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ABSTRACT Chronic stress or chronically high glucocorticoids attenuate adult hippocampal neurogenesis by reducing cell proliferation, survival, and differentiation in male rodents. Neurons are still produced in the dentate gyrus during chronically high glucocorticoids, but it is not known whether these new neurons are appropriately activated in response to spatial memory. Thus, the goal of this study was to determine whether immature granule neurons generated during chronically high glucocorticoids (resulting in a depressive-like phenotype) are differentially activated by spatial memory retrieval. Male Sprague Dawley rats received either 40 mg/kg corticosterone (CORT) or vehicle for 18 days prior to behavioral testing. Rats were tested in the forced swim test (FST) and then tested in a spatial (hippocampus-dependent) or cued (hippocampus-independent) Morris Water Maze. Tissue was then processed for doublecortin (DCX) to identify immature neurons and zif268, an immediate early gene product. As expected, CORT increased depressive-like behavior (greater immobility in the FST) however, prior CORT modestly enhanced spatial learning and memory compared with oil. Prior CORT reduced the number of DCX-expressing cells and proportion of DCX-expressing cells colabeled for zif268, but only in the ventral hippocampus. Prior CORT shifted the proportion of cells in the ventral hippocampus away from postmitotic cells and toward immature, proliferative cells, likely due to the fact that postmitotic cells were produced and matured during CORT exposure but proliferative cells were produced after high CORT exposure ceased. Compared with cue training, spatial training slightly increased DCX-expressing cells and shifted cells toward the postmitotic stage in the ventral hippocampus. These data suggest that the effects of CORT and spatial training on immature neurons are more pronounced in the ventral hippocampus. Further, high CORT reduced activation of immature neurons, suggesting that exposure to high CORT may have long-term effects on cell integration or function. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT Cannabinoid exposure during adolescence has adverse effects on neuroplasticity, emotional behavior, cognition, and reward sensitivity in adult rats. We investigated whether escalating doses of the cannabinoid receptor 1 (CB1R) agonist, HU-210, in adolescence would affect adult hippocampal neurogenesis and behavioral processes putatively modulated by hippocampal neurogenesis, in adult male and female Sprague-Dawley rats. Escalating doses of HU-210 (25, 50, and 100 µg/kg), or vehicle were administered from postnatal day (PND) 35 to 46. Animals were left undisturbed until PND 70, when they were treated with 5-bromo-2-deoxyuridine (BrdU; 200 mg/kg) and perfused 21 days later to examine density of BrdU-ir and BrdU/NeuN cells in the dentate gyrus. In another cohort, hypothalamic-pituitary-adrenal (HPA) axis reactivity to an acute restraint stress (30 min; PND 75) and behavioral sensitization to d-amphetamine sulfate (1-2 mg/kg; PND 105-134) were assessed in adulthood. Adolescent HU-210 administration suppressed the density of BrdU-ir cells in the dentate gyrus in adult male, but not adult female rats. Adolescent HU-210 administration also induced significantly higher peak corticosterone levels and reminiscent of the changes in neurogenesis, this effect was more pronounced in adult males than females. However, adolescent cannabinoid treatment resulted in significantly higher stereotypy scores in adult female, but not male, rats. Thus, adolescent CB1R activation suppressed hippocampal neurogenesis and increased stress responsivity in adult males, but not females, and enhanced amphetamine sensitization in adult female, but not male, rats. Taken together, increased CB1R activation during adolescence results in sex-dependent, long-term, changes to hippocampal structure and function, an effect that may shed light on differing vulnerabilities to developing disorders following adolescent cannabinoid exposure, based on sex. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

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

Pregnancy and mothering result in a number of hormonal, neurological, and behavioral changes that are necessary to ensure reproductive success. With subsequent reproductive experience (multiparity and mothering), further neurological and behavioral changes may result. Recent research has shown that previous motherhood enhances both hippocampus-dependent learning and memory and long-term potentiation (LTP); together with decreases in hippocampus volumes during pregnancy it is suggested that the hippocampus is affected by pregnancy and/or mothering. The present experiment aimed to investigate the effect of reproductive experience (nulli, primi-, and multiparity and mothering) on dendritic morphology in the CA1 and CA3 regions of the hippocampus. Brains were stained with a modified version of the single-section Golgi impregnation technique, and dendritic length, number of branch points, and spine density was analyzed for apical and basal regions of CA1 and CA3 pyramidal neurons. Primiparity and/or mothering resulted in dendritic remodeling in both the CA1 and CA3 hippocampal regions, and multiparity resulted in enhanced spine density in the basal CA1 region, which was positively correlated with number of male pups in a litter. These findings point to the effect of reproductive experience and offspring on plasticity in the hippocampus, an area not traditionally associated with motherhood. © 2005 Wiley Periodicals, Inc. J Neurobiol, 2006 [ABSTRACT FROM AUTHOR]

Examines developmental, neural and hormonal aspects of sexually dimorphic spatial learning in meadow voles (Microtus pennsylvanicus) and deer mice (Peromyscus maniculatus). Breeding status and spatial learning in adult deer mice; Effects of reproductive status on spatial learning in female meadow voles; Effect of juvenile age; Effect of litter sex-ratio.

Menopause is associated with cognitive decline, and hormone therapies (HTs) may improve cognition depending on type and timing of HTs. Previous parity may influence cognition in later life. We investigated how primiparity and long-term ovariectomy influence cognition, neurogenesis, hormones, cytokines, and neuronal activation in middle-aged rats in response to Premarin, an HT. Nulliparous and primiparous rats were sham-ovariectomized or ovariectomized, administered vehicle or Premarin 6 months later, and all rats were trained in the Morris water maze. Premarin improved early spatial learning and memory in nulliparous rats but impaired early learning in primiparous rats. With training, primiparity increased hippocampal neurogenesis, and Premarin decreased immature neurons, regardless of parity. Moreover, Premarin increased serum tumor necrosis factor α and the CXC chemokine ligand 1 (CXCL1) in trained nulliparous, but not primiparous, rats. However, Premarin decreased the expression of the immediate early gene zif268 in the dorsal CA3 region in primiparous rats after training. Thus, primiparity alters how Premarin affects spatial learning, neuronal activation, and serum cytokines. These findings have implications for the treatment of age-associated cognitive decline in women. [ABSTRACT FROM AUTHOR]

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

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

Depression is more prevalent in women than in men, and women are at a heightened risk for depression during the postpartum and perimenopause. There is also evidence to suggest that the ovarian hormone milieu may dictate antidepressant efficacy. Thus, it is important to investigate the role of ovarian hormones in the pathogenesis of depression and in the mechanisms that may underlie antidepressant efficacy. In the present study, we used 10-month-old female Sprague-Dawley rats to examine the effects of long-term ovarian hormone deprivation on the development of depressive-like endophenotypes after chronic stress, and on antidepressant efficacy. Four months following ovariectomy (OVX) or sham surgery, all rats were subjected to 6 weeks of chronic unpredictable stress (CUS). During the last 3 weeks of CUS, rats received daily injections of fluoxetine (5 mg/kg) or vehicle. All rats were assessed on measures of anxiety- and depressive-like behavior, hypothalamic-pituitary-adrenal (HPA) negative feedback inhibition, and on markers of neurogenesis and microglia in the dentate gyrus. Our findings demonstrate that long-term ovarian hormone deprivation increased anxiety and depressive-like behavior, as seen by increased immobility in the forced swim test and latency to feed in the novelty suppressed feeding test, and decreased sucrose preference. Further, long-term OVX resulted in impaired HPA negative feedback inhibition, as seen in the dexamethasone suppression test. Fluoxetine treatment showed limited behavioral and neuroendocrine efficacy, however it reduced microglial (Iba-1) expression, and increased cell proliferation, neurogenesis (via cell survival), and the expression of the polysialylated neuronal cell adhesion molecule (PSA-NCAM) in the dentate gyrus, although these effects varied by region (dorsal, ventral) and ovarian status. Taken together, our findings demonstrate that ovarian hormones may impart resilience against the behavioral and neuroendocrine consequences of chronic unpredictable stress, and may modulate the effects of fluoxetine on cell proliferation, neurogenesis, and PSA-NCAM in the middle-aged female. [ABSTRACT FROM AUTHOR]

The postpartum confers considerable risk for developing depression. Depressed patients have elevated cortisol concentrations and impaired hypothalamic-pituitary-adrenal (HPA) axis negative feedback. Chronic stress or corticosterone (CORT) induces a depressive-like phenotype in rodents, including during the postpartum. The present study examined whether nulliparous and postpartum rats were differentially vulnerable to chronic high CORT and whether fluoxetine (FLX) would differentially alter the brain, behavior, and neuroendocrine function depending on reproductive experience. Nulliparous and postpartum female Sprague–Dawley rats were divided into 4 groups that received 21 d of injections of CORT or oil plus FLX or saline. CORT reduced maternal behaviors whereas FLX reversed CORT-induced decreases in maternal care. CORT increased immobility in the forced swim test (FST), but FLX did not significantly alter immobility in either nulliparous or postpartum rats. Dams spent less time immobile and had lower CORT concentrations after the FST compared with nulliparae, indicating that aspects of the postpartum period may provide resilience against a depressive-like phenotype. Both CORT and parity reduced neurogenesis (doublecortin expression) in the dentate gyrus. FLX-treated rats had lower CORT concentrations following the FST and more immature neurons, but only in the nulliparous, and not postpartum, groups. These data suggest that the postpartum may inherently protect against some deleterious effects of high CORT but also confer resistance to the neurogenic and endocrine effects of FLX. Our findings are important for understanding how females in different reproductive states respond to glucocorticoids and antidepressants. [ABSTRACT FROM AUTHOR]

Hypogonadal men are more likely to develop depression, while testosterone supplementation shows antidepressant-like effects in hypogonadal men and facilitates antidepressant efficacy. Depression is associated with hypothalamic–pituitary–adrenal (HPA) axis hyperactivity and testosterone exerts suppressive effects on the HPA axis. The hippocampus also plays a role in the feedback regulation of the HPA axis, and depressed patients show reduced hippocampal neuroplasticity. We assessed the antidepressant-like effects of testosterone with, or without, imipramine on behavioral and neural endophenotypes of depression in a chronic unpredictable stress (CUS) model of depression. A 21-day CUS protocol was used on gonadectomized male Sprague–Dawley rats treated with vehicle, 1 mg of testosterone propionate, 10 mg/kg of imipramine, or testosterone and imipramine in tandem. Testosterone treatment reduced novelty-induced hypophagia following CUS exposure, but not under non-stress conditions, representing state-dependent effects. Further, testosterone increased the latency to immobility in the forced swim test (FST), reduced basal corticosterone, and reduced adrenal mass in CUS-exposed rats. Testosterone also facilitated the effects of imipramine by reducing the latency to immobility in the FST and increasing sucrose preference. Testosterone treatment had no significant effect on neurogenesis, though the combination of testosterone and imipramine increased PSA-NCAM expression in the ventral dentate gyrus. These findings demonstrate the antidepressant- and anxiolytic-like effects of testosterone within a CUS model of depression, and provide insight into the mechanism of action, which appears to be independent of enhanced hippocampal neurogenesis. [ABSTRACT FROM AUTHOR]

This article is part of a Special Issue “Estradiol and Cognition”. There are sex differences in hippocampus-dependent cognition and neurogenesis suggesting that sex hormones are involved. Estrogens modulate certain forms of spatial and contextual memory and neurogenesis in the adult female rodent, and to a lesser extent male, hippocampus. This review focuses on the effects of sex and estrogens on hippocampal learning, memory, and neurogenesis in the young and aged adult rodent. We discuss how factors such as the type of estrogen, duration and dose of treatment, timing of treatment, and type of memory influence the effects of estrogens on cognition and neurogenesis. We also address how reproductive experience (pregnancy and mothering) and aging interact with estrogens to modulate hippocampal cognition and neurogenesis in females. Given the evidence that adult hippocampal neurogenesis plays a role in long-term spatial memory and pattern separation, we also discuss the functional implications of regulating neurogenesis in the hippocampus. [ABSTRACT FROM AUTHOR]

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

Summary Chronic alcohol consumption negatively affects health, and has additional consequences if consumption occurs during pregnancy as prenatal alcohol exposure adversely affects offspring development. While much is known on the effects of prenatal alcohol exposure in offspring less is known about effects of alcohol in dams. Here, we examine whether chronic alcohol consumption during gestation alters maternal behavior, hippocampal neurogenesis and HPA axis activity in late postpartum female rats compared with nulliparous rats. Rats were assigned to alcohol, pair-fed or ad libitum control treatment groups for 21 days (for pregnant rats, this occurred gestation days 1–21). Maternal behavior was assessed throughout the postpartum period. Twenty-one days after alcohol exposure, we assessed doublecortin (DCX) (an endogenous protein expressed in immature neurons) expression in the dorsal and ventral hippocampus and HPA axis activity. Alcohol consumption during pregnancy reduced nursing and increased self-directed and negative behaviors, but spared licking and grooming behavior. Alcohol consumption increased corticosterone and adrenal mass only in nulliparous females. Surprisingly, alcohol consumption did not alter DCX-expressing cell density. However, postpartum females had fewer DCX-expressing cells (and of these cells more immature proliferating cells but fewer postmitotic cells) than nulliparous females. Collectively, these data suggest that alcohol consumption during pregnancy disrupts maternal care without affecting HPA function or neurogenesis in dams. Conversely, alcohol altered HPA function in nulliparous females only, suggesting that reproductive experience buffers the long-term effects of alcohol on the HPA axis. [ABSTRACT FROM AUTHOR]

Summary: Effects of prenatal alcohol exposure (PAE) on central nervous system function include an increased prevalence of mental health problems, including substance use disorders (SUD). The hypothalamic–pituitary–adrenal (HPA) and dopamine (DA) systems have overlapping neurocircuitries and are both implicated in SUD. PAE alters both HPA and dopaminergic activity and regulation, resulting in increased HPA tone and an overall reduction in tonic DA activity. However, effects of PAE on the interaction between HPA and DA systems have not been investigated. The present study examined PAE effects on basal regulation of central stress and DA systems in key brain regions where these systems intersect. Adult Sprague-Dawley male and female offspring from prenatal alcohol-exposed (PAE), pairfed (PF), and ad libitum-fed control (C) groups were subjected to chronic variable stress (CVS) or remained as a no stress (non-CVS) control group. Corticotropin releasing hormone (CRH) mRNA, as well as glucocorticoid and DA receptor (DA-R) expression were measured under basal conditions 24h following the end of CVS. We show, for the first time, that regulation of basal HPA and DA systems, and likely, HPA–DA interactions, are altered differentially in males and females by PAE and CVS. PAE augmented the typical attenuation in weight gain during CVS in males and caused increased weight loss in females. Increased basal corticosterone levels in control, but not PAE, females suggest that PAE alters the profile of basal hormone secretion throughout CVS. CVS downregulated basal CRH mRNA in the prefrontal cortex and throughout the bed nucleus of the stria terminalis (BNST) in PAE females but only in the posterior BNST of control females. PAE males and females exposed to CVS exhibited more widespread upregulation of basal mineralocorticoid receptor mRNA throughout the hippocampus, and an attenuated decrease in DA-R expression throughout the nucleus accumbens and striatum compared to CVS-exposed control males and females. Overall, these findings enhance our understanding of PAE effects on the cross-talk between HPA and DA systems, and provide insight into possible mechanisms underlying mental health problems that are related to stress and DA signaling, including SUD, which have a high prevalence among individuals with FASD. [Copyright &y& Elsevier]

Summary: Adult hippocampal neurogenesis is often associated with hippocampus-dependent learning and memory. Throughout a new neuron's development, it is differentially sensitive to factors that can influence its survival and functionality. Previous research shows that spatial training that occurred 6–10 days after an injection of the DNA synthesis marker, bromodeoxyuridine (BrdU), increased cell survival in male rats. Because sex differences in spatial cognition and hippocampal neurogenesis have been reported, it is unclear whether spatial training would influence hippocampal neurogenesis in the same way in males and females. Therefore, this study examined sex differences in hippocampal neurogenesis following training in a spatial task. Male and female rats were trained in the spatial or cued version of the Morris water maze 6–10 days after one injection of BrdU (200mg/kg). Twenty days following BrdU injection, all animals were given a probe trial and perfused. Males performed better in the spatial, but not cue, task than females. Spatial training increased BrdU-labeled cells relative to cue training only in males, but both males and females showed greater activation of new cells (BrdU co-labeled with immediate early gene product zif268) after spatial training compared to cue training. Furthermore, performance during spatial training was positively correlated with cell activation in females but not males. This study shows that while spatial training differentially regulates hippocampal neurogenesis in males and females, the activity of new neurons in response to spatial memory retrieval is similar. These findings highlight the importance of sex on neural plasticity and cognition. [ABSTRACT FROM AUTHOR]

Abstract: Reproductive experiences in females comprise substantial hormonal and experiential changes and can exert long lasting changes in cognitive function, stress physiology, and brain plasticity. The goal of this research was to determine whether prior reproductive experience could alter a prefrontal–cortical dependent form of learning (strategy set shifting) in an operant box. In this study, female Sprague–Dawley rats were mated and mothered once or twice to produce either primiparous or biparous dams, respectively. Age-matched nulliparous controls (reproductively-naïve females with no exposure to pup cues) were also used. Maternal behaviors were also assessed to determine whether these factors would predict cognitive flexibility. For strategy set shifting, rats were trained in a visual-cue discrimination task on the first day and on the following day, were required to switch to a response strategy to obtain a reward. We also investigated a simpler form of behavioral flexibility (reversal learning) in which rats were trained to press a lever on one side of the box the first day, and on the following day, were required to press the opposite lever to obtain a reward. Estrous phase was determined daily after testing. Neither parity nor estrous phase altered total errors or trials to reach criterion in either the set-shifting or reversal-learning tasks, suggesting that PFC-dependent cognitive performance remains largely stable after 1 or 2 reproductive experiences. However, parity and estrous phase interacted to alter the frequency of particular error types, with biparous rats in estrus committing more perseverative but fewer regressive errors during the set-shifting task. This suggests that parity and estrous phase interfere with the ability to disengage from a previously used, but no longer relevant strategy. These data also suggest that parity alters the behavioral sensitivity to ovarian hormones without changing overall performance. [Copyright &y& Elsevier]

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

Abstract: Prenatal alcohol exposure (PAE) alters adult neurogenesis and the neurogenic response to stress in male rats. As the effects of stress on neurogenesis are sexually dimorphic, the present study investigated the effects of PAE on adult hippocampal neurogenesis under both nonstressed and stressed conditions in female rats. Pregnant females were assigned to one of three prenatal treatments: (1) alcohol (PAE)—liquid alcohol (ethanol) diet ad libitum (36% ethanol-derived calories); (2) pair-fed—isocaloric liquid diet, with maltose–dextrin substituted for ethanol, in the amount consumed by a PAE partner (g/kg body wt/day of gestation); and (3) control—lab chow ad libitum. Female offspring were assigned to either nonstressed (undisturbed) or stressed (repeated restraint stress for 9days) conditions. On day 10, all rats were injected with bromodeoxyuridine (BrdU) and perfused either 24hours (cell proliferation) or 3weeks (cell survival) later. We found that PAE did not significantly alter cell proliferation or survival, whereas females from the pair-fed condition exhibited elevated levels of cell survival compared to control females. Importantly, however, the proportion of both new neurons and new glial cells in the hippocampal dentate gyrus was reduced in PAE compared to control females. Exposure to stress did not alter neurogenesis in any of the prenatal treatment groups. In summary, compared to females from the control condition, prenatal dietary restriction enhanced the survival of new neurons, whereas PAE altered the differentiation of newly produced cells in the adult dentate gyrus. Alterations in hippocampal neurogenesis following PAE may contribute to learning and memory deficits seen in individuals with fetal alcohol spectrum disorders. [Copyright &y& Elsevier]

Perinatal depression (PND) affects 15% of mothers. Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line of treatment for PND but are not always efficacious. Previously, we found significant reductions in plasma tryptophan concentrations and higher hippocampal proinflammatory cytokine, IL-1β levels, due to maternal SSRI treatment. Both inflammation and tryptophan-kynurenine metabolic pathway (TKP) are associated with SSRI efficacy in individuals with major depressive disorder (MDD). TKP is divided into neuroprotective and neurotoxic pathways. Higher metabolite concentrations of the neurotoxic pathway are associated with depression onset and implicated in SSRI efficacy. Metabolites in TKP were investigated in a rodent model of de novo postpartum depression (PPD) given treatment with the SSRI, fluoxetine (FLX). Dams were administered corticosterone (CORT) (40 mg/kg, s.c.), and treated with the SSRI, fluoxetine (FLX) (10 mg/kg, s.c.), during the postpartum for 22 days after parturition. Plasma TKP metabolite concentrations were quantified on the last day of treatment. Maternal postpartum CORT increased neurotoxic metabolites and co-enzyme/cofactors in dams (3-hydroxykynurenine, 3-hydroxyanthranilic acid, vitamin B2, flavin adenine dinucleotide). The combination of both CORT and FLX shifted the neuroprotective-to-neurotoxic ratio towards neurotoxicity. Postpartum FLX decreased plasma xanthurenic acid concentrations. Together, our data indicate higher neurotoxic TKP expression due to maternal postpartum CORT treatment, similar to clinical presentation of MDD. Moreover, maternal FLX treatment showed limited efficacy to influence TKP metabolites, which may correspond to its limited efficacy to treat depressive-like endophenotypes in the postpartum. Overall suggesting changes in TKP may be used as a biomarker of de novo PPD and antidepressant efficacy and targeting this pathway may serve as a potential therapeutic target. • Tryptophan-kynurenine pathway (TKP) is altered by postpartum corticosterone (CORT). • Postpartum CORT increased neurotoxic metabolites (3-HK, 3-HAA). • Postpartum fluoxetine (FLX) increased xanthurenic acid concentrations. • Postpartum CORT and FLX together shifted the TKP balance towards neurotoxicity. [ABSTRACT FROM AUTHOR]

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

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 17β-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 17β-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, 17β-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. • Male rats made more risky choices in the probability discounting task than females. • Gonadectomy (GDX) did not influence risk-based decision making in both sexes. • A high dose of amphetamine enhanced risky choices in intact male and female rats. • 17β-estradiol did not affect risk-based decision making in male or female rats. [ABSTRACT FROM AUTHOR]

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]

The estrogen receptor (ER) mechanisms by which 17β-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 ERβ to the effects of 17β-estradiol under non-stress and chronic stress conditions. Ovariectomized (OVX) or sham-operated mice were treated chronically (47 days) with 17β-estradiol (E2), the ERβ 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. • Ovariectomy increased depressive-like behaviour under non-stress conditions • Estrogen receptor agonists potentiated the inflammatory effects of chronic stress • Chronic stress decreased neurogenesis in the ventral hippocampus only • Estradiol increased neurogenesis in the dorsal hippocampus only [ABSTRACT FROM AUTHOR]