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Exercise training is among the main strategies that have been proposed to promote cognitive and brain health outcomes in older individuals with and without cognitive impairment. The effects of exercise on cognition are mediated, in part, by structural and functional adaptations in the brain, including changes in gray matter volumes and white matter microstructural integrity. Muscular contractions during exercise produce a category of cytokines referred to as myokines, which represent a potential molecular pathway mediating neuroplastic adaptations and associated cognitive improvements in response to exercise. Understanding the ideal combination of exercise training parameters across populations and life stages could lead to interventions that promote greater effects on cognitive and brain health outcomes. Exercise training is an important strategy to counteract cognitive and brain health decline during aging. Evidence from systematic reviews and meta-analyses supports the notion of beneficial effects of exercise in cognitively unimpaired and impaired older individuals. However, the effects are often modest, and likely influenced by moderators such as exercise training parameters, sample characteristics, outcome assessments, and control conditions. Here, we discuss evidence on the impact of exercise on cognitive and brain health outcomes in healthy aging and in individuals with or at risk for cognitive impairment and neurodegeneration. We also review neuroplastic adaptations in response to exercise and their potential neurobiological mechanisms. We conclude by highlighting goals for future studies, including addressing unexplored neurobiological mechanisms and the inclusion of under-represented populations. [ABSTRACT FROM AUTHOR]

Background: Aerobic exercise promotes cognitive function in older adults; however, variability exists in the degree of benefit. The brain-derived neurotropic factor (BDNF) Val66Met polymorphism and biological sex are biological factors that have been proposed as important modifiers of exercise efficacy. Therefore, we assessed whether the effect of aerobic exercise on executive functions was dependent on the BDNFval66met genotype and biological sex. Methods: We used data from a single-blind randomized controlled trial in older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Fifty-eight older adults were randomly assigned to either the 6 months, three times per week progressive aerobic training (AT) group or the usual care plus education control (CON) group. The secondary aim of the parent study included executive functions which were assessed with the Trail Making Test (B–A) and the Digit Symbol Substitution Test at baseline and trial completion at 6 months. Results: Analysis of covariance, controlling for baseline global cognition and baseline executive functions performance (Trail Making Test or Digit Symbol Substitution Test), tested the three-way interaction between experimental group (AT, CON), BDNFval66met genotype (Val/Val carrier, Met carrier), and biological sex (female, male). Significant three-way interactions were found for the Trail Making Test (F(1,48) = 4.412, p < 0.04) and Digit Symbol Substitution Test (F(1,47) = 10.833, p < 0.002). Posthoc analyses showed female Val/Val carriers benefited the most from 6 months of AT compared with CON for Trail Making Test and Digit Symbol Substitution Test performance. Compared with CON, AT did not improve Trail Making Test performance in male Val/Val carriers or Digit Symbol Substitution Test performance in female Met carriers. Conclusions: These results suggest that future randomized controlled trials should take into consideration BDNF genotype and biological sex to better understand the beneficial effects of AT on cognitive function in vascular cognitive impairment to maximize the beneficial effects of exercise and help establish exercise as medicine for cognitive health. Highlights: Aerobic training improves cognitive health and identifying biological moderators of aerobic training will maximize the precision of exercise as medicine for cognitive health. The common BDNFval66met polymorphism and biological sex interact to moderate the cognitive-enhancing effects of aerobic training in older adults with vascular cognitive impairment, with female Val/Val carriers benefitting the most. Future randomized controlled trials of exercise should take into consideration genotype and biological sex of participants [ABSTRACT FROM AUTHOR]

Background Older females show greater cognitive gains from physical activity (PA) than males, which may be related to long-term consequences of female-specific reproductive events (eg, pregnancy) on cognitive health. Methods To determine whether previous parity could moderate the relationship between PA and cognitive decline in older women, we conducted secondary analyses of data from the Health, Aging, and Body Composition Study. We tested whether the association between average PA over 10 years and cognition (Modified Mini-Mental State Examination [3MS]) and executive functioning (digit symbol substitution test [DSST]) over 10 years varied by previous parity (nulliparity, low parity, medium parity, and grand multiparity). An analysis of covariance was performed with cognition (average and change over 10 years) as the dependent variables, parity as a categorical predictor, average PA as a continuous predictor, and a set of relevant covariates. Results Significant interactions were found between PA and parity group for all 4 comparisons: average 3MS (p =.014), average DSST (p =.032), change in 3MS (p =.016), and change in DSST (p =.017). Simple slope analyses indicated the positive relationship between PA and average 3MS and DSST was only significant in the nulliparity and grand multiparity groups, and the positive relationship between PA and change in 3MS and DSST was only significant in the grand multiparity group. Conclusion The findings suggest the relationship between self-reported walking and cognitive performance was strongest in the groups at risk for cognitive decline and dementia, the nulliparous and grand multiparous groups. [ABSTRACT FROM AUTHOR]

Background: Targeted exercise training is a promising strategy for promoting cognitive function and preventing dementia in older age. Despite the utility of exercise as an intervention, variation still exists in exercise-induced cognitive gains and questions remain regarding the type of training (i.e., what), as well as moderators (i.e., for whom) and mechanisms (i.e., how) of benefit. Both aerobic training (AT) and resistance training (RT) enhance cognitive function in older adults without cognitive impairment; however, the vast majority of trials have focused exclusively on AT. Thus, more research is needed on RT, as well as on the combination of AT and RT, in older adults with mild cognitive impairment (MCI), a prodromal stage of dementia. Therefore, we aim to conduct a 6-month, 2 × 2 factorial randomized controlled trial in older adults with MCI to assess the individual effects of AT and RT, and the combined effect of AT and RT on cognitive function and to determine the possible underlying biological mechanisms.Methods: Two hundred and sixteen community-dwelling adults, aged 65 to 85 years, with MCI from metropolitan Vancouver will be recruited to participate in this study. Randomization will be stratified by biological sex and participants will be randomly allocated to one of the four experimental groups: (1) 4×/week balance and tone (BAT; i.e., active control); (2) combined 2×/week AT + 2×/week RT; (3) 2×/week AT + 2×/week BAT; or (4) 2×/week RT + 2×/week BAT. The primary outcome is cognitive function as measured by the Alzheimer's Disease Assessment Scale-Cognitive-Plus. Secondary outcomes include cognitive function, health-related quality of life, physical function, actigraphy measures, questionnaires, and falls. Outcomes will be measured at baseline, 6 months (i.e., trial completion), and 18 months (i.e., 12-month follow-up).Discussion: Establishing the efficacy of different types and combinations of exercise training to minimize cognitive decline will advance our ability to prescribe exercise as "medicine" to treat MCI and delay the onset and progression of dementia. This trial is extremely timely as cognitive impairment and dementia pose a growing threat to global public health.Trial Registration: ClinicalTrials.gov NCT02737878 . Registered on April 14, 2016. [ABSTRACT FROM AUTHOR]

Aerobic training (AT) can promote cognitive function in adults with Subcortical Ischemic Vascular Cognitive Impairment (SIVCI) by modifying cardiovascular risk factors. However, pre-existing cardiovascular health may attenuate the benefits of AT on cognitive outcomes in SIVCI. We examined whether baseline cardiovascular risk moderates the effect of a 6-month progressive AT program on executive functions with a secondary analysis of a randomized controlled trial in 71 adults, who were randomized to either: (1) 3×/week progressive AT; or (2) education program (CON). Three executive processes were measured: (1) response inhibition by Stroop Test; (2) working memory by digits backward test; and (3) set shifting by the Trail Making Test. Baseline cardiovascular risk was calculated using the Framingham cardiovascular disease (CVD) Risk Score (FCRS), and participants were classified as either low risk (< 20% FCRS score; LCVR) or high risk (≥ 20% FCRS score; HCVR). A complete case analysis (n = 58) was conducted using an analysis of covariance (ANCOVA) to evaluate between-group differences in the three executive processes. A significant interaction was found between cardiovascular risk group and intervention group (AT or CON) for the digit span backward and the Trail Making Test. AT improved performance compared with CON in those with LCVR, while in those with HCVR, AT did not improve performance compared with CON. Baseline cardiovascular risk significantly moderates the efficacy of AT on cognition. Our findings highlight the importance of intervening early in the disease course of SIVCI, when cardiovascular risk may be lower, to reap maximum benefits of aerobic exercise. [ABSTRACT FROM AUTHOR]

Dementia is one of the most pressing health care issues of this century. As no curative treatment for dementia exists, research efforts are growing to identify effective lifestyle interventions to prevent or delay onset. One such promising strategy that promotes cognitive and brain health is engaging in physical exercise. However, current exercise recommendations are imprecise. To advance the potential of exercise as a preventative and treatment strategy, important questions regarding moderators (ie, biological sex and age) are being addressed in the literature. Biological sex is recognized as an important variable to consider in exercise efficacy on brain health, with females showing greater cognitive gains. This may be related to sex differences in underlying mechanisms. Here, we argue to better understand the sex differences in exercise efficacy, the timing of exercise intervention should also be considered. Specifically, we present the hypothesis that midlife in females is a critical window for the implementation of exercise as an early intervention to promote brain health and prevent dementia. Further, we speculate that exercise interventions targeting midlife will be of critical importance for the female brain, as females exit this period of the lifespan at greater risk for cognitive impairment. Given the potential sex differences in dementia risk and prevalence, it is imperative to assess potential sex differences in exercise efficacy as an early intervention during midlife. [ABSTRACT FROM AUTHOR]

Background: Physical activity (PA) is a promising strategy for the promotion of brain health, although substantial variation exists in the effects of PA at the individual level. Given the greater prevalence and faster progression of Alzheimer's disease in women compared to men, and known sex differences in brain architecture, analysis of sex differences in the relationship between PA, cognition, and brain region volumes is warranted.Methods: To address this, we conducted secondary analyses of data from the Health, Aging, and Body Composition study. To determine whether longitudinal changes in PA over 10 years predicted declines in global cognitive functioning and executive functions and processing speed differently in males and females, latent growth curve modeling was utilized. Magnetic resonance imaging was performed at year 10, and the hippocampus and dorsolateral prefrontal cortex were identified as regions of interest.Results: Maintaining PA over 10 years predicted less declines in executive functions and processing speed in females but not males. Maintaining PA over 10 years was significantly associated with greater volume of the left dorsolateral prefrontal cortex, a brain region involved in executive functions, in year 10 in females only. Maintaining physical activity was associated with better global cognitive function in both males and females, and also predicted volume of the left hippocampus, albeit in different directions with females showing a negative relationship and males showing a positive relationship.Conclusions: These findings suggest that the relationship of PA with cognition and its neurobiological correlates differ by sex, with females apparently benefiting from PA to a greater extent than males. Development of personalized, tailored exercise recommendations to promote healthy brain aging should account for sex differences. [ABSTRACT FROM AUTHOR]

Abstract Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism may be an important source of heterogeneity seen in cognitive aging, although the specific relationship between this polymorphism and cognition remains controversial and may depend on the sex of participants. We assessed 2668 older black and white adults and fit linear mixed models to digit symbol substitution test (DSST) performance assessed in years 0 (baseline), 4, 7, and 9 to examine the interaction between sex and BDNF genotype on the intercept (i.e., estimated baseline DSST) and change in DSST over 9 years, adjusted for covariates. Sex interacted with BDNF genotype to predict DSST intercept (F [1,1599] = 7.4, p < 0.01) and 9-year change (F [1,1183] = 4.1, p = 0.04) in white participants only. Initially, white male Val/Val carriers had lower DSST scores (37.6, SE = 0.8) in comparison with male Met carriers (difference, −1.7; 95% CI, −3.2 to −0.3) and female Val/Val carriers (difference, −5.6; 95% CI, −6.8 to −4.3). White female Met carriers showed a slower rate of change (annual rate of change = −0.6, SE = 0.1) in comparison with female Val/Val carriers (difference, −0.2; 95% CI, −0.4 to −0.02) and male Met carriers (difference, −0.3; 95% CI, −0.5 to −0.02). Our findings suggest that BDNF Val66Met and sex should be considered in future endeavors aimed at treating or preventing neurodegenerative disorders. Highlights • BDNF Val66Met polymorphism effect on cognitive decline is controversial and may be due to an interaction with biological sex. • There was an interaction such that the Met allele was protective against declines in executive functioning for females, but in white participants only. • Interaction between sex and BDNF Val66Met polymorphism was not seen in black participants. [ABSTRACT FROM AUTHOR]

Physical activity is a promising strategy for dementia prevention and disease modification. Here, we provide a narrative review of the current evidence from epidemiological and intervention studies on the role of physical activity and exercise in promoting cognitive health in older adults both without and with cognitive impairment. We highlight some of the potential underlying mechanisms and discuss biological sex as a potential moderating factor. We conclude with limitations and future directions for this rapidly expanding line of research. [ABSTRACT FROM AUTHOR]

Aerobic training (AT) is a promising, non-pharmacological intervention to mitigate the deleterious effects of aging and disease on brain health. However, a large amount of variation exists in its efficacy. This is a secondary analysis of a randomized controlled trial of AT in 71 older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Specifically, we investigated: 1) whether sex moderates the relationship between AT and executive functions, and 2) the role of brain derived neurotrophic factor (BDNF) and gains in functional fitness capacity. Older adults were randomly assigned to either 6-month, thrice-weekly AT or to usual care plus education (CON). At baseline, trial completion, and 6-month follow-up, executive functions were assessed with the Trail Making Test (A & B), verbal digits forward and backward test, and the Stroop Test. Functional fitness capacity was assessed with the 6-Minute Walk Test. Compared with CON, AT significantly improved Trail Making Test performance in females but not males, an effect that was retained at follow-up. AT significantly increased BDNF levels in females but decreased levels in males. On the other hand, AT led to significant gains in functional fitness capacity in males only. This study provides evidence that sex differences exist in AT efficacy on brain health as well as in the biological mechanisms subserving AT. [ABSTRACT FROM AUTHOR]

Exercise is a non-pharmacological strategy to mitigate the deleterious effects of aging on brain health. However, a large amount of variation exists in its efficacy. Sex of participants and exercise type are two possible factors contributing to this variation. To better understand this, we conducted a concurrent systematic review and meta-analysis of cognitively healthy older adults. Executive functions, episodic memory, visuospatial function, word fluency, processing speed and global cognitive function were examined for exercise- and sex-dependent effects. For executive functions, three types of exercise interventions – aerobic training, resistance training, and multimodal training (i.e., both aerobic and resistance training) – were associated with larger effect sizes in studies comprised of a higher percentage of women compared to studies with a lower percentage of women. This suggests that women’s executive processes may benefit more from exercise than men. Regardless of sex, compared to control, all three exercise training approaches enhanced visuospatial function, but only multimodal training enhanced episodic memory. Overall, aerobic training led to greater benefits than resistance training in global cognitive function and executive functions, while multimodal combined training led to greater benefits than aerobic training for global cognitive function, episodic memory, and word fluency. Possible underlying mechanisms, including brain-derived neurotrophic factor and sex steroid hormones, are discussed. [ABSTRACT FROM AUTHOR]

Research in humans indicates that women may show greater cognitive benefits from aerobic training (AT) than men. To determine whether this sex difference extends to rodents, we conducted a systematic review and meta-analysis of studies in healthy, older rodents. Results indicate that compared to controls, AT improved hippocampus-dependent and -independent learning and memory. A sex difference was found with males showing larger benefits from AT on conditioned-avoidance and non-spatial memory tasks. AT also increased brain-derived neurotrophic factor compared to controls, with larger effects in females. As an exploratory analysis, sex differences in voluntary AT were examined separately from forced AT. Voluntary AT enhanced non-spatial memory to a greater extent in males. Forced AT enhanced hippocampus-dependent learning and memory more so in females. These findings suggest that sex is an important factor to consider, and studies directly assessing sex differences in the ability of exercise to improve brain function are needed. [ABSTRACT FROM AUTHOR]

Psychological challenges, including traumatic events, have been hypothesized to increase the age-related pace of biological aging. Here we test the hypothesis that psychological challenges can affect the pace of telomere attrition, a marker of cellular aging, using data from an ongoing longitudinal-cohort study of Kaqchikel Mayan women living in a population with a high frequency of child mortality, a traumatic life event. Specifically, we evaluate the associations between child mortality, maternal telomere length and the mothers’ hypothalamic-pituitary-adrenal axis (HPAA), or stress axis, activity. Child mortality data were collected in 2000 and 2013. HPAA activity was assessed by quantifying cortisol levels in first morning urinary specimens collected every other day for seven weeks in 2013. Telomere length (TL) was quantified using qPCR in 55 women from buccal specimens collected in 2013. Results: Shorter TL with increasing age was only observed in women who experienced child mortality (p = 0.015). Women with higher average basal cortisol (p = 0.007) and greater within-individual variation (standard deviation) in basal cortisol (p = 0.053) presented shorter TL. Non-parametric bootstrapping to estimate mediation effects suggests that HPAA activity mediates the effect of child mortality on TL. Our results are, thus, consistent with the hypothesis that traumatic events can influence cellular aging and that HPAA activity may play a mediatory role. Future large-scale longitudinal studies are necessary to confirm our results and further explore the role of the HPAA in cellular aging, as well as to advance our understanding of the underlying mechanisms involved. [ABSTRACT FROM AUTHOR]

Life history theory (LHT) predicts a trade-off between reproductive effort and the pace of biological aging. Energy invested in reproduction is not available for tissue maintenance, thus having more offspring is expected to lead to accelerated senescence. Studies conducted in a variety of non-human species are consistent with this LHT prediction. Here we investigate the relationship between the number of surviving children born to a woman and telomere length (TL, a marker of cellular aging) over 13 years in a group of 75 Kaqchikel Mayan women. Contrary to LHT’s prediction, women who had fewer children exhibited shorter TLs than those who had more children (p = 0.045) after controlling for TL at the onset of the 13-year study period. An “ultimate” explanation for this apparently protective effect of having more children may lay with human’s cooperative-breeding strategy. In a number of socio-economic and cultural contexts, having more chilren appears to be linked to an increase in social support for mothers (e.g., allomaternal care). Higher social support, has been argued to reduce the costs of further reproduction. Lower reproductive costs may make more metabolic energy available for tissue maintenance, resulting in a slower pace of cellular aging. At a “proximate” level, mechanisms involved may include the actions of the gonadal steroid estradiol, which increases dramatically during pregnancy. Estradiol is known to protect TL from the effects of oxidative stress as well as increase telomerase activity, an enzyme that maintains TL. Future research should explore the potential role of social support as well as that of estradiol and other potential biological pathways in the trade-offs between reproductive effort and the pace of cellular aging within and among human as well as in non-human populations. [ABSTRACT FROM AUTHOR]

Menopause is associated with cognitive decline, and previous parity can increase or delay the trajectory of cognitive aging. Furthermore, parity enables the hippocampus to respond to estrogens in middle age. The present study investigated how previous parity and estrogens influence cognition, neurogenesis, and neuronal activation in response to memory retrieval in the hippocampus of middle-aged females. Multiparous and nulliparous rats were ovariectomized (OVX) or received sham surgery and were treated with vehicle, 17β-estradiol, 17α-estradiol, or estrone. Rats were trained on the spatial working and reference memory versions of the Morris water maze. Multiparous rats had a significantly greater density of immature neurons in the hippocampus, enhanced acquisition of working memory, but poorer reference memory compared with nulliparous rats. Furthermore, OVX increased, while treatment with estrogens reduced, the density of immature neurons, regardless of parity. OVX improved reference memory only in nulliparous rats. Thus, motherhood has long-lasting effects on the neuroplasticity and function of the hippocampus. These findings have wide-ranging implications for the treatment of age-associated decline in women. [ABSTRACT FROM AUTHOR]

Abstract: Estrogens have been implicated as possible therapeutic agents for improving cognition in postmenopausal women and have been linked to neurodegenerative disorders such as Alzheimer''s disease. However, the utility of Premarin (Wyeth Pharmaceuticals, Markham, ON, Canada), a conjugated equine estrogen and the most commonly prescribed hormone therapy, has recently been questioned. The purpose of this study was to investigate the effects of Premarin at 2 different doses (10 or 20 μg) on hippocampus-dependent spatial learning and memory, hippocampal neurogenesis, and new neuronal activation using a rodent model of surgical menopause. Rats were treated daily with subcutaneous injections of Premarin and trained on the spatial working/reference memory version of the radial arm maze. Premarin impaired spatial reference and working learning and memory, increased hippocampal neurogenesis, but either decreased or increased activation of new neurons in response to memory retrieval as indexed by the expression of the immediate early gene product zif268, depending on the maturity of cells examined. This activation of new neurons was related to impaired performance in Premarin-treated but not control-treated female rats. These results indicate that Premarin may be impairing hippocampus-dependent learning and memory by negatively altering the neurogenic environment in the dentate gyrus thus disrupting normal activity of new neurons. [Copyright &y& Elsevier]

Abstract: Estrogens fluctuate across the lifespan in women, with circulating 17β-estradiol levels higher pre-menopause than estrone and circulating estrone levels higher postmenopause than 17β-estradiol. Estrone is a common component of hormone replacement therapies, but research shows that 17β-estradiol may have a greater positive impact on cognition. Previous studies show that acute estrone and 17β-estradiol impact hippocampus-dependent learning and cell proliferation in the dentate gyrus in a dose-dependent manner in adult female rats. The current study explores how chronic treatment with estrone and 17β-estradiol differentially influences spatial learning, hippocampal neurogenesis and activation of new neurons in response to spatial memory. Adult female rats received daily injections of vehicle (sesame oil), or a 10μg dose of either 17β-estradiol or estrone for 20days. One day following the first hormone injection all rats were injected with the DNA synthesis marker, bromodeoxyuridine. On days 11–15 after BrdU injection rats were trained on a spatial reference version of the Morris water maze, and five days later (day 20 of estrogens treatment) were given a probe trial to assess memory retention. Cell proliferation was assessed by the endogenous cell cycle marker, Ki67, cell survival was assessed by counting the number and density of BrdU-ir cells in the dentate gyrus and cell activation was assessed by the percentage of BrdU-ir cells that were co-labelled with the immediate early gene product zif268. There were no significant differences between groups in acquisition or retention of Morris water maze. However, the 17β-estradiol group had significantly higher, while the estrone group had significantly lower, levels of cell survival (BrdU-ir cells) in the dentate gyrus compared to controls. Furthermore, rats injected with 17β-estradiol showed significantly higher levels of activation of new neurons in response to spatial memory compared to controls. These results provide insight into how estrogens differentially influence the brain and behavior, and may provide insight into the development of hormone replacement therapies for women. [Copyright &y& Elsevier]

Objectives: Physical activity (PA) and total sleep time (TST) are each associated with cognition; however, whether these relationships vary by age and biological sex is unclear. We examined the relationships of PA or TST with cognition, and whether age and sex moderated these relationships, using baseline data from the Canadian Longitudinal Study on Aging (CLSA; 2010-2015).Study Design: A cross-sectional analysis of participants from the Comprehensive cohort of the CLSA with complete PA and sleep data (n = 20,307; age range 45-86 years).Main Outcome Measures: PA and TST were measured using the Physical Activity Scale for the Elderly (PASE) and self-reported TST over the past month. Cognition was indexed using a three-factor structural equation model (i.e., memory, executive function, and verbal fluency).Results: Non-linear restricted cubic spline models indicated that PA and TST explained statistically significant (p < 0.01) but modest variance of each cognitive domain (<1 % of 23-24 % variance). Age and sex did not moderate associations of PA with any cognitive domain. However, age and sex moderated relationships of TST with cognition, whereby: 1) associations of TST with memory decreased with age for males and females; and 2) males and females had different age-associated relationships of TST with executive function and verbal fluency.Conclusions: PA and TST modestly contribute to multiple domains of cognition across middle and older adulthood. Importantly, the association of PA with cognition does not appear to vary across middle or older adulthood, nor does it vary by biological sex; however, TST appears to have a complex relationship with multiple domains of cognition which is both age- and sex-dependent. [ABSTRACT FROM AUTHOR]

Pregnancy and motherhood constitute periods of tremendous hormonal variation that orchestrate parturition, lactation, maternal care, maternal aggression, and recognition of offspring, among other functions. Cognitive processing also varies during pregnancy and motherhood and may serve an adaptive function in preparation for parturition and rearing. Additionally, maternal experience may have enduring consequences for the brain, behavior, and cognition long after offspring are mature. However, the early postpartum period also renders women psychologically vulnerable as approximately 15% of women experience postpartum depression, with estimates of 50-80% reporting a milder form of depression termed "maternal blues." This review will present literature on pregnancyand parity-related changes in both cognition and affect and how these changes likely involve plastic changes within the hippocampus, a region that is sensitive to reproductive hormones. Further, this review will discuss steroid and peptide hormones that may contribute to affective and cognitive disruptions during pregnancy and postpartum. Research in this area may reveal insight into how pregnancy and motherhood alter the likelihood of developing postpartum depression and related disorders. [ABSTRACT FROM AUTHOR]

Previous studies have shown a relationship between adversity in adolescence and health outcomes in adulthood in a sex-specific manner. Adolescence is characterized by major changes in stress-responsive regions of the brain, including the hippocampus, the site of ongoing neurogenesis throughout the lifespan. Prepubertal male and female rats exhibit different acute reactions to chronic stress compared to adults, but less is known about whether these stress-induced changes persist into adulthood. Therefore, in this study, we investigated the effects of chronic, intermittent stress during adolescence on basal corticosterone levels, dentate gyrus (DG) volume, and neurogenesis in the hippocampus of adult male and female Sprague-Dawley rats. Adolescent male and female rats were either restrained for 1 h every other day for 3 weeks from postnatal days (PDs) 30-52 at unpredictable times or left undisturbed. All rats received a single injection of bromodeoxyuridine (BrdU; 200 mg/kg) in adulthood on PD70 and were perfused 3 weeks later. Brains were processed for Ki67 (endogenous marker of cell proliferation) and BrdU (to estimate effects on cell survival). In addition, blood samples were taken during the restraint stress period and in adulthood. Results show that males and females exhibit different corticosterone responses to chronic stress during adolescence and that only adult female rats exposed to stress during adolescence show higher basal corticosterone levels compared to nonstressed controls. Furthermore, stressed females showed a reduced number of proliferating and surviving cells in the DG in adulthood compared to nonstressed same-sex controls. The majority of BrdU-labeled cells were co-labeled with NeuN, an endogenous marker of mature neurons, indicating that neurogenesis was decreased in the DG of adult female rats that had undergone chronic restraint stress in adolescence. Although male rats were more responsive to the chronic stress as adolescents showing higher corticosterone levels and reduced body weight, as adults they showed a slight increase in cellsurvival and no effect of adolescent stress on basal corticosterone levels. These results suggest that stress during adolescence can have effects on hypothalamic-pituitary-adrenal axis function and hippocampus plasticity in adulthood, particularly in female rats. ©2010 Wiley-Liss,Inc. [ABSTRACT FROM AUTHOR]

Abstract: Although controversial, estrogen replacement therapy has been implicated as a possible therapeutic agent for ameliorating age-related cognitive decline in postmenopausal women. We have shown previously that different types of estrogen promote hippocampal neurogenesis in a dose-dependent manner in young adult female rats. However, previous studies have not found a beneficial effect of 17β-estradiol in middle-aged female rats. The aim of the present study was to determine the acute effects of 17β-estradiol, 17α-estradiol, and estrone on hippocampal cell proliferation in middle-aged ovariectomized female rats and to determine whether effects are dependent on previous reproductive experience. Middle-aged multiparous female rats or age-matched virgin female rats were injected subcutaneously with vehicle or 10μg dose of 17β-estradiol, 17α-estradiol, or estrone, and then given BrdU 30min later and perfused 24h later to assess cell proliferation. All estrogens significantly upregulated cell proliferation in the hippocampus in middle-aged multiparous females but none of the estrogens upregulated cell proliferation in the middle-aged virgins. Therefore, previous reproductive experience may make the older brain more responsive to estrogens later in life. We also found that 17α-estradiol upregulated cell proliferation to a greater degree than the other estrogens in the multiparous females. Together these findings may lead to the development of new therapeutic advances in the treatment of symptoms associated with menopause in women. [Copyright &y& Elsevier]

Abstract: Traumatic brain injury (TBI) increases cell death in the hippocampus and impairs hippocampus-dependent cognition. The hippocampus is also the site of ongoing neurogenesis throughout the lifespan. Progesterone treatment improves behavioral recovery and reduces inflammation, apoptosis, lesion volume, and edema, when given after TBI. The aim of the present study was to determine whether progesterone altered cell proliferation and short-term survival in the dentate gyrus after TBI. Male Sprague–Dawley rats with bilateral contusions of the frontal cortex or sham operations received progesterone or vehicle at 1 and 6h post-surgery and daily through post-surgery Day 7, and a single injection of bromodeoxyuridine (BrdU) 48h after injury. Brains were then processed for Ki67 (endogenous marker of cell proliferation), BrdU (short-term cell survival), doublecortin (endogenous marker of immature neurons), and Fluoro-Jade B (marker of degenerating neurons). TBI increased cell proliferation compared to shams and progesterone normalized cell proliferation in injured rats. Progesterone alone increased cell proliferation in intact rats. Interestingly, injury and/or progesterone treatment did not influence short-term cell survival of BrdU-ir cells. All treatments increased the percentage of BrdU-ir cells that were co-labeled with doublecortin (an immature neuronal marker in this case labeling new neurons that survived 5days), indicating that cell fate is influenced independently by TBI and progesterone treatment. The number of immature neurons that survived 5days was increased following TBI, but progesterone treatment reduced this effect. Furthermore, TBI increased cell death and progesterone treatment reduced cell death to levels seen in intact rats. Together these findings suggest that progesterone treatment after TBI normalizes the levels of cell proliferation and cell death in the dentate gyrus of the hippocampus. [Copyright &y& Elsevier]

Abstract: Background: Estrogens modulate the morphology and function of the hippocampus. Recent studies have focused on the effects of different types of estrogens on neuroplasticity in the hippocampus and cognition. There are three main forms of estrogens found in mammals: estradiol, estrone, and estriol. The vast majority of studies have used estradiol to investigate the effects of estrogens on the brain. Scope of review: This review focuses on the effects of different estrogens on adult hippocampal neurogenesis, synaptic plasticity in the hippocampus, and cognition in female rats. Major conclusions: Different forms of estrogens modulate neuroplasticity and cognition in complex and intriguing ways. Specifically, estrogens upregulate adult hippocampal neurogenesis (via cell proliferation) and synaptic protein levels in the hippocampus in a time- and dose-dependent manner. Low levels of estradiol facilitate spatial working memory and contextual fear conditioning while high levels of estradiol impair spatial working, spatial reference memory and contextual fear conditioning. In addition, estrone impairs contextual fear conditioning. General significance: Advances in our knowledge of how estrogens exert their effects on the brain may ultimately lead to refinements in targeted therapies for cognitive impairments at all stages of life. However caution should be taken in interpreting current research and in conducting future studies as estrogens likely work differently in males than in females. [ABSTRACT FROM AUTHOR]

Estrogens are known to exert significant structural and functional effects in the hippocampus of adult rodents. In particular, 17β-estradiol can improve, impair, or have no effect on hippocampus-dependent learning and memory depending on dose and time of administration. The effects of other forms of estrogen, such as estrone and 17α-estradiol, on hippocampus-dependent learning have not been as thoroughly investigated. Therefore, the purpose of this study was to investigate the effects of 17β-estradiol, estrone, and 17α-estradiol at three different doses on two different tasks: hippocampus-dependent contextual fear conditioning and hippocampus-independent cued fear conditioning. Adult ovariectomized female rats were injected with one of the estrogens at one of the three doses 30 mins before conditioning to assess the rapid effects of these estrogens on acquisition. Twenty-four hours later memory for the context was examined and 1 h later memory for the cue (tone) was assessed. Levels of synaptophysin were examined in the dorsal hippocampus of rats to identify a potential synaptic correlate of hormonal effects on contextual fear conditioning. Low 17β-estradiol and 17α-estradiol enhanced, whereas high 17β-estradiol and 17α-estradiol impaired, contextual fear conditioning. Only the middle dose of estrone severely impaired contextual fear conditioning. Estrogens did not alter performance in the hippocampus-independent cued task. Synaptophysin expression was increased by estrone (at a middle and high dose) and 17β-estradiol (at a middle dose) in the CA3 region of the hippocampus and was not correlated with cognition. The results of this study indicate that estradiol can positively or negatively influence hippocampus-dependent learning and memory, whereas estrone impairs hippocampus-dependent learning and memory in a dose-dependent manner. These results have important therapeutic implications, as estrone, a main component of a widely used hormone replacement therapy, was shown to have either a negative effect or no effect on learning and memory. It may be possible to use 17α-estradiol and lower doses of estrogens as potential alternatives in hormone replacement therapies. [ABSTRACT FROM AUTHOR]

Abstract: Variations in maternal care affect the development of individual differences in learning and memory and neuroendocrine responses to stress in adult male offspring, but it is not known how variations in maternal care affect adult female offspring. The present study investigated the performance of adult Sprague–Dawley male and female offspring exposed to either low or high levels of maternal licking/grooming on a spatial memory task (Experiment 1) and the effects of acute stress on corticosterone levels and spatial memory performance (Experiment 2). In Experiment 1 rats were trained for 24 days on the spatial working/reference memory version of the radial arm maze (RAM). In Experiment 2, rats were trained on the same RAM task, exposed to an acute stress, and the effect of stress on corticosterone levels and subsequent spatial memory was examined. In Experiment 1, adult female offspring of low licking/grooming dams had enhanced working memory compared to all other groups. In Experiment 2, all groups of male and female offspring had enhanced working memory 24 h after exposure to acute 2 h restraint stress while reference memory was enhanced after stress in male and female offspring of low licking/grooming dams. Furthermore, female offspring of low licking/grooming dams showed the largest corticosterone response to the acute restraint stress compared to all other groups. Male offspring of low licking/grooming dams showed a flattened corticosterone response to stress. Thus variations in maternal care differentially affect working memory and stress reactivity in male and female offspring. [Copyright &y& Elsevier]

Background: Sex differences for subsequent falls and falls risk factors in community-dwelling older adults who have fallen are unknown. Our aim was to: (1) compare the number of falls between sexes, (2) identify modifiable falls risk factors, and (3) explore the interaction of sex on falls risk factors in older adults who fall. Methods: Four hundred sixty-two community dwellers seeking medical attention after an index fall were recruited from the Vancouver Falls Prevention Clinic and participated in this 12-month prospective cohort study. Ninety-six participants were part of a randomized controlled trial of exercise. Falls were tracked with monthly falls calendars. Demographics, falls risk measures, and the number of subsequent falls were compared between sexes. A principal component analysis (PCA) was employed to reduce the falls risk measures to a smaller set of factors. The PCA factors were used in negative binomial regression models to predict the number of subsequent falls. Age, exposure time (i.e., number of falls monitoring days), and prescribed exercise (yes/no) were used as covariates, and sex (male/female) and PCA factors were used as main effects. The interaction of sex by PCA factor was then included. Results: Males fell more over 12 months (males: 2.80 ± 6.86 falls; females: 1.25 ± 2.63 falls) than females, and poorer executive function predicted falls in males. Four PCA factors were defined – impaired cognition and mobility, low mood and self-efficacy, mobility resilience, and perceived poor health – each predicted the number of falls. The sex by mobility resilience interaction suggested that mobility resilience was less protective of falls in males. Conclusion: Modifiable risk factors related to cognition, physical function, psychological wellbeing, and health status predicted subsequent falls. In males, better mobility was not as protective of falls compared with females. This may be due to males' poorer executive function, contributing to decreased judgement or slowed decision-making during mobility. These results may inform efficacious sex-specific falls prevention strategies. [ABSTRACT FROM AUTHOR]

• Exercise helps maintain executive functions during prolonged bed rest in adults aged 55–65 years. • Exercise mitigates the effects of bed rest on the intraindividual variability in cognition. • The benefits of exercise for executive functions are more robust in women. Prolonged bed rest is prevalent among middle-aged and older adults and is associated with multiple negative health outcomes. Therefore, it is important that we better understand the utility of exercise training as a countermeasure to the adverse effects of bed rest. We examined the effect of exercise training on intraindividual variability in cognitive performance among adults aged 55–65 exposed to 14 days of physical inactivity modelled via 6° head-down tilt bed rest. The study is a non-blinded, parallel-group, proof-of-concept randomized controlled trial. Twenty-three healthy middle-aged and older adults (12 males, 11 females) aged 55–65 were randomized to: (1) 14 days of 6° head-down tilt bed rest (Control) or (2) 14 days of 6° head-down tilt bed rest with daily exercise (Exercise). The National Institutes of Health Toolbox Cognitive Battery assessed executive functions (Flanker incongruent/congruent and Dimensional Change Card Sort) and processing speed (Pattern Comparison). We assessed cognitive function at baseline, 6° head-down tilt bed rest midpoint, completion, and seven days following completion. We indexed intraindividual variability with two metrics: (1) residual intraindividual standard deviation and (2) intraindividual coefficient of variation. Flanker congruent and incongruent residual intraindividual standard deviations were the primary outcomes. Linear mixed models assessed between-group differences and the moderating effect of biological sex. At bed rest completion, Exercise had significantly lower (better) Flanker incongruent residual intraindividual standard deviation (estimated mean difference = −3.63, 95%CI -6.10;-1.17, p = 0.005) and intraindividual coefficient of variation (estimated mean difference = −0.10, 95%CI -0.19;-0.003, p = 0.022) vs. Control. Sex moderated the effect of exercise on Flanker incongruent intraindividual coefficient of variation. Exercise females had significantly lower intraindividual coefficient of variation vs. Control (estimated mean difference = −0.23; 95%CI -0.34;-0.12, p < 0.001). There were no significant between-group differences in processing speed intraindividual variability and summary scores of executive functions and processing speed (p s > 0.05). Exercise training during bed rest preserved intraindividual variability of executive functions but not processing speed. ClinicalTrials.gov NCT04964999 [ABSTRACT FROM AUTHOR]

Background: Limited mobility in older adults consistently predicts both morbidity and mortality. As individuals age, the rates of mobility disability increase from 1.0% in people aged 15–24 to 20.6% in adults over 65 years of age. Physical activity can effectively improve mobility in older adults, yet many older adults do not engage in sufficient physical activity. Evidence shows that increasing physical activity by 50 min of moderate intensity physical activity in sedentary older adults with mobility limitations can improve mobility and reduce the incidence of mobility disability. To maximize the healthy life span of older adults, it is necessary to find effective and efficient interventions that can be delivered widely to prevent mobility limitations, increase physical activity participation, and improve quality of life in older adults. We propose a randomized controlled trial to assess the effect of a physical activity health coaching intervention on mobility in older adults with mobility limitations. Methods: This randomized controlled trial among 290 (145 per group) community-dwelling older adults with mobility limitations, aged 70–89 years old, will compare the effect of a physical activity health coaching intervention versus a general healthy aging education program on mobility, as assessed with the Short Physical Performance Battery. The physical activity health coaching intervention will be delivered by exercise individuals who are trained in Brief Action Planning. The coaches will use evidence-based behavior change techniques including goal-setting, action planning, self-monitoring, and feedback to improve participation in physical activity by a known dose of 50 min per week. There will be a total of 9 health coaching or education sessions delivered over 26 weeks with a subsequent 26-week follow-up period, wherein both groups will receive the same duration and frequency of study visits and activities. Discussion: The consequences of limited mobility pose a significant burden on the quality of life of older adults. Our trial is novel in that it investigates implementing a dose of physical activity that is known to improve mobility in older adults utilizing a health coaching intervention. Trial registration: ClinicalTrials.gov Protocol Registration System: NCT05978336; registered on 28 July 2023. [ABSTRACT FROM AUTHOR]

The authors discuss a study which found that maternal exposure to bisphenol A (BPA) impairs spatial ability and reduces attractiveness of male deer mice progeny. They offer information on the chemical BPA and its physiological effect. The impact of BPA on maternal behavior and hormones is discussed, as is BPA exposure during adolescence and adulthood and BPA's effect on sex differences. The authors contend that sex hormones play a vital role in reproductive and nonreproductive behavior.

It is unclear whether cardiometabolic risk shares an interactive relationship with age-associated differences in cognition, and whether this relationship varies by biological sex. We conducted a cross-sectional analysis using baseline data from the Canadian Longitudinal Study on Aging (CLSA; 2010–2015) to examine whether 1) cardiometabolic risk has an interactive relationship with age-associated cognition; and 2) interactive effects are sex-dependent. We measured memory, executive function, and verbal fluency in the Comprehensive cohort (N = 25 830; 45–86 years). Each cognitive domain was modeled using restricted cubic splines for age and each cardiometabolic risk factor (HbA1c, HSCRP, TG, and LDL and HDL cholesterol). Sex was included as a predictor in all models. Wald χ2 statistics were used to determine the relative importance of age, cardiometabolic risk, sex, and their interactive effects on cognition. Age was the most important variable in each model (proportion χ2 = 34%–48%). Biological sex was the second most important variable for memory (proportion χ2 = 26%) but was unimportant for executive function and verbal fluency (proportion χ2 = 3%–5%). Cardiometabolic risk factors were unimportant predictors in each model (proportion χ2 = 1%–3%). Two- and 3-way interactions between cardiometabolic risk, age, and sex were also unimportant (proportion χ2 = 0%–2%). Thus, cardiometabolic risk factors did not meaningfully account for age-associated differences in cognition, and these associations (or lack thereof) did not vary by sex. Novelty: Males have poorer age-associated cognitive performance than females. Females and males differ in cardiometabolic risk across middle and older adulthood. Cardiometabolic risk has a small association with age-associated cognition, and there are no sex differences in this relationship. [ABSTRACT FROM AUTHOR]

Abstract: Adult neurogenesis exists in most mammalian species, including humans, in two main areas: the subventricular zone (new cells migrate to the olfactory bulbs) and the dentate gyrus of the hippocampus. Many factors affect neurogenesis in the hippocampus and the subventricular zone, however the focus of this review will be on factors that affect hippocampal neurogenesis, particularly in females. Sex differences are often seen in levels of hippocampal neurogenesis, and these effects are due in part to differences in circulating levels of steroid hormones such as estradiol, progesterone, and corticosterone during the estrous cycle, in response to stress, with reproduction (including pregnancy and lactation), and aging. Depletion and administration of these same steroid hormones also has marked effects on hippocampal neurogenesis in the adult female, and these effects are dependent upon reproductive status and age. The present review will focus on current research investigating how hippocampal neurogenesis is altered in the adult female rodent across the lifespan. [Copyright &y& Elsevier]

Alzheimer's disease (AD) is characterized by severe cognitive decline and pathological changes in the brain (brain atrophy, hyperphosphorylation of tau, and deposition of amyloid-beta protein). Females have greater neuropathology (AD biomarkers and brain atrophy rates) and cognitive decline than males, however these effects can depend on diagnosis (amnestic mild cognitive impairment (aMCI) or AD) and APOE genotype (presence of ε4 alleles). Using the ADNI database (N = 630 females, N = 830 males), we analyzed the effect of sex, APOE genotype (non-carriers or carriers of APOEε4 alleles), and diagnosis (cognitively normal (CN), early aMCI (EMCI), late aMCI (LMCI), probable AD) on cognition (memory and executive function), hippocampal volume, and AD biomarkers (CSF levels of amyloid beta, tau, and ptau). Regardless of APOE genotype, memory scores were higher in CN, EMCI, and LMCI females compared to males but this sex difference was absent in probable AD, which may suggest a delay in the onset of cognitive decline or diagnosis and/or a faster trajectory of cognitive decline in females. We found that, regardless of diagnosis, CSF tau-pathology was disproportionately elevated in female carriers of APOEε4 alleles compared to males. In contrast, male carriers of APOEε4 alleles had reduced levels of CSF amyloid beta compared to females, irrespective of diagnosis. We also detected sex differences in hippocampal volume but the direction was dependent on the method of correction. Altogether results suggest that across diagnosis females show greater memory decline compared to males and APOE genotype affects AD neuropathology differently in males and females which may influence sex differences in incidence and progression of aMCI and AD. • CSF tau pathology was elevated in female APOEε4 carriers compared to male carriers. • CSF amyloid beta levels were reduced in male APOEε4 carriers relative to female carriers. • Severity of diagnosis decreased memory scores to a greater extent in females. [ABSTRACT FROM AUTHOR]

Background: Subcortical ischemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. Importantly, SIVCI is considered the most treatable form of cognitive impairment in older adults, due to its modifiable risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia. Exercise training is a promising intervention to delay the progression of SIVCI, as it actively targets these cardiometabolic risk factors. Despite the demonstrated benefits of resistance training on cognitive function and emerging evidence suggesting resistance training may reduce the progression of white matter hyperintensities (WMHs), research on SIVCI has predominantly focused on the use of aerobic exercise. Thus, the primary aim of this proof-of-concept randomized controlled trial is to investigate the efficacy of a 12-month, twice-weekly progressive resistance training program on cognitive function and WMH progression in adults with SIVCI. We will also assess the efficiency of the intervention.Methods: Eighty-eight community-dwelling adults, aged > 55 years, with SIVCI from metropolitan Vancouver will be recruited to participate in this study. SIVCI will be determined by the presence of cognitive impairment (Montreal Cognitive Assessment < 26) and cerebral small vessel disease using computed tomography or magnetic resonance imaging. Participants will be randomly allocated to a twice-weekly exercise program of (1) progressive resistance training or (2) balance and tone training (i.e., active control). The primary outcomes are cognitive function measured by the Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-13 with additional cognitive tests) and WMH progression.Discussion: The burden of SIVCI is immense, and to our knowledge, this will be the first study to quantify the effect of progressive resistance training on cognitive function and WMH progression among adults with SIVCI. Slowing the rate of cognitive decline and WMH progression could preserve functional independence and quality of life. This could lead to reduced health care costs and avoidance of early institutional care.Trial Registration: ClinicalTrials.gov NCT02669394 . Registered on February 1, 2016. [ABSTRACT FROM AUTHOR]

Background: Myelin damage is a salient feature in cerebral small vessel disease (cSVD). Of note, myelin damage extends into the normal appearing white matter (NAWM). Currently, the specific role of myelin content in cognition is poorly understood.Objective: The objective of this exploratory study was to investigate the association between NAWM myelin and cognitive function in older adults with cSVD.Methods: This exploratory study included 55 participants with cSVD. NAWM myelin was measured using myelin water imaging and was quantified as myelin water fraction (MWF). Assessment of cognitive function included processing speed (Trail Making Test Part A), set shifting (Trail Making Test Part B minus A), working memory (Verbal Digit Span Backwards Test), and inhibition (Stroop Test). Multiple linear regression analyses assessed the contribution of NAWM MWF on cognitive outcomes controlling for age, education, and total white matter hyperintensity volume. The overall alpha was set at ≤0.05.Results: After accounting for age, education, and total white matter hyperintensity volume, lower NAWM MWF was significantly associated with slower processing speed (β  = -0.29, p = 0.037) and poorer working memory (β= 0.30, p = 0.048). NAWM MWF was not significantly associated with set shifting or inhibitory control (p > 0.132).Conclusion: Myelin loss in NAWM may play a role in the evolution of impaired processing speed and working memory in people with cSVD. Future studies, with a longitudinal design and larger sample sizes, are needed to fully elucidate the role of myelin as a potential biomarker for cognitive function. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) disproportionately affects females with steeper cognitive decline and more neuropathology compared to males, which is exacerbated in females carrying the APOEɛ4 allele. The risk of developing AD is also higher in female APOEɛ4 carriers in earlier age groups (aged 65-75), and the progression from cognitively normal to mild cognitive impairment (MCI) and to AD may be influenced by sex. Inflammation is observed in AD and is related to aging, stress, and neuroplasticity, and although studies are scarce, sex differences are noted in inflammation.Objective: The objective of this study was to investigate underlying physiological inflammatory mechanisms that may help explain why there are sex differences in AD and APOEɛ4 carriers.Methods: We investigated, using the ADNI database, the effect of sex and APOE genotype (non-carriers or carriers of 1 and 2 APOEɛ4 alleles) and sex and diagnosis (cognitively normal (CN), MCI, AD) on CSF (N = 279) and plasma (N = 527) markers of stress and inflammation.Results: We found CSF IL-16 and IL-8 levels differed by sex and APOE genotype, as IL-16 was higher in female APOEɛ4 carriers compared to non-carriers, while the opposite pattern was observed in males with IL-8. Furthermore, females had on average higher levels of plasma CRP and ICAM1 but lower levels of CSF ICAM1, IL-8, IL-16, and IgA than males. Carrying APOEɛ4 alleles and diagnosis (MCI and AD) decreased plasma CRP in both sexes.Conclusion: Sex and APOE genotype differences in CSF and plasma inflammatory biomarkers support that the underlying physiological changes during aging differ by sex and tissue origin. [ABSTRACT FROM AUTHOR]

Sex differences are well-established in Alzheimer's disease (AD) frequency and pathogenesis, but are not mechanistically understood. Accelerated epigenetic age has been associated with both cognitive aging and AD pathophysiology, but has not been studied by sex in AD or related cognitive impairment. Using the ADNI cohort, we found that none of sex, cognitive impairment diagnosis, nor load of APOEε4 alleles (strongest genetic AD risk factor) were associated with epigenetic age acceleration (DNAmAge, Intrinsic DNAmAge, PhenoAge, or GrimAge), although females exhibit more accelerated epigenetic aging using the Skin & Blood clock in the transition from normal cognition to cognitive impairment than males. [ABSTRACT FROM AUTHOR]

Females show greater benefits of exercise on cognition in both humans and rodents, which may be related to brain-derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP), the Val66Met polymorphism, within the human BDNF gene, causes impaired activity-dependent secretion of neuronal BDNF and impairments to some forms of memory. We evaluated whether sex and BDNF genotype (Val66Met polymorphism (Met/Met) versus wild-type (Val/Val)) influenced the ability of voluntary running to enhance cognition and hippocampal neurogenesis in mice. Middle-aged C57BL/6J (13 months) mice were randomly assigned to either a control or an aerobic training (AT) group (running disk access). Mice were trained on the visual discrimination and reversal paradigm in a touchscreen-based technology to evaluate cognitive flexibility. BDNF Met/Met mice had fewer correct responses compared to BDNF Val/Val mice on both cognitive tasks. Female BDNF Val/Val mice showed greater cognitive flexibility compared to male mice regardless of AT. Despite running less than BDNF Val/Val mice, AT improved performance in both cognitive tasks in BDNF Met/Met mice. AT increased neurogenesis in the ventral hippocampus of BDNF Val/Val mice of both sexes and increased the proportion of mature type 3 doublecortin-expressing cells in the dorsal hippocampus of female mice only. Our results indicate AT improved cognitive performance in BDNF Met/Met mice and increased hippocampal neurogenesis in BDNF Val/Val mice in middle age. Furthermore, middle-aged female mice may benefit more from AT than males in terms of neuroplasticity, an effect that was influenced by the BDNF Val66Met polymorphism. • BDNF Met/Met mice performed worse than BDNF Val/Val mice in middle-age. • Aerobic training (AT) increased cognitive performance in BDNF Met/Met mice. • AT increased neurogenesis in middle-aged BDNF Val/Val mice only. • Female BDNF Val/Val mice had better cognitive flexibility than males regardless of AT. • AT increased more mature new neurons in middle-aged female mice. [ABSTRACT FROM AUTHOR]

The hippocampus and dorsal striatum are important structures involved in place and response learning strategies respectively. Both sex and estrous cycle phase differences in learning strategy preference exist following cue competition paradigms. Furthermore, significant effects of sex and learning strategy on hippocampal neural plasticity have been reported. However, associations between learning strategy and immediate early gene (IEG) expression in the hippocampus and dorsal striatum are not completely understood. In the current study we investigated the effects of sex and estrous cycle phase on strategy choice and IEG expression in the hippocampus and dorsal striatum of rats following cue competition training in the Morris water maze. We found that proestrous rats were more likely to choose a place strategy than non-proestrous or male rats. Although male cue strategy users travelled greater distances than the other groups on the first day of training, there were no other sex or strategy differences in the ability to reach a hidden or a visible platform. Female place strategy users exhibited greater zif268 expression and male place strategy users exhibited greater cFos expression compared to all other groups in CA3. Furthermore, cue strategy users had greater expression of cFos in the dorsal striatum than place strategy users. Shorter distances to reach a visible platform were associated with less activation of cFos in CA3 and CA1 of male place strategy users. Our findings indicate multiple differences in brain activation with sex and strategy use, despite limited behavioral differences between the sexes on this cue competition paradigm. [ABSTRACT FROM AUTHOR]

Summary: 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 6–10 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 6–10 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. [ABSTRACT FROM AUTHOR]

Gonadal and stress hormones modulate neuroplasticity and behaviour. This review focuses on our findings over the past decade on the effects of estrogens and androgens on hippocampal neurogenesis, hippocampus-dependent learning and memory and the effects of reproductive experience in the rodent. Evidence suggests that acute estradiol initially enhances and subsequently suppresses cell proliferation in the dentate gyrus of adult female rodents. Repeated exposure to estradiol modulates hippocampal neurogenesis and cell death in adult female, but not male, rodents while, testosterone and dihydrotestosterone upregulate hippocampal neurogenesis in adult male rodents. Estradiol dose-dependently affects different brain regions involved in working memory (prefrontal cortex, hippocampus), reference memory (hippocampus) and conditioned place preference (amygdala). Pregnancy and motherhood differentially regulate adult hippocampal neurogenesis and spatial working memory in the dam after weaning. These studies and others demonstrate that the female brain responds to steroid hormones differently than the male brain. It is of the upmost importance to investigate the effects on neuroplasticity and behaviour in both the male and the female, particularly when modelling diseases that exhibit sex differences in incidence, etiology or treatment. [ABSTRACT FROM AUTHOR]