex-specific regions to target in future cognitive bias studies.

Sex differences exist in many neurological and psychiatric diseases. Mandates have been initiated across funding agencies for research to include males and females. What has been lacking in the literature is a detailed assessment of how sex is incorporated into the design (e.g. balanced design) and into the analyses (e.g. covariate). We surveyed papers in 2009 and 2019 across six journals in Neuroscience and Psychiatry. There was a 30% increase in the percentage of papers that included both sexes to 68% in 2019. Despite this increase, in 2019 only 19% of studies used an optimal design for discovery of possible sex differences and only 5% analyzed sex as a discovery variable. Here we show that little progress has been made in harnessing the power that sex differences can afford in research for discovery and therapeutic potential for neurological and psychiatric disease to improve the health of men, women and gender diverse individuals. Highlights 68% of Neuroscience and Psychiatry papers reported the use of both sexes in 2019 Only 19% of studies in 2019 used sex consistently throughout the study analyses Of the studies that used males and females, 59% did not include sex in the analyses Only 5% of studies in 2019 used sex as a discovery variable in their analyses Male only papers were 8.4 times more prevalent than female-only papers

Adolescence is a critical time of brain development for regions governing social behaviour and social learning. Social experiences influence the ongoing maturation of the neural structures and ultimately modify the social behaviour of adults in response to social cues. Social instability stress in adolescence (SS; daily 1-hour isolation + change of cage partner in postnatal days [PND] 30-45) leads to a long-lasting reduction in social interaction in SS rats compared with non-stressed (CTL) rats in males; here we investigate females. In a first experiment, we found that female rats exposed to adolescent SS also showed the decrement in social interaction irrespective of age at which tested, and replicated the effects previously found in males. In experiment 2, which involved females only, SS and CTL rats did not differ in anxiety-like behaviour in the elevated plus maze (EPM) and the reduction in social interaction was not significant. Nevertheless, when tested in adolescence at P47 (and not at P71), SS female rats had higher corticosterone release during the social interaction test than did CTL rats, and they exhibited a different pattern of neural activation as measured by immunoreactivity to the protein products of zif268 and c-fos (SS < CTL in medial prefrontal cortex and SS > CTL in hippocampus), and reduced oxytocin immunoreactivity in the paraventricular nucleus of the hypothalamus than did CTL rats. These results extend our previous findings of effects of SS in adolescent female rats on behavioural responses to psychostimulants to social behaviour, and point to directions for investigations of the neural mechanisms involved. (c) 2021 IBRO. Published by Elsevier Ltd. All rights reserved.

Objective Older adults with amnestic mild cognitive impairment (aMCI) develop Alzheimer's type dementia approximately 10 times faster annually than the normal population. Adrenal hormones are associated with aging and cognition. We investigated the relationship between acute stress, cortisol, and memory function in aMCI with an exploratory analysis of sex. Method Salivary cortisol was sampled diurnally and during two test sessions, one session with the Trier Social Stress Test (TSST), to explore differences in the relationship between cortisol and memory function in age-normal cognition (NA) and aMCI. Participants with aMCI (n = 6 women, 9 men; mean age = 75) or similarly aged NA (n = 9 women, 7 men, mean age = 75) were given tests of episodic, associative, and spatial working memory with a psychosocial stressor (TSST) in the second session. Results The aMCI group performed worse on the memory tests than NA as expected, and males with aMCI had elevated cortisol levels on test days. Immediate episodic memory was enhanced by social stress in NA but not in the aMCI group, indicating that stress-induced alterations in memory are different in individuals with aMCI. High cortisol was associated with impaired performance on episodic memory in aMCI males only. Cortisol in Session 1 moderated the relationship with spatial working memory, whereby higher cortisol was associated with worse performance in NA, but better spatial working memory in aMCI. In addition, effects of aMCI on perceived anxiety in response to stress exposure were moderated by stress-induced cortisol in a sex-specific manner. Conclusions We show effects of aMCI on Test Session cortisol levels and effects on perceived anxiety, and stress-induced impairments in memory in males with aMCI in our exploratory sample. Future studies should explore sex as a biological variable as our findings suggest that effects at the confluence of aMCI and stress can be obfuscated without sex as a consideration.

Social instability stress (SS; daily 1 h isolation and change of cage partner from postnatal day (P) 30-45) in adolescence produces elevations in corticosterone during the procedure in male and female rats, but no lasting changes in hypothalamic-pituitary-adrenal (HPA) responses to psychological stressors, although deficits in social and cognitive function are evident in adulthood. Here we investigated the effects of SS in corticosterone response to an immune challenge (lipopolysaccharide, LPS, 0.1 mg/kg), on gene expression in the hippocampus, and on gut microbiota, when tested soon- (P46) or long- (P70) after SS. The temporal pattern of corticosterone release after LPS differed between SS and control rats irrespective of the time since SS exposure in females, whereas in males, SS did not alter corticosterone release after LPS. Expression of genes in the hippocampus relevant to immune and HPA function differed between saline-treated SS and control rats depending on sex and time tested, but with lasting consequences of SS in both sexes. LPS-treatment altered hippocampal gene expression, with bigger effects of LPS evident in control than in SS female rats, and the opposite in male rats. Further, effects sometimes depended on the age at time of LPS treatment. SS and control rats differed in both fecal and colon microbiome composition in all but P46 males, and stress history, sex, and age influenced the effects of an immune challenge on the gut microbiome. In sum, adolescent stress history has consequences for immune function into adulthood that may involve effects on the gut microbiome.

Perinatal depression (PND) can have either an antepartum or postpartum onset. Although the greatest risk factor for PND is previous depression history, de novo PND occurs with the majority of cases occurring in the postpartum. Timing of depression can impact etiology, prognosis, and response to treatment. Thus, it is crucial to study the impact of the heterogeneity of PND for better health outcomes. In this review, we outline the differences between antepartum and postpartum depression onset of PND. We discuss maternal physiological changes that differ between pregnancy and postpartum and how these may differentially impact depression susceptibility. We highlight changes in the maternal steroid and peptide hormone levels, immune signalling, serotonergic tone, metabolic factors, brain morphology, and the gut microbiome. Finally, we argue that studying the heterogeneity of PND in clinical and preclinical models can lead to improved knowledge of disease etiopathology and treatment outcomes.

Adolescents show greater and/or more prolonged activation of the hypothalamic‐pituitary‐adrenal axis in response to stressors than adults, although the basis for such an age difference is not understood. We investigated developmental shifts in the regulation of HPA function by testosterone using androgen replacement in orchiectomised (OCX) pre‐pubertal and post‐pubertal adolescent rats and in adults, as well as using inhibitors of testosterone synthesis in non‐operated rats. The expected dampening effect of testosterone in adult OCX rats did not meet statistical significance in all of the three experiments. Nevertheless, in each, adolescents had higher post‐stress concentrations of corticosterone compared to adults despite similar concentrations of testosterone. The effect of testosterone was in the opposite direction in post‐pubertal adolescents compared to that in adults, with testosterone replacement leading to increased rather than lower corticosterone concentration. Testosterone replacement decreased arginine vasopressin and corticotrophin‐releasing hormone immune‐reactive cell counts in the paraventricular nucleus at all ages. In a fourth experiment, we provide evidence that the basis of the age difference in corticosterone release is because of a greater conversion of testosterone to oestradiol in adolescents and a greater conversion of testosterone to dihydrotestosterone in adults: aromatase inhibition had little effect in adults and attenuated the age difference by decreasing stress‐induced corticosterone release in adolescents. By contrast, 5α‐reductase inhibition or an androgen receptor antagonist had little effect in adolescents and attenuated the age difference by increasing stress‐induced corticosterone release in adults. In the adrenal gland, adolescents had reduced 5α‐reductase and androgen receptor gene expression. There also were age differences in the regulation of hypothalamic mRNA expression of androgen receptors, oestrogen receptors and aromatase by testosterone. In sum, the results suggest that developmental shifts in the synthesis of testosterone and the regulation of gene expression are factors with respect to age differences in corticosterone release in response to stressors.

Oxytocin influences social behaviour and hypothalamic-pituitary-adrenal (HPA) function. We previously found that social instability stress (SS) from postnatal day 30 to 45 increased oxytocin receptor (OTR) densities in the lateral septum and nucleus accumbens of adolescent male rats. Here, we investigated social behaviour and HPA function in adolescent male SS rats compared with age- and sex-matched controls after intraperitoneal treatment with an OTR antagonist L-368,899 (OTR-A). Regardless of OTR antagonism, adolescent SS rats spent more time in social approach (investigation through wire mesh) but less time in social interaction (physical interaction) with unfamiliar same-sex and same-age peers than did controls. However, OTR-A-treatment caused SS rats to be more socially avoidant than OTR-A-treated controls and saline-treated rats of the same condition. Additionally, the predicted rise in plasma corticosterone in response to OTR-A treatment was blunted in SS rats. Fos immunoreactivity (IR) was used as a marker of neural activation in social brain regions and oxytocin-IR was examined in the paraventricular nucleus of the hypothalamus (PVN) in response to interacting with unfamiliar peers in SS and control rats after OTR-A treatment. OTR-A treatment had little effect on Fos-IR and oxytocin-IR in the analyzed brain regions, but SS rats had lower Fos-IR and oxytocin-IR in the PVN and greater Fos-IR in subregions of the prefrontal cortex, and hippocampus, and lateral septum than did controls. Finally, binding density of OTR was measured in the PVN and hippocampus, and greater OTR binding density was found in the PVN of SS rats. Together, these data demonstrate a greater influence of OTR antagonism on social behaviour and a reduced influence of OTR antagonism on HPA responses after adolescent SS in male rats. The results also suggest that differences in neural functioning in the prefrontal cortex, hippocampus and lateral septum of adolescent SS rats may be involved in their altered social behaviour relative to that of controls.

Excessive drinking in adolescence continues to be a problem, and almost a quarter of young Canadians have reported consuming five or more alcoholic drinks in one occasion in recent surveys. The consequences of such drinking may be more pronounced when commenced in adolescence, given the ongoing brain development during this period of life. Here, we investigated the consequences of 3 weeks' intermittent access to ethanol in mid-adolescence to early adulthood in rats, and the extent to which a stress history moderated the negative consequences of ethanol access. In experiment 1, male rats that underwent adolescent social instability stress (SS; daily 1 h isolation + return to unfamiliar cage partner every day from postnatal day [PND] 30-45) did not differ from control (CTL) rats in intake of 10% ethanol sweetened with 0.1% saccharin (access period; PND 47-66). Ethanol drinking reduced proteins relevant for synaptic plasticity (alpha CaMKII, beta CaMKII, and PSD-95) in the dorsal hippocampus, and in CTL rats only in the prefrontal cortex (alpha CaMKII and PSD 95), attenuating the difference between CTL and SS rats in the water-drinking group. In experiment 2, ethanol also attenuated the difference between SS and CTL rats in a social interaction test by reducing social interaction in SS rats; CTL rats, however, had a higher intake of ethanol than did SS rats during the access period. Ethanol drinking reduced baseline and fear recall recovery concentrations of corticosterone relative to those exposed only to water, although there was no effect of either ethanol or stress history on fear conditioning. Ethanol drinking did not influence intake after 9 days of withdrawal; however, ethanol-naive SS rats drank more than did CTL rats when given a 24-h access in adulthood. These results reveal a complex relationship between stress history and ethanol intake in adolescence on outcomes in adulthood. (C) 2019 Elsevier Inc. All rights reserved.

Social instability stress in adolescent rats (SS; postnatal day 30-45, daily 1 hr isolation +new cage partner) alters behavioural responses to psychostimulants, but differences in voluntary consumption of natural and drug rewards are unknown. SS also is associated with an atypical behavioural repertoire, for example reduced social interactions. Here, we investigated whether SS rats differ from control (CTL) rats in ethanol (EtOH) or sucrose intake in experiments involving different social contexts: alone, in the presence of an unfamiliar peer, in the presence of its cage partner, or in competition against its cage partner. SS rats drank more EtOH than CTL rats irrespective of social context, although the effects were driven primarily by those tested soon after the test procedure rather than weeks later in adulthood. SS and CTL rats did not differ in sucrose intake, except in adulthood under conditions of competition for limited access (SS>CTL). Adolescent rats drank more sucrose than adults, in keeping with evidence that adolescents are more sensitive to natural rewards than adult animals. Overall, adolescent SS modified the reward value of EtOH and sucrose, perhaps through stress/glucocorticoids modifying the development of the mesocorticolimbic system.