Estrogens dynamically regulate neurogenesis in the dentate gyrus of adult female rats.

Estrone and estradiol differentially modulate neuroplasticity and cognition. How they influence the maturation of new neurons in the adult hippocampus, however, is not known. The present study assessed the effects of estrone and estradiol on the maturation timeline of neurogenesis in the dentate gyrus (DG) of ovariectomized (a model of surgical menopause) young adult Sprague-Dawley rats using daily subcutaneous injections of 17ß-estradiol, estrone or vehicle. Rats were injected with a DNA synthesis marker, 5-bromo-2-deoxyuridine (BrdU), and were perfused 1, 2, or 3 weeks after BrdU injection and daily hormone treatment. Brains were sectioned and processed for various markers including: sex-determining region Y-box 2 (Sox2), glial fibrillary acidic protein (GFAP), antigen kiel 67 (Ki67), doublecortin (DCX), and neuronal nuclei (NeuN). Immunofluorescent labeling or co-labelling of BrdU with Sox2 (progenitor cells), Sox2/GFAP (neural progenitor cells), Ki67 (cell proliferation), DCX (immature neurons), NeuN (mature neurons) was used to examine the trajectory and maturation of adult-born neurons over time. Estrogens had early (1 week of exposure) effects on different stages of neurogenesis (neural progenitor cells, cell proliferation and early maturation of new cells into neurons) but these effects were less pronounced after prolonged treatment. Estradiol enhanced, whereas estrone reduced cell proliferation after 1 week but not after longer exposure to either estrogen. Both estrogens increased the density of immature neurons (BrdU/DCX-ir) after 1 week of exposure compared to vehicle treatment but this increased density was not sustained over longer durations of treatments to estrogens, suggesting that the enhancing effects of estrogens on neurogenesis were short-lived. Longer duration post-ovariectomy, without treatments with either of the estrogens, was associated with reduced neural progenitor cells in the DG. These results demonstrate that estrogens modulate several aspects of adult hippocampal neurogenesis differently in the short term, but may lose their ability to influence neurogenesis after long-term exposure. These findings have potential implications for treatments involving estrogens after surgical menopause.

Exploring the parity paradox: Differential effects on neuroplasticity and inflammation by APOEe4 genotype at middle age.

Female sex and Apolipoprotein E (APOE) ε4 genotype are top non-modifiable risk factors for Alzheimer's disease (AD). Although female-unique experiences like parity (pregnancy and motherhood) have positive effects on neuroplasticity at middle age, previous pregnancy may also contribute to AD risk. To explore these seemingly paradoxical long-term effects of parity, we investigated the impact of parity with APOEε4 genotype by examining behavioural and neural biomarkers of brain health in middle-aged female rats. Our findings show that primiparous (parous one time) hAPOEε4 rats display increased use of a non-spatial cognitive strategy and exhibit decreased number and recruitment of new-born neurons in the ventral dentate gyrus of the hippocampus in response to spatial working memory retrieval. Furthermore, primiparity and hAPOEε4 genotype synergistically modulate inflammatory markers in the ventral hippocampus. Collectively, these findings demonstrate that previous parity in hAPOEε4 rats confers an added risk to present with reduced activity and engagement of the hippocampus as well as elevated pro-inflammatory signaling, and underscore the importance of considering female-specific factors and genotype in health research.

Pregnancy history and estradiol influence spatial memory, hippocampal plasticity, and inflammation in middle-aged rats.

Pregnancy and motherhood can have long-term effects on cognition and brain aging in both humans and rodents. Estrogens are related to cognitive function and neuroplasticity. Estrogens can improve cognition in postmenopausal women, but the evidence is mixed, partly due to differences in age of initiation, type of menopause, dose, formulation and route of administration. Additionally, past pregnancy influences brain aging and cognition as a younger age of first pregnancy in humans is associated with poorer aging outcomes. However, few animal studies have examined specific features of pregnancy history or the possible mechanisms underlying these changes. We examined whether maternal age at first pregnancy and estradiol differentially affected hippocampal neuroplasticity, inflammation, spatial reference cognition, and immediate early gene activation in response to spatial memory retrieval in middle-age. Thirteen-month-old rats (who were nulliparous (never mothered) or previously primiparous (had a litter) at three or seven months) received daily injections of estradiol (or vehicle) for sixteen days and were tested on the Morris Water Maze. An older age of first pregnancy was associated with impaired spatial memory but improved performance on reversal training, and increased number of new neurons in the ventral hippocampus. Estradiol decreased activation of new neurons in the dorsal hippocampus, regardless of parity history. Estradiol also decreased the production of anti-inflammatory cytokines based on age of first pregnancy. This work suggests that estradiol affects neuroplasticity and neuroinflammation in middle age, and that age of first pregnancy can have long lasting effects on hippocampus structure and function.

The effects of estrogens on spatial learning and memory in female rodents - A systematic review and meta-analysis.

Estrogens have inconsistent effects on learning and memory in both the clinical and preclinical literature. Preclinical literature has the advantage of investigating an array of potentially important factors contributing to the varied effects of estrogens on learning and memory, with stringently controlled studies. This study set out to identify specific factors in the animal literature that influence the effects of estrogens on cognition, for possible translation back to clinical practice. The literature was screened and studies meeting strict inclusion criteria were included in the analysis. Eligible studies included female ovariectomized rodents with an adequate vehicle for the estrogen treatment, with an outcome of spatial learning and memory in the Morris water maze. Training days of the Morris water maze were used to assess acquisition of spatial learning, and the probe trial was used to evaluate spatial memory recall. Continuous outcomes were pooled using a random effects inverse variance method and reported as standardized mean differences with 95 % confidence intervals. Subgroup analyses were developed a priori to assess important factors. The overall analysis favoured treatment for the later stages of training and for the probe trial. Factors including the type of estrogen, route, schedule of administration, age of animals, timing relative to ovariectomy, and duration of treatment were all found to be important. The subgroup analyses showed that chronic treatment with 17ß-estradiol, either cyclically or continuously, to young animals improved spatial recall. These results, observed in animals, can inform and guide further clinical research on hormone replacement therapy for cognitive benefits.

High estradiol reduces adult neurogenesis but strengthens functional connectivity within the hippocampus during spatial pattern separation in adult female rats.

Adult neurogenesis in the dentate gyrus plays an important role for pattern separation, the process of separating similar inputs and forming distinct neural representations. Estradiol modulates neurogenesis and hippocampus function, but to date no examination of estradiol's effects on pattern separation have been conducted. Here, we examined estrogenic regulation of adult neurogenesis and functional connectivity in the hippocampus after the spatial pattern separation task in female rats. Ovariectomized Sprague-Dawley rats received daily injections of vehicle, 0.32 µg (Low) or 5 µg (High) of estradiol benzoate until the end of experiment. A single bromodeoxyuridine (BrdU) was injected one day after initiation of hormone or vehicle treatment and rats were tested in the delayed nonmatching to position spatial pattern separation task in the 8-arm radial maze for 12 days beginning two weeks after BrdU injection. Rats were perfused 90 min after the final trial and brain sections were immunohistochemically stained for BrdU/neuronal nuclei (NeuN) (new neurons), Ki67 (cell proliferation), and the immediate early gene, zif268 (activation). Results showed that high, but not low, estradiol reduced the density of BrdU/NeuN-ir cells and had significant inter-regional correlations of zif268-ir cell density in the hippocampus following pattern separation. Estradiol treatment did not influence pattern separation performance or strategy use. These results show that higher doses of estradiol can reduce neurogenesis but at the same time increases correlations of activity of neurons within the hippocampus during spatial pattern separation.

Sex and BDNF Val66Met polymorphism matter for exercise-induced increase in neurogenesis and cognition in middle-aged mice.

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.

Sex Differences and Estradiol Effects in MAPK and Akt Cell Signaling across Subregions of the Hippocampus.

INTRODUCTION: Rapid effects of estrogens within the hippocampus of rodents are dependent upon cell-signaling cascades, and activation of these cascades by estrogens varies by sex. Whether these pathways are rapidly activated within the dentate gyrus (DG) and CA1 by estrogens across sex and the anatomical longitudinal axis has been overlooked. METHODS: Gonadally intact female and male rats were given either vehicle or physiological systemic low (1.1 µg/kg) or high (37.3 µg/kg) doses of 17ß-estradiol 30 min prior to tissue collection. To control for the effects of circulating estrogens, an additional group of female rats was ovariectomized (OVX) and administered 17ß-estradiol. Brains were extracted, and tissue punches of the CA1 and DG were taken along the longitudinal hippocampal axis (dorsal and ventral) and analyzed for key mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) cascade phosphoproteins. RESULTS: Intact females had higher Akt pathway phosphoproteins (pAkt, pGSK-3ß, and pp70S6K) than males in the DG (dorsal and ventral) and lower pERK1/2 in the dorsal DG. Most effects of 17ß-estradiol on cell signaling occurred in OVX animals. In OVX animals, 17ß-estradiol increased cell signaling of MAPK and Akt phosphoproteins (pERK1/2, pJNK, pAkt, and pGSK-3ß) in the CA1 and pERK1/2 and pJNK DG. DISCUSSION/CONCLUSIONS: Systemic 17ß-estradiol treatment rapidly alters phosphoprotein levels in the hippocampus, dependent on reproductive status, and intact females have greater expression of Akt phosphoproteins than that in intact males in the DG. These findings shed light on underlying mechanisms of sex differences in hippocampal function and response to interventions that affect MAPK or Akt signaling.

Intention to Receive a COVID-19 Vaccine by HIV Status Among a Population-Based Sample of Women and Gender Diverse Individuals in British Columbia, Canada.

COVID-19 vaccination is recommended for people living with HIV (PLWH), among whom social inequities and co-morbidities may drive risks of COVID-19 infection and outcome severity. Among a provincial (British Columbia) sample, we determined the prevalence of COVID-19 vaccine intention by HIV status and assessed socio-demographic, vaccine hesitancy, and psychological predictors of vaccine intention. Individuals (25-69 years) recruited from province-wide research cohorts and the general public completed an online survey examining COVID-19 impacts (August/2020-March/2021). In an analysis restricted to women and gender diverse participants (n = 5588), we compared intention to receive a recommended COVID-19 vaccine (Very likely/Likely vs Neutral/Unlikely/Very Unlikely) by self-reported HIV status. Logistic regression models assessed the independent effect of HIV status and other factors on COVID-19 vaccine intention. Of 5588 participants, 69 (1.2%) were living with HIV, of whom 79.7% were on antiretroviral therapy. In bivariate analyses, intention to vaccinate was significantly lower among PLWH compared to participants not living with HIV (65.2% vs 79.6%; OR 0.44; 95%CI 0.32-0.60). However, this association was not statistically significant after adjustment for ethnicity, income, education, and essential worker status (aOR 0.85; 95%CI 0.48-1.55). Among PLWH, those with greater vaccine confidence, positive attitudes towards the COVID-19 vaccine, and more strongly influenced by direct and indirect social norms to vaccinate had significantly higher odds of vaccine intention. Tailored messaging is needed to build vaccine confidence, address questions about vaccine benefits, and support informed vaccination decision-making to promote COVID-19 vaccine uptake among women and gender diverse people living with HIV.

Sex differences in inflammation in the hippocampus and amygdala across the lifespan in rats: associations with cognitive bias.

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-1ß, IL-4, IL-5, and IL-10 in the ventral HPC than females in adolescence. In young adulthood, females had more IFN-γ, IL-1ß, 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.

Assessing the role of adolescent hormonal contraceptive use on risk for depression: a 3-year longitudinal study protocol.

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.

Barriers To Accessing Contraception and Cervical and Breast Cancer Screening During COVID-19: A Prospective Cohort Study.

OBJECTIVE: This study sought to examine how access to contraception and cervical and breast cancer screening in British Columbia, Canada, has been affected by the COVID-19 pandemic. METHODS: From August 2020 to March 2021, 3691 female residents of British Columbia (age 25-69 y) participated in this study. We used generalized estimating equations to analyze the proportion of females accessing contraception and the proportion having difficulty accessing contraception across the different phases of pandemic control measures, and logistic regression to analyze attendance at cervical and breast cancer screening. We added sociodemographic and biological variables individually into the models. Self-reported barriers to accessing contraception and attending screening were summarized. RESULTS: During phases with the highest pandemic controls, self-reported access to contraception was lower (OR 0.94; 95% CI 0.90-0.98; P = 0.005) and difficulty with access was higher (OR 2.74; 95% CI 1.54-4.88; P = 0.001). A higher proportion of adults aged 25-34 years reported difficulty accessing contraception than those aged 35-39 years (P < 0.0001), and participants identifying as Indigenous had higher odds of access difficulties (OR 5.56; 95% CI 2.44-12.50; P < 0.001). Of those who required screening during the COVID-19 pandemic, 62% and 54.5% did not attend at least one of their cervical or breast screening appointments, respectively. Those with a history of breast cancer had significantly higher odds of self-reporting having attended their mammogram appointment compared with those without a history of breast cancer (OR 5.62; 95% CI 2.69-13.72; P < 0.001). The most common barriers to screening were difficulty getting an appointment and appointments being considered non-urgent. CONCLUSIONS: The COVID-19 pandemic has uniquely affected access to contraception and cancer screening participation for various subgroups. Self-reported data present potential avenues for mitigating barriers.

The promises and pitfalls of sex difference research.

Funding agencies in North America and Europe are recognizing the importance of the integration of sex differences into basic and clinical research. Although these mandates are in place to improve our knowledge of health for both men and women, there have been a number of implementation issues that require vigilance on the part of funders and the research community. Here we discuss issues on simple inclusion of both sexes in studies to specialisation of sex differences with attention paid to statistics and the need for sex-specific treatments. We suggest differing mandates need to be considered regarding simple integration versus the need for studies in the specialisation of sex differences and/or the need for research that recognises the importance of male-specific or female-specific factors that influence subsequent health such as menstruation, menopause or pregnancy.

Perinatal depression: Heterogeneity of disease and in animal models.

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

Maternal fluoxetine reduces hippocampal inflammation and neurogenesis in adult offspring with sex-specific effects of periadolescent oxytocin.

Untreated perinatal depression can have severe consequences for the mother and her children. However, both the efficacy to mothers and safety to exposed infants of pharmacological antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been questioned. We previously reported that maternal SSRI exposure increased hippocampal IL-1ß levels, which may be tied to limited efficacy of SSRIs during the postpartum to the dam but is not yet known whether maternal postpartum SSRIs affect the neuroinflammatory profile of adult offspring. In addition, although controversial, perinatal SSRI exposure has been linked to increased risk of autism spectrum disorder (ASD) in children. Oxytocin (OT) is under investigation as a treatment for ASD, but OT is a large neuropeptide that has difficulty crossing the blood-brain barrier (BBB). TriozanTM is a nanoformulation that can facilitate OT to cross the BBB. Thus, we investigated the impact of maternal postpartum SSRIs and offspring preadolescent OT treatment on adult offspring neuroinflammation, social behavior, and neurogenesis in the hippocampus. Using a model of de novo postpartum depression, corticosterone (CORT) was given in the postpartum to the dam with or without treatment with the SSRI, fluoxetine (FLX) for 21 days postpartum. Offspring were then subsequently treated with either OT, OT + TriozanTM, or vehicle for 10 days prior to adolescence (PD25-34). Maternal FLX decreased hippocampal IL-10 and IL-13 and neurogenesis in both sexes, whereas maternal CORT increased hippocampal IL-13 in both sexes. Maternal CORT treatment shifted the neuroimmune profile towards a more proinflammatory profile in offspring hippocampus, whereas oxytocin, independent of formulation, normalized this profile. OT treatment increased hippocampal neurogenesis in adult males but not in adult females, regardless of maternal treatment. OT treatment increased the time spent with a novel social stimulus animal (social investigation) in both adult male and female offspring, although this effect depended on maternal CORT. These findings underscore that preadolescent exposure to OT can reverse some of the long-lasting effects of postpartum maternal CORT and FLX treatments in the adult offspring. In addition, we found that maternal treatments that reduce (CORT) or increase (FLX) hippocampal inflammation in dams resulted in opposing patterns of hippocampal inflammation in adult offspring.

Intention to receive a COVID-19 vaccine: results from a population-based survey in Canada.

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.

The long and short term effects of motherhood on the brain.

Becoming a mother is associated with dramatic changes in physiology, endocrinology, immune function, and behaviour that begins during pregnancy and persists into the postpartum. Evidence also suggests that motherhood is accompanied by long-term changes in brain function. In this review, we summarize the short (pregnancy and postpartum) and long-term (beyond the postpartum and into middle age) effects of pregnancy and motherhood on cognition, neuroplasticity, and neuroimmune signalling. We also discuss the effects of previous history of pregnancy and motherhood (parity) on brain health and disease (neurodegenerative diseases and stroke outcomes) and on efficacy of hormone and antidepressant treatments. Finally, we argue that pregnancy and motherhood are unique female experiences that need to be taken into account to better understand female brain function and aging.

Risk-based decision making in rats: Modulation by sex and amphetamine.

Decision-making is a complex process essential to daily adaptation in many species. Risk is an inherent aspect of decision-making and it is influenced by gonadal hormones. Testosterone and 17ß-estradiol may modulate decision making and impact the mesocorticolimbic dopamine pathway. Here, we explored sex differences, the effect of gonadal hormones and the dopamine agonist amphetamine on risk-based decision making. Intact or gonadectomised (GDX) male and female rats underwent to a probabilistic discounting task. High and low doses of testosterone propionate (1.0 or 0.2 mg) and 17ß-estradiol benzoate (0.3 µg) were administered to assess acute effects on risk-based decision making. After 3-days of washout period, intact and GDX rats received high or low (0.5 or 0.125 mg/kg) doses of amphetamine and re-tested in the probabilistic discounting task. Under baseline conditions, males made more risky choices during probability discounting compared to female rats, particularly in the lower probability blocks, but GDX did not influence risky choice. The high, but not the low dose, of testosterone modestly reduced risky decision making in GDX male rats. Conversely, 17ß-estradiol had no significant effect on risky choice regardless of GDX status in either sex. Lastly, a higher dose of amphetamine increased risky decision making in both intact males and females, but had no effect in GDX rats. These findings demonstrated sex differences in risk-based decision making, with males showing a stronger bias toward larger, uncertain rewards. GDX status influenced the effects of amphetamine, suggesting different dopaminergic regulation in risk-based choices among males and females.

Oxytocin has sex-specific effects on social behaviour and hypothalamic oxytocin immunoreactive cells but not hippocampal neurogenesis in adult rats.

Oxytocin regulates social behaviours, pair bonding and hippocampal neurogenesis but most studies have used adult males. Our study investigated the effects of oxytocin on social investigation and adult hippocampal neurogenesis in male and female rats. Oxytocin has poor penetration of the blood-brain barrier, therefore we tested a nanoparticle drug, TRIOZAN™ (Ovensa Inc.), which permits greater blood-brain-barrier penetration. Adult male and female rats were injected daily (i.p.) for 10 days with either: oxytocin in PBS (0.5 or 1.0 mg/kg), oxytocin in TRIOZAN™ (0.5 or 1.0 mg/kg), or vehicle (PBS) and tested for social investigation. Oxytocin decreased body mass and increased social investigation and number of oxytocin-immunoreactive cells in the supraoptic nucleus (SON) of the hypothalamus in male rats only. In both sexes, oxytocin decreased the number of immature neurons (doublecortin+ cells) in the ventral hippocampus and reduced plasma 17ß-estradiol levels in a dose- and delivery-dependent way. Oxytocin in TRIOZAN™ reduced "sedation" observed post-injection and increased certain central effects (oxytocin levels in the hypothalamus and neurogenesis in the ventral hippocampus) relative to oxytocin in PBS, indicating that the nanoparticle may be used as an alternative brain delivery system. We showed that oxytocin has sex-specific effects on social investigation, body mass, "sedation", and the oxytocin system. In contrast, similar effects were observed in both sexes in neurogenesis and plasma 17ß-estradiol. Our work suggests that sex differences in oxytocin regulation of brain endpoints is region-specific (hypothalamus versus hippocampus) and that oxytocin does not promote social investigation in females.

Selective activation of estrogen receptors α and ß: Implications for depressive-like phenotypes in female mice exposed to chronic unpredictable stress.

The estrogen receptor (ER) mechanisms by which 17ß-estradiol influences depressive-like behaviour have primarily been investigated acutely and not within an animal model of depression. Therefore, the current study aimed to dissect the contribution of ERα and ERß to the effects of 17ß-estradiol under non-stress and chronic stress conditions. Ovariectomized (OVX) or sham-operated mice were treated chronically (47 days) with 17ß-estradiol (E2), the ERß agonist diarylpropionitrile (DPN), the ERα agonist propylpyrazole-triol (PPT), or vehicle. On day 15 of treatment, mice from each group were assigned to chronic unpredictable stress (CUS; 28 days) or non-CUS conditions. Mice were assessed for anxiety- and depressive-like behaviour and hypothalamic-pituitary-adrenal (HPA) axis function. Cytokine and chemokine levels, and postsynaptic density protein 95 were measured in the hippocampus and frontal cortex, and adult hippocampal neurogenesis was assessed. Overall, the effects of CUS were more robust that those of estrogenic treatments, as seen by increased immobility in the tail suspension test (TST), reduced PSD-95 expression, reduced neurogenesis in the ventral hippocampus, and HPA axis negative feedback dysregulation. However, we also observe CUS-dependent and -independent effects of ovarian status and estrogenic treatments. The effects of CUS on PSD-95 expression, the cytokine milieu, and in TST were largely driven by PPT and DPN, indicating that these treatments were not protective. Independent of CUS, estradiol increased neurogenesis in the dorsal hippocampus, blunted the corticosterone response to an acute stressor, and increased anxiety-like behaviour. These findings provide insights into the complexities of estrogen signaling in modulating depressive-like phenotypes under non-stress and chronic stress conditions.