Search

2020; 93 (4): 539 - 48. 19 Johnson JL, Greaves L, Repta R. Better science with sex and gender: facilitating the use of a sex and gender-based analysis in health research. To be able to discover and remedy health disparities across the rich diversity of sex and gender, we fully endorse this suggestion for gender-additive language throughout women's health research. Thus, how can we ensure that women's health is researched alongside health research of those persons who align minimally (or not at all) with sex and gender labels of female and woman, respectively? More attention is being paid to health inequities worldwide, which is welcome given long-standing health disparities across under-represented communities, including those based on sex and gender.1-4 The widespread under-representation of females and women in basic and clinical studies contributes directly to the health disparities seen between the sexes and genders that continues to this day.4-6 Sex refers to biological and physiological differences between sexes including chromosomes and hormones. [Extracted from the article]

2020; 93 (4): 539 - 48. 19 Johnson JL, Greaves L, Repta R. Better science with sex and gender: facilitating the use of a sex and gender-based analysis in health research. To be able to discover and remedy health disparities across the rich diversity of sex and gender, we fully endorse this suggestion for gender-additive language throughout women's health research. More attention is being paid to health inequities worldwide, which is welcome given long-standing health disparities across under-represented communities, including those based on sex and gender.1-4 The widespread under-representation of females and women in basic and clinical studies contributes directly to the health disparities seen between the sexes and genders that continues to this day.4-6 Sex refers to biological and physiological differences between sexes including chromosomes and hormones. Thus, how can we ensure that women's health is researched alongside health research of those persons who align minimally (or not at all) with sex and gender labels of female and woman, respectively?. [Extracted from the article]

Depression is a devastating and prevalent disease, with profound effects on neural structure and function; however the etiology and neuropathology of depression remain poorly understood. Though antidepressant drugs exist, they are not ideal, as only a segment of patients are effectively treated, therapeutic onset is delayed, and the exact mechanism of these drugs remains to be elucidated. Several theories of depression do exist, including modulation of monoaminergic neurotransmission, alterations in neurotrophic factors, and the upregulation of adult hippocampal neurogenesis, and are briefly mentioned in the review. However none of these theories sufficiently explains the pathology and treatment of depression unto itself. Recently, neural plasticity theories of depression have postulated that multiple aspects of brain plasticity, beyond neurogenesis, may bridge the prevailing theories. The term "neural plasticity" encompasses an array of mechanisms, from the birth, survival, migration, and integration of new neurons to neurite outgrowth, synaptogenesis, and the modulation of mature synapses. This review critically assesses the role of adult hippocampal neurogenesis and the cell adhesion molecule, PSA-NCAM (which is known to be involved in many facets of neural plasticity), in depression and antidepressant treatment. [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]

Deficient prefrontal cortex (PFC) GABA function is hypothesized to play a role in schizophrenia and other psychiatric disorders. In rodents, PFC GABAA receptor antagonism produces cognitive and behavioral changes relevant to these disorders, including impaired spatial memory assessed with the traditional working/reference memory radial maze task. This aspect of spatial memory does not depend on PFC, suggesting that deficient PFC GABAergic transmission may interfere with non-PFC-dependent cognitive functions via aberrant increases in PFC output. To test this, we assessed whether PFC GABAA antagonism (50 ng bicuculline methbromide) alters neuronal activation in PFC terminal regions, including the striatum, thalamus, hippocampus, amygdala, and cortical regions, of adult male rats using the immediate early gene, c-Fos, as an activity marker. A subset of these animals were also trained and/or tested on the working/reference memory radial maze task. These treatments caused widespread increases in neuronal activation in animals under baseline conditions, with notable exception of the hippocampus. Furthermore, PFC GABAA antagonism impaired task performance. In most instances, training and/or testing on the radial maze had no additional effects on neuronal activation. However, in both the hippocampus and rhomboid thalamic nucleus, PFC GABAA antagonism caused a selective increase in neuronal activation in animals trained on the maze. These results indicate that deficiencies in PFC GABAergic transmission may have widespread impacts on neuronal activity that may interfere with certain PFC-independent cognitive functions. Furthermore, these alterations in activity are modulated by plasticity induced by spatial learning in the hippocampus and rhomboid thalamic nucleus. [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.

Background: Sex and gender impacts health outcomes and disease risk throughout life. The health of women and members of the Two-Spirit, Lesbian, Gay, Bisexual, Transgender, Queer or Questioning (2S/LGBTQ +) community is often compromised as they experience delays in diagnosis. Distinct knowledge gaps in the health of these populations have prompted funding agencies to mandate incorporation of sex and gender into research. Sex- and gender-informed research perspectives and methodology increases rigor, promotes discovery, and expands the relevance of health research. Thus, the Canadian Institutes of Health Research (CIHR) implemented a sex and gender-based analysis (SGBA) framework recommending the inclusion of SGBA in project proposals in 2010 and then mandating the incorporation of SGBA into grant proposals in 2019. To examine whether this mandate resulted in increased mention of sex or gender in funded research abstracts, we searched the publicly available database of grant abstracts funded by CIHR to analyze the percentage of abstracts that mentioned sex or gender of the population to be studied in the funded research. To better understand broader health equity issues we also examined whether the funded grant abstracts mentioned either female-specific health research or research within the 2S/LGBTQ + community. Results: We categorized a total of 8,964 Project and Operating grant abstracts awarded from 2009 to 2020 based on their study of female-specific or a 2S/LGBTQ + populations or their mention of sex or gender. Overall, under 3% of grant abstracts funded by CIHR explicitly mentioned sex and/or gender, as 1.94% of grant abstracts mentioned sex, and 0.66% mentioned gender. As one of the goals of SGBA is to inform on health equity and understudied populations with respect to SGBA, we also found that 5.92% of grant abstracts mentioned female-specific outcomes, and 0.35% of grant abstracts focused on the 2S/LGBTQ + community. Conclusions: Although there was an increased number of funded grants with abstracts that mentioned sex and 2S/LGBTQ + health across time, these increases were less than 2% between 2009 and 2020. The percentage of funded grants with abstracts mentioning female-specific health or gender differences did not change significantly over time. The percentage of funding dollars allocated to grants in which the abstracts mentioned sex or gender also did not change substantially from 2009 to 2020, with grant abstracts mentioning sex or female-specific research increasing by 1.26% and 3.47%, respectively, funding allocated to research mentioning gender decreasing by 0.49% and no change for 2S/LGBTQ +-specific health. Our findings suggest more work needs to be done to ensure the public can evaluate what populations will be examined with the funded research with respect to sex and gender to advance awareness and health equity in research. Highlights: The percentage of funded grants in which the abstracts mentioned sex or gender in health research remained largely unchanged from 2009 to 2020 with the largest increase of 1.57% for those mentioning sex. Total funding amounts for grants that mentioned sex or gender in the abstract stagnated or declined from 2009 to 2020. The percentage of funded grants in which the abstracts focusing on female-specific health did not change across 2009–2020, but the percentage of funding dollars increased by 3.47%. The percentage of grants in which the abstracts mentioned 2S/LGBTQ +-specific health more than tripled across 2009–2020 but remained less than 1% of all funded grants. Plain language summary: This paper examined the publicly available database of grant abstracts funded by the Canadian Institute of Health Research (CIHR) from 2009 to 2020 to determine the percentage of abstracts that mentioned sex or gender of the population to be studied. To better understand broader health equity issues we also examined whether the funded grant abstracts mentioned either female-specific health research or research within the 2S/LGBTQ + community. Although there was an increased number of funded grants with abstracts that mentioned sex and 2S/LGBTQ + health across time, these increases were less than 2% between 2009 and 2020. The percentage of funded grants with abstracts mentioning female-specific health or gender differences did not change significantly over time. The percentage of CIHR funding dollars allocated to grants in which the abstracts mentioned sex or female-specific research increased by 1.26% and 3.47%, respectively. However, funding allocated to research mentioning gender decreased by 0.49% and there was no significant change in funding amounts for 2S/LGBTQ +-specific health across time. We outline several recommendations for funding agencies to improve access to information especially on sex, gender and broader health equity populations to ensure the public can evaluate what populations will be examined within the funded research. Our findings suggest that to advance greater health equity in research, different strategies need to be employed to improve researcher utilization of sex and gender-based analysis as well as to advance health equity with respect to 2S/LGBTQ and women's health questions in research. [ABSTRACT FROM AUTHOR]

An abstract of the article "Neonatal S100B Protein Levels After Prenatal Exposure to Selective Serotonin Reuptake Inhibitors," by Jodi L. Pawluski and colleagues is presented.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Highlights: • Adolescent male rats had more hippocampal inflammation than females after cognitive bias testing. • Adult female rats had more basolateral amygdalar inflammation than males after cognitive bias testing. • HPC neurogenesis was negatively associated to cognitive bias in young adult male rats. [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]

Background: Females are more likely to present with anxiety disorders such as post-traumatic stress disorder (PTSD) compared to males, which are associated with disrupted hippocampal integrity. Sex differences in the structure and function of hippocampus exist. Here, we examined sex differences in contextual pattern separation, functional connectivity, and activation of new neurons during fear memory. Methods: Two-month-old male and female Sprague-Dawley rats were injected with the DNA synthesis markers, iododeoxyuridine (IdU) and chlorodeoxyuridine (CldU) 3 weeks and 4 weeks before perfusion, respectively. One week after CldU injection, the rats underwent a context discrimination task in which rats were placed in context A (shock) and context A' (no shock) every day for 12 days. On the test day, rats were placed in the shock context (context A) to measure fear memory and expression of zif268, an immediate early gene across 16 different limbic and reward regions. Repeated-measures or factorial analysis of variance was conducted on our variables of interest. Pearson product-moment calculations and principal component analyses on zif268 expression across regions were also performed. Results: We found that females, but not males, showed contextual discrimination during the last days of training. On the test day, both sexes displayed similar levels of freezing, indicating equivalent fear memory for context A. Despite similar fear memory, males showed more positive correlations of zif268 activation between the limbic regions and the striatum, whereas females showed more negative correlations among these regions. Females showed greater activation of the frontal cortex, dorsal CA1, and 3-week-old adult-born dentate granular cells compared to males. Conclusions: These results highlight the importance of studying sex differences in fear memory and the contribution of adult neurogenesis to the neuronal network and may contribute to differences in susceptibility to fear-related disorders such as post-traumatic stress disorder. Highlights Female rats, but not male rats, show faster discrimination during a contextual pattern separation task. Three-week-old adult-born neurons are more active in response to fear memory in females compared to males. Females had greater neural activation compared to males in the frontal cortex and dorsal CA1 region of the hippocampus in response to fear memory. Males and females show distinct patterns in functional connectivity for fear memory across limbic regions. Males have many positive correlations between activated new neurons of different ages between the dorsal and ventral hippocampus, while females show more correlations between activated new neurons and other limbic regions. [ABSTRACT FROM AUTHOR]

Background: The incidence of depression in human females rises steadily throughout adolescence, a critical period of pubertal maturation marked by increasing levels of gonadal hormones including estrogens and progesterone. These gonadal hormones play a central role in social and emotional development and may also contribute to the increased occurrence of depression in females that begins in early adolescence. In this study, we examine whether and how introducing synthetic estrogen and progestin derivatives through the use of combined hormonal contraceptives (CHC), affects adolescent females' risk for developing depression. We further assess potential links between CHC use and alterations in stress responses and social-emotional functioning.Methods: Using a longitudinal cohort design, we will follow a sample of adolescent females over the span of three years. Participants will be assessed at three time points: once when they are between 13 and 15 years of age, and at approximately 18 and 36 months after their initial assessment. Each time point will consist of two online sessions during which participants will complete a clinical interview that screens for key symptoms of mental health disorders, along with a series of questionnaires assessing their level of depressive symptoms and history of contraceptive use. They will also complete a standardized social-evaluative stress test and an emotion recognition task, as well as provide saliva samples to allow for assessment of their circulating free cortisol levels.Discussion: In this study we will assess the effect of CHC use during adolescence on development of Major Depressive Disorder (MDD). We will control for variables previously found to or proposed to partially account for the observed relationship between CHC use and MDD, including socioeconomic status, age of sexual debut, and CHC-related variables including age of first use, reasons for use, and its duration. In particular, we will discover whether CHC use increases depressive symptoms and/or MDD, whether elevated depressive symptoms and/or MDD predict a higher likelihood of starting CHC, or both. Furthermore, this study will allow us to clarify whether alterations in stress reactivity and social-emotional functioning serve as pathways through which CHC use may result in increased risk of depressive symptoms and/or MDD. [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]

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]

Background: The success of any COVID-19 vaccine program ultimately depends on high vaccine uptake. This study determined overall intention to receive a COVID-19 vaccine and identified factors that predict intentions to be vaccinated against COVID-19 in Canada, specifically in key priority groups identified by the American Committee on Immunization Practice (ACIP) and the National Advisory Committee on Immunization (NACI) for early immunization.Methods: Individuals from research cohorts from the general population of British Columbia aged 25-69 were invited complete an online survey based on validated scales and theoretical frameworks to explore intention to receive a COVID-19 vaccine. Two multivariable logistic regression models were conducted to determine factors associated with intention to receive the COVID-19 vaccine.Results: Of 4948 respondents, 79.8% intended to receive a COVID-19 vaccine. In multivariable modeling, respondents who intended to receive the vaccine had higher vaccine attitudinal scores (p <  0.001), reported greater influence of direct social norms (p = 0.001), and indirect social norms, including their family physician (p = 0.024), and Provincial Health Officer (p = 0.011). Older individuals (> 60 years) were more likely to intend to receive the vaccine, while females (95%CI 0.57,0.93), those with less than high school education (95%CI 0.5,0.76), those who self-identified as non-white (95%CI 0.60,0.92), self-identified as Indigenous (95%CI 0.36,0.84) and essential non-health care workers (95%CI 0.59,0.86) had lower adjusted odds of intending to receive a COVID-19 vaccine.Conclusions: To optimize vaccine coverage, public health should focus on key messages around vaccine safety and benefit, and leverage trusted practitioners for messaging. As certain key populations identified by NACI and ACIP for early immunization report a lower intention to vaccinate, there is a need for in-depth education and support for these communities to ensure optimal uptake. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Folate is an important regulator of hippocampal neurogenesis, and folic acid is needed prenatally to reduce the risk of neural tube defects. Both high levels of folic acid and low levels of folate can be harmful to health because low levels of folate have been linked to several diseases while high folic acid supplements can mask a vitamin B12 deficiency. Depressed patients exhibit folate deficiencies, lower levels of hippocampal neurogenesis, elevated levels of homocysteine and elevated levels of the stress hormone, cortisol, which may be inter‐related. In the present study, we were interested in whether different doses of natural folate or synthetic folic acid diets can influence neurogenesis in the hippocampus, levels of plasma homocysteine and serum corticosterone in adult female rats. Adult female Sprague‐Dawley rats underwent dietary interventions for 29 days. Animals were randomly assigned to six different dietary groups: folate deficient + succinylsulphathiazole (SST), low 5‐methyltetrahydrofolate (5‐MTHF), low 5‐MTHF + (SST), high 5‐MTHF + SST, low folic acid and high folic acid. SST was added to a subset of the 5‐MTHF diets to eliminate folic acid production in the gut. Before and after dietary treatment, blood samples were collected for corticosterone and homocysteine analysis, and brain tissue was collected for neurogenesis analysis. High folic acid and low 5‐MTHF without SST increased the number of immature neurones (doublecortin‐expressing cells) within the ventral hippocampus compared to folate deficient controls. Low 5‐MTHF without SST significantly increased the number of immature neurones compared to low and high 5‐MTHF + SST, indicating that SST interfered with elevations in neurogenesis. Low folic acid and high 5‐MTHF + SST reduced plasma homocysteine levels compared to controls, although there was no significant effect of diet on serum corticosterone levels. In addition, low folic acid and high 5‐MTHF + SST reduced the number of mature new neurones in the ventral hippocampus (bromodeoxyuridine/NeuN‐positive cells) compared to folate deficient controls. Overall, folic acid dose‐dependently influenced neurogenesis with low levels decreasing but high levels increasing neurogenesis in the ventral hippocampus, suggesting that this region, which is important for regulating stress, is particularly sensitive to folic acid in diets. Furthermore, the addition of SST negated the effects of 5‐MTHF to increase neurogenesis in the ventral hippocampus. [ABSTRACT FROM AUTHOR]

It is well established that estrogens affect neuroplasticity in a number of brain regions. In particular, estrogens modulate and mediate spine and synapse formation as well as neurogenesis in the hippocampal formation. In this review, we discuss current research exploring the effects of estrogens on dendritic spine plasticity and neurogenesis with a focus on the modulating factors of sex, age, and pregnancy. Hormone levels, including those of estrogens, fluctuate widely across the lifespan from early life to puberty, through adulthood and into old age, as well as with pregnancy and parturition. Dendritic spine formation and modulation are altered both by rapid (likely non-genomic) and classical (genomic) actions of estrogens and have been suggested to play a role in the effects of estrogens on learning and memory. Neurogenesis in the hippocampus is influenced by age, the estrous cycle, pregnancy, and parity in female rodents. Furthermore, sex differences exist in hippocampal cellular and molecular responses to estrogens and are briefly discussed throughout. Understanding how structural plasticity in the hippocampus is affected by estrogens and how these effects can influence function and be influenced by other factors, such as experience and sex, is critical and can inform future treatments in conditions involving the hippocampus. [ABSTRACT FROM AUTHOR]

Background: Postpartum depression affects approximately 15% of mothers and represents a form of early life adversity for developing offspring. Postpartum depression can be treated with prescription antidepressants like fluoxetine (FLX). However, FLX can remain active in breast milk, raising concerns about the consequences of neonatal FLX exposure. The hippocampus is highly sensitive to developmental stress, and males and females respond differently to stress at many endpoints, including hippocampal plasticity. However, it is unclear how developmental exposure to FLX alters the trajectory of hippocampal development. The goal of this study was to examine the long-term effects of maternal postpartum corticosterone (CORT, a model of postpartum depression) and concurrent FLX on hippocampal neurogenesis in male and female offspring. Methods: Female Sprague-Dawley rat dams were treated daily with either CORT or oil and FLX or saline from postpartum days 2-23. Offspring were perfused on postnatal day 31 (pre-adolescent), postnatal day 42 (adolescent), and postnatal day 69 (adult). Tissue was processed for doublecortin (DCX), an endogenous marker of immature neurons, in the dorsal and ventral hippocampus. Results: Maternal postpartum CORT reduced density of DCX-expressing cells in the dorsal hippocampus of pre-adolescent males and increased it in adolescent males, suggesting that postpartum CORT exposure disrupted the typical progression of the density of DCX-expressing cells. Further, among offspring of oil-treated dams, pre-adolescent males had greater density of DCX-expressing cells than pre-adolescent females, and maternal postpartum CORT prevented this sex difference. In pre-adolescent females, maternal postpartum FLX decreased the density of DCX-expressing cells in the dorsal hippocampus compared to saline. As expected, maternal CORT reduced the density of DCX-expressing cells in adult female, but not male, offspring. The combination of maternal postpartum CORT/FLX diminished density of DCX-expressing cells in dorsal hippocampus regardless of sex or age. Conclusions: These findings reveal how modeling treatment of postpartum depression with FLX alters hippocampal neurogenesis in developing offspring differently depending on sex, predominantly in the dorsal dentate gyrus and earlier in life. [ABSTRACT FROM AUTHOR]

Estradiol increases cell proliferation in the dentate gyrus of the female rodent but it is not known whether the G protein-coupled estrogen receptor (GPER), a membrane receptor, is involved in this process, nor whether there are regional differences in estradiol’s effects on cell proliferation. Thus, we investigated whether estradiol exerts its effects on cell proliferation in the dorsal and ventral dentate gyrus through GPER, using the GPER agonist, G1, and antagonist, G15. Ovariectomized adult female rats received a single injection of either: 17β-estradiol (10 μg), G1 (0.1, 5, 10 μg), G15 (40 μg), G15 and estradiol, or vehicle (oil, DMSO, or oil+DMSO). After 30 min, animals received an injection of bromodeoxyuridine (BrdU) and were perfused 24 h later. Acute treatment with estradiol increased, while the GPER agonist G1 (5 μg) decreased, the number of BrdU+ cells in the dentate gyrus relative to controls. The GPER antagonist, G15 increased the number of BrdU+ cells relative to control in the dorsal region and decreased the number of BrdU+ cells in the ventral region. However, G15 treatment in conjunction with estradiol partially eliminated the estradiol-induced increase in cell proliferation in the dorsal dentate gyrus. Furthermore, G1 decreased the expression of GPER in the dentate gyrus but not the CA1 and CA3 regions of the hippocampus. In summary, we found that activation of GPER decreased cell proliferation and GPER expression in the dentate gyrus of young female rats, presenting a potential and novel estrogen-independent role for this receptor in the adult hippocampus. [ABSTRACT FROM AUTHOR]

Disorders of the dopamine system, such as schizophrenia or stimulant addiction, are associated with impairments in different forms of cost/benefit decision making. The neural circuitry (ie amygdala, prefrontal cortex, nucleus accumbens) underlying these functions receives dopamine input, which is thought to have a central role in mediating cost/benefit decisions. Estradiol modulates dopamine activity, and estrogen receptors (ERs) are found within this neurocircuitry, suggesting that decision making may be influenced by estradiol. The present study examined the contribution of estradiol and selective ERα and β agonists on cost/benefit decision making in adult female Long-Evans rats. An effort-discounting task was utilized, where rats could either emit a single response on a low-reward lever to receive two pellets, or make 2, 5, 10, or 20 responses on a high-reward lever to obtain four pellets. Ovariectomy increased the choice on the high-reward lever, whereas replacement with high (10 μg), but not low (0.3 μg), levels of estradiol benzoate reduced the choice on the high-reward lever. Interestingly, both an ERα agonist (propyl-pyrazole triol (PPT)) and an ERβ agonist (diarylpropionitrile (DPN)) increased choice on the high-reward lever when administered independently, but when these two agonists were combined, a decrease in choice for the high-reward lever was observed. The effects of estradiol, PPT, and DPN were more pronounced 24 h post-administration, suggesting that these effects may be genomic in nature. Together, these results demonstrate that estradiol modulates cost/benefit decision making in females, whereby concomitant activation of ERα and β receptors shifts the decision criteria and reduces preference for larger, yet more costly rewards. [ABSTRACT FROM AUTHOR]

Converging evidence indicates that pregnant women report experiencing problems with memory, but the results of studies using objective measures are ambiguous. The present study investigated potential reason(s) for the discrepancy between findings of subjective and objective memory deficits, as well as potential source(s) of pregnant women's problems with memory. Sixty-one pregnant and 24 nonpregnant women completed a series of memory tests which included field and laboratory measures of prospective memory. Three standardized questionnaires were used to assess subjective aspects of memory. The influence of cortisol, depressed mood, anxiety, physical symptoms, sleep/fatigue, and busyness on pregnancy-related deficits was also examined. The findings revealed objective pregnancy-related deficits on two of the field measures of prospective memory. Pregnancy-related subjective deficits were also detected on all of the questionnaires. In contrast, no objective pregnancy-related deficits were found on the laboratory measures of memory. Increased physical symptoms accounted for one of the objective deficits in memory, while depressed mood and physical symptoms accounted for two of the subjective memory deficits. Collectively, these findings suggest that pregnant women experience everyday life problems with memory that are not readily detected in the laboratory environment. The predominant use of laboratory tests may explain the myriad of previous failures to detect objective deficits in pregnant women's memory. [ABSTRACT FROM AUTHOR]

Sleep deprivation (SD) can suppress cell proliferation in the hippocampal dentate gyrus of adult male rodents, suggesting that sleep may contribute to hippocampal functions by promoting neurogenesis. However, suppression of cell proliferation in rats by the platform-over-water SD method has been attributed to elevated corticosterone (Cort), a potent inhibitor of cell proliferation and nonspecific correlate of this procedure. We report here results that do not support this conclusion. Intact and adrenalectomized (ADX) male rats were subjected to a 96-h SD using multiple- and single-platform methods. New cells were identified by immunoreactivity for 5-bromo-2′-deoxyuridine (BrdU) or Ki67 and new neurons by immunoreactivity for BrdU and doublecortin. EEG recordings confirmed a 95% deprivation of rapid eye movement (REM) sleep and a 40% decrease of non-REM sleep. Cell proliferation in the dentate gyms was suppressed by up to 50% in sleep-deprived rats relative to apparatus control or home cage control rats. This effect was also observed in ADX rats receiving continuous low-dose Cort replacement via subcutaneous minipumps but not in ADX rats receiving Cort replacement via drinking water. In these latter rats, Cort intake via water was reduced by 60% during SD; upregulation of cell proliferation by reduced Cort intake may obscure inhibitory effects of sleep loss on cell proliferation. SD had no effect on the percentage of new cells expressing a neuronal phenotype. These results demonstrate that the Cort replacement method is critical for detecting an effect of SD on cell proliferation and support a significant role for sleep in adult neurogenesis. [ABSTRACT FROM AUTHOR]

The endocannabinoid system has been shown to regulate both the hypothalamic–pituitary–adrenal (HPA) axis and emotionality. The present experiment was designed to examine whether pharmacological modulation of the endocannabinoid system would affect the suppression of hippocampal cell proliferation and increase in defensive behaviours seen following exposure to predator odour (trimethylthiazoline; TMT) stress. Rats were administered either an endocannabinoid uptake inhibitor (AM404; 2 mg/kg) or a cannabinoid CB1 receptor antagonist (AM251; 5 mg/kg) 30 min prior to exposure to TMT. Exposure to TMT reduced cell proliferation in the dentate gyrus and increased the expression of defensive burying. Administration of AM404 significantly inhibited defensive burying, and attenuated the reduction in cell proliferation in response to TMT exposure. Administration of AM251 alone significantly increased cell proliferation; however, pretreatment with AM251 prevented neither the stress-induced suppression of cell proliferation nor the stress-induced increase in behavioural responses. These results support previous research demonstrating that augmentation of endocannabinoid signalling can suppress stress-responsive systems. They also suggest that endocannabinoids may play a complex role in the regulation of neurogenesis via cell proliferation in the hippocampus. [ABSTRACT FROM AUTHOR]