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Biological differences between males and females are found at multiple levels. However, females have too often been under-represented in behavioral neuroscience research, which has stymied the study of potential sex differences in neurobiology and behavior. This review focuses on the study of sex differences in the neurobiology of social behavior, memory, emotions, and recovery from brain injury, with particular emphasis on the role of estrogens in regulating forebrain function. This work, presented by the authors at the 2016 meeting of the International Behavioral Neuroscience Society, emphasizes varying approaches from several mammalian species in which sex differences have not only been documented, but also become the focus of efforts to understand the mechanistic basis underlying them. This information may provide readers with useful experimental tools to successfully address recently introduced regulations by granting agencies that either require (e.g. the National Institutes of Health in the United States and the Canadian Institutes of Health Research in Canada) or recommend (e.g. Horizon 2020 in Europe) the inclusion of both sexes in biomedical research. [ABSTRACT FROM AUTHOR]

Abstract: Estradiol affects the structure and function of the hippocampus. We have found that repeated estradiol affects neurogenesis and cell death in the hippocampus of adult female, but not male rats. In the present study we sought to determine whether using the same regimen of estradiol would influence hippocampus-dependent behaviour. Adult male and female rats were given estradiol or sesame oil for 15days, and then tested using a contextual pre-exposure paradigm in which performance depends on the hippocampus. The time spent freezing displayed by rats was scored on subsequent days in (1) the training context, (2) a novel context in which rats had never been shocked, and (3) the training context a second time. Irrespective of treatment, males showed stronger memory for the context by exhibiting greater freezing in both the training context exposures and the novel context. Previous estradiol treatment, in either sex, did not affect the ability to learn and retain information about the training context. However, female rats treated with estradiol and exposed to a novel context after fear conditioning exhibited less freezing behaviour than controls. Taken together, our results demonstrate that gonadectomized male rats outperform females, regardless of previous treatment with estradiol, on a hippocampus-contextual fear conditioning test, and that previous estradiol treatment has a subtle effect on performance in female but not male rats. [Copyright &y& Elsevier]

Abstract: In general, the behavioral and neural effects of estradiol administration to males and females differ. While much attention has been paid to the potential structural, cellular and sub-cellular mechanisms that may underlie such differences, as of yet there has been no examination of whether the differences observed may be related to differential uptake or storage of estradiol within the brain itself. We administered estradiol benzoate to gonadectomized male and female rats, and compared the concentration of estradiol in serum and brain tissue found in these rats to those of gonadectomized, oil-treated rats and intact rats of both sexes. Long-term gonadectomy (3weeks) reduced estradiol concentration in the male and female hippocampus, but not in the male or female amygdala or in the female prefrontal cortex. Furthermore, exogenous treatment with estradiol increased estradiol content to levels above intact animals in the amygdala, prefrontal cortex and the male hippocampus. Levels of estradiol were undetectable in the prefrontal cortex of intact males, but were detectable in all other brain regions of intact rats. Here we demonstrate (1) that serum concentrations of estradiol are not necessarily reflective of brain tissue concentrations, (2) that within the brain, there are regional differences in the effects of gonadectomy and estradiol administration, and (3) that there is less evidence for local production of estradiol in males than females, particularly in the prefrontal cortex and perhaps the hippocampus. Thus there are regional differences in estradiol concentration in the prefrontal cortex, amygdala and hippocampus that are influenced by sex and hormone status. [Copyright &y& Elsevier]

Abstract: Estradiol withdrawal after pregnancy is hypothesized to precipitate depressive symptoms in vulnerable women. A hormone-simulated pregnancy was induced in female rats and the effects of a ‘postpartum’ drop in estradiol on hippocampal cell proliferation were examined. All groups were ovariectomized or given sham surgery prior to treatment. Rats were randomly assigned to ‘postpartum’, ‘postpartum’+EB (estradiol benzoate), ‘postpartum’+DPN (diarylpropionitrile; an ERβ agonist), ‘postpartum’+IMI (imipramine; a tricyclic antidepressant), sham, ovariectomized (OVX), sham+IMI or OVX+IMI groups. All ‘postpartum’ groups received hormone injections (estradiol and progesterone) over 23 days to simulate pregnancy, while IMI groups also received daily imipramine injections. After day 23, ‘postpartum’ rats were withdrawn from the hormone-simulated pregnancy (mimicking the postpartum drop in gonadal hormones), while other ‘postpartum’ treatment groups received daily injections of DPN, EB or IMI. On day 3 ‘postpartum’ all rats were injected with bromodeoxyuridine (BrdU; a DNA synthesis marker) and perfused 24 h later to assess cell proliferation and cell death in the dentate gyrus. ‘Postpartum’ hormone withdrawal decreased hippocampal cell proliferation in the ‘postpartum’ and ‘postpartum’+EB groups only. Chronic imipramine significantly increased hippocampal cell proliferation in sham+IMI, but not OVX+IMI rats suggesting that imipramine''s effects to increase hippocampal cell proliferation in female rats is related to reproductive status. Cell death (pyknotic cells) was decreased only in the ‘postpartum’ group. Together, these results suggest an important, though complex, role for gonadal hormones in the cellular changes accompanying this model of postpartum depression. [Copyright &y& Elsevier]

Abstract: Gonadal hormones modulate neurogenesis in the dentate gyrus differentially in male and female adult rodents. Neurogenesis is comprised of at least two components: cell proliferation (the production of new cells) and cell survival (the number of new neurons that survive to maturity). Previous studies have found sex differences in the level of cell proliferation in the dentate gyrus only when comparing females in a high estrogen state to males. This review focuses on the effects of acute and chronic levels of estrogens or androgens on hippocampal neurogenesis in the adult male and female rodent. Evidence is also reviewed for the co-localization of androgen receptors and estrogen receptors (ER) with markers for cell proliferation or immature new cell survival. Briefly, evidence suggests that acute estradiol initially enhances and subsequently suppresses cell proliferation in the dentate gyrus of adult female rodents but may have limited effects in male rodents. Both the two known ER subtypes, ERα and β upregulate hippocampal neurogenesis via cell proliferation. Intriguingly, repeated exposure to estradiol modulates hippocampal neurogenesis and cell death in adult female, but not male, rodents. However short-term estradiol treatment (5 days) in male meadow voles enhances new cell survival in the dentate gyrus but only when administered during the ‘axon extension’ phase. Furthermore, evidence is also reviewed showing a difference in response to acute and chronic estradiol treatment in older female rats compared to younger female rats. Recent findings from our laboratory indicate that testosterone and dihydrotestosterone upregulate hippocampal neurogenesis (via cell survival), but not cell proliferation, in adult male rodents. Effects of endogenous fluctuations in gonadal hormones on adult neurogenesis are observed across the seasons in meadow voles and during pregnancy and lactation in the rat dam. Pregnancy and motherhood differentially regulate adult hippocampal neurogenesis in the adult female rodent, with primiparous rats displaying lower levels of hippocampal cell proliferation and survival after parturition. Few studies have compared males and females but existing research suggests a sex difference in the hormonal regulation of hippocampal neurogenesis in the adult. Clearly more work is needed to elucidate the effects of gonadal hormones on neurogenesis in the dentate gyrus of both male and female rodents across the lifespan, especially if we are to use our knowledge of how adult neurogenesis is regulated to develop strategies to repair neuron loss in neurodegenerative diseases. [Copyright &y& Elsevier]

The present study investigated sex differences and the effect of a high level of estradiol in the female meadow vole on performance in the forced swim test (FST) and the Morris water maze in meadow voles. Female meadow voles were ovariectomized (OVX) and administered either vehicle (sesame oil) or estradiol for 2 days prior to performing the FST. Four days following the FST, all animals were run in the Morris water maze. Results indicated that estradiol-injected female meadow voles showed more ‘depressive-like’ behaviors in the FST (greater time spent immobile and less time spent swimming) than vehicle-treated female or male meadow voles. In addition, estradiol-treated females had impaired performance (greater latencies and distance swum to reach the hidden platform) than both vehicle-treated female and male meadow voles, consistent with previous data. Despite the fact that estradiol administration increased ‘depressive-like’ behaviors in the FST and impaired performance in the Morris water maze, there was no correlation between the two behaviors indicating that ‘depressive-like’ behaviors did not account for the differences seen in spatial performance in the Morris water maze. To our knowledge, this is the first demonstration in rodents indicating that estradiol-mediated changes in behavior in the FST is not indicative of subsequent performance in the Morris water maze. [Copyright &y& Elsevier]

• Hormones confer neuroplasticity during life stage transitions in males and females. • Sex steroid hormones modulate social recognition behavior in males and females. • Gonadal steroid hormones influence paternal behavior and structural plasticity. • Peripartum fluctuations in steroid hormones alter the brain and behavior in females. • Previous parity reduces hormone levels, brain aging and alters disease risk. Major life transitions often co-occur with significant fluctuations in hormones that modulate the central nervous system. These hormones enact neuroplastic mechanisms that prepare an organism to respond to novel environmental conditions and/or previously unencountered cognitive, emotional, and/or behavioral demands. In this review, we will explore several examples of how hormones mediate neuroplastic changes in order to produce adaptive responses, particularly during transitions in life stages. First, we will explore hormonal influences on social recognition in both males and females as they transition to sexual maturity. Next, we will probe the role of hormones in mediating the transitions to motherhood and fatherhood, respectively. Finally, we will survey the long-term impact of reproductive experience on neuroplasticity in females, including potential protective effects and risk factors associated with reproductive experience in mid-life and beyond. Ultimately, a more complete understanding of how hormones influence neuroplasticity throughout the lifespan, beyond development, is necessary for understanding how individuals respond to life changes in adaptive ways. [ABSTRACT FROM AUTHOR]

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. • High estradiol reduces the survival of adult-born new neurons in the dentate gyrus. • High estradiol enhances intra-hippocampal activity during spatial pattern separation. • High estradiol increases neural activation in the ventral cornus ammonis (CA)1. [ABSTRACT FROM AUTHOR]

Neurogenesis within the adult hippocampus is modulated by endogenous and exogenous factors. Here, we review the role of sex hormones in the regulation of adult hippocampal neurogenesis in males and females. The review is framed around the potential functional implications of sex hormone regulation of adult hippocampal neurogenesis, with a focus on cognitive function and mood regulation, which may be related to sex differences in incidence and severity of dementia and depression. We present findings from preclinical studies of endogenous fluctuations in sex hormones relating to reproductive function and ageing, and from studies of exogenous hormone manipulations. In addition, we discuss the modulating roles of sex, age, and reproductive history on the relationship between sex hormones and neurogenesis. Because sex hormones have diverse targets in the central nervous system, we overview potential mechanisms through which sex hormones may influence hippocampal neurogenesis. Lastly, we advocate for a more systematic consideration of sex and sex hormones in studying the functional implications of adult hippocampal neurogenesis. [ABSTRACT FROM AUTHOR]

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]

Abstract: Adult neurogenesis occurs in the hippocampus of most mammals. While the function of adult hippocampal neurogenesis is not known, there is a relationship between neurogenesis and hippocampus-dependent learning and memory. Ovarian hormones can influence learning and memory and strategy choice. In competitive memory tasks, higher levels of estradiol shift female rats towards the use of the place strategy. Previous studies using a cue-competition paradigm find that 36% of male rats will use a hippocampus-dependent place strategy and place strategy users had lower levels of cell proliferation in the hippocampus. Here, we used the same paradigm to test whether endogenous or exogenous ovarian hormones influence strategy choice in the cue-competition paradigm and whether cell proliferation was related to strategy choice. We tested ovariectomized estradiol-treated (10μg of estradiol benzoate) or sham-operated female rats on alternating blocks of hippocampus-dependent and hippocampus-independent versions of the Morris water task. Rats were then given a probe session with the platform visible and in a novel location. Preferred strategy was classified as place strategy (hippocampus-dependent) if they swam to the old platform location or cue strategy (hippocampus-independent) if they swam to the visible platform. All groups showed a preference for the cue strategy. However, proestrous rats were more likely to be place strategy users than rats not in proestrus. Female place strategy users had increased cell proliferation in the dentate gyrus compared to cue strategy users. Our study suggests that 78% of female rats chose the cue strategy instead of the place strategy. In summary the present results suggest that estradiol does not shift strategy use in this paradigm and that cell proliferation is related to strategy use with greater cell proliferation seen in place strategy users in female rats. [ABSTRACT FROM AUTHOR]

Abstract: Previously, a hormone-simulated pregnancy (HSP), and the subsequent ‘postpartum’ withdrawal in estradiol has been shown to precipitate depressive-like behaviours in the forced swim test in female rats. In this study, we used the HSP and ‘postpartum’ withdrawal to investigate the impact on sucrose consumption, a model of anhedonia. Rats were assigned to “postpartum”, “postpartum”+EB (estradiol benzoate), “postpartum”+IMI (imipramine; a tricyclic antidepressant), “postpartum”+DPN (diarylpropionitrile; an ERβ agonist), or ovariectomized (OVX) controls and OVX+IMI treatments. All “postpartum” groups received daily hormone injections (estradiol and progesterone) over 23 days to simulate pregnancy, while IMI groups also received daily injections of imipramine. After Day 23, “postpartum” rats were withdrawn from the hormone regimen (mimicking the postpartum decrease in gonadal hormones), and then received daily injections of compounds indicated (DPN, EB, IMI). Rats were tested for consumption of, and preference for, sucrose weekly at baseline, during ‘pregnancy’ and on ‘Postpartum’ Days 2–3. During the ‘postpartum’ period rats in the “postpartum” group had lower sucrose consumption and preference compared to during late-‘pregnancy’, but no decrease in ‘postpartum’ consumption or preference was seen in any other groups except “postpartum”+IMI and a decrease in sucrose preference only in the postpartum+EB group from mid-‘pregnancy’ to ‘postpartum’. The OVX +IMI group had decreased sucrose consumption relative to OVX controls, suggesting a negative effect of imipramine on sucrose consumption. Together, these results suggest an important, though complex, role for gonadal hormones in the behavioral changes accompanying this model of depression. [Copyright &y& Elsevier]

Abstract: The influence of estradiol on learning and memory is dependent on a number of factors. The effects of physiological levels of estradiol on the acquisition of a spatial working memory task mediated by the prefrontal cortex (PFC) and the hippocampus were examined in Experiment 1. Ovariectomized Long–Evans rats received daily injections of estradiol or vehicle were tested on the win-shift version of the radial arm maze. A high dose of estradiol benzoate (5μg) enhanced acquisition of the task, whereas a low dose of estradiol (0.3μg) increased the number of errors committed over 17 days of testing. Experiment 2 was conducted to examine site-specific influences of estradiol on spatial working memory in well-trained rats. Saline and estradiol cyclodextrin (0.1 and 0.9μg) were infused into the prelimbic region of the PFC or dorsal hippocampus 40min prior to testing on the win-shift task. Infusions of estradiol into both brain areas attenuated saline-infusion disruptions in working memory. Specifically, the higher dose of estradiol facilitated working memory when infused into the PFC, whereas the lower dose of estradiol facilitated performance when infused into the dorsal hippocampus. Moreover, working memory was significantly impaired 24h after infusions of estradiol into the dorsal hippocampus but not the PFC. These data provide further evidence for the notion that estradiol can dose-dependently alter memory processes and suggest that facilitation or disruptions of working memory by estradiol are site- and time-specific. [Copyright &y& Elsevier]

Examines whether the inconsistencies of estradiol's effects on learning were due to dose-dependent effects of estradiol on different memory processes in rats. Factor that may mediate differential effects of estradiol on learning and memory; Results of the apparatus training on an eight-arm maze; Effects of estradiol on hippocampal subregions.

Perinatal depression (PND) affects 15% of women. During the perinatal period both stress- and gonadal hormones fluctuate widely. Putatively, these fluctuations are involved in PND disease mechanisms. The serotonin system is sensitive to such hormone fluctuations, and serotonin reuptake inhibitors (SSRIs) are used to treat PND, although treatment is suboptimal and it is not known at which peripartum time-point SSRI treatment may be most efficacious. In this study, we investigate the effect of the SSRI paroxetine (5 mg/kg s.c.) on swim stress-induced corticosterone in a rat model of postpartum depression. In the rat model corticosterone (CORT; 40 mg/kg s.c.) was administered in Sprague Dawley rats across postpartum day (PD)2 to PD14. Stress response was measured during the first exposure to the forced swim test (FST1), and depressive-like behavior was measured in both FST1 and FST2. We found that paroxetine completely blunted the swim stress-induced CORT response and increased depressive-like behavior in both FST1 and FST2. Our findings suggest that in the postpartum context, SSRIs compromise stress axis dynamics, which are needed for a healthy stress response. This is likely unfavorable for reversing depressive-like behavior and may provide a rationale for augmentation strategies beyond SSRIs alone to optimize the clinical management of PND. [ABSTRACT FROM AUTHOR]

The present study investigated the effect of different doses of estradiol treatment on performance in the non-spatial delayed alternation T-maze a task in which performance is mediated by the integrity of the prefrontal cortex (PFC). Ovariectomized (OVX) female rats were injected with estradiol benzoate (0.3 μg/0.1 ml sesame oil (EB0.3), 5 μg/0.1 ml sesame oil (EB5) or 10 μg/0.1 ml sesame oil (EB10)) or vehicle (sesame oil, 0.1 ml). Approximately 2 h after each injection, animals were trained daily on the T-maze with an initial delay of 10 s (short delay). Following a month with no treatment animals were re-trained at a 40 s delay (long delay). Days to reach criterion (one error per day for three consecutive days), mean total errors, errors across days, change in performance across training (short subtracted from long delay), and latency to reach goal arm, were scored. At the short delay, there was a weak effect for the low dose of estradiol (EB0.3 low-to-medium physiological) to significantly decrease the number of working memory errors compared to controls. However at the longer delay the higher doses of estradiol EB5 (high physiological) and to a lesser extent EB10 (suupraphysiological) significantly increased the number of working memory errors compared to controls. These data demonstrate the differential effect of estradiol during short and long delays on prefrontal cortex dependent working memory. High levels of estradiol impair PFC-dependent working memory at longer delays, while low level estradiol weakly facilitates PFC-dependent working memory at a shorter delay. These data suggest that estradiol’s facilitatory effects on working memory may not be mediated through the PFC, while estradiols inhibitory effects on working memory may be mediated at least in part through the PFC. [Copyright &y& Elsevier]

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 17β-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 17β-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. [ABSTRACT FROM AUTHOR]