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Sex-dependent effects of maternal corticosterone and SSRI treatment on hippocampal neurogenesis across… Gobinath, Aarthi R; Workman, Joanna L; Chow, Carmen; Lieblich, Stephanie E; Galea, Liisa A M Jun 2, 2017

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RESEARCH Open AccessSex-dependent effects of maternalcorticosterone and SSRI treatment onhippocampal neurogenesis acrossdevelopmentAarthi R. Gobinath1, Joanna L. Workman2,4, Carmen Chow3, Stephanie E. Lieblich3 and Liisa A. M. Galea1,2,3*AbstractBackground: Postpartum depression affects approximately 15% of mothers and represents a form of early lifeadversity for developing offspring. Postpartum depression can be treated with prescription antidepressants likefluoxetine (FLX). However, FLX can remain active in breast milk, raising concerns about the consequences ofneonatal FLX exposure. The hippocampus is highly sensitive to developmental stress, and males and femalesrespond differently to stress at many endpoints, including hippocampal plasticity. However, it is unclear howdevelopmental exposure to FLX alters the trajectory of hippocampal development. The goal of this study was toexamine the long-term effects of maternal postpartum corticosterone (CORT, a model of postpartum depression)and concurrent FLX on hippocampal neurogenesis in male and female offspring.Methods: Female Sprague-Dawley rat dams were treated daily with either CORT or oil and FLX or saline frompostpartum days 2–23. Offspring were perfused on postnatal day 31 (pre-adolescent), postnatal day 42 (adolescent),and postnatal day 69 (adult). Tissue was processed for doublecortin (DCX), an endogenous marker of immatureneurons, in the dorsal and ventral hippocampus.Results: Maternal postpartum CORT reduced density of DCX-expressing cells in the dorsal hippocampus ofpre-adolescent males and increased it in adolescent males, suggesting that postpartum CORT exposuredisrupted the typical progression of the density of DCX-expressing cells. Further, among offspring of oil-treateddams, pre-adolescent males had greater density of DCX-expressing cells than pre-adolescent females, andmaternal postpartum CORT prevented this sex difference. In pre-adolescent females, maternal postpartum FLXdecreased the density of DCX-expressing cells in the dorsal hippocampus compared to saline. As expected,maternal CORT reduced the density of DCX-expressing cells in adult female, but not male, offspring. The combinationof maternal postpartum CORT/FLX diminished density of DCX-expressing cells in dorsal hippocampus regardlessof sex or age.Conclusions: These findings reveal how modeling treatment of postpartum depression with FLX alters hippocampalneurogenesis in developing offspring differently depending on sex, predominantly in the dorsal dentate gyrus andearlier in life.Keywords: Postpartum corticosterone, Fluoxetine, Doublecortin, Sex differences, Hippocampus, SSRIs, Neurogenesis,Dentate gyrus, Postpartum depression* Correspondence: lgalea@psych.ubc.ca1Program in Neuroscience, University of British Columbia, 2215 WesbrookMall, Vancouver, BC V6T 1Z3, Canada2Department of Psychology, University of British Columbia, 2136 West Mall,Vancouver, BC V6T 1Z4, CanadaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Gobinath et al. Biology of Sex Differences  (2017) 8:20 DOI 10.1186/s13293-017-0142-xBackgroundEarly life adversity can impose detrimental effects on theneurobiological outcome of the developing child. One ofthe most potent mediators of early health is quality ofmaternal care. Maternal mood disorders, such as post-partum depression (PPD), can disrupt the mother–infantbond as well as negatively affect maternal caregivingbehaviors (reviewed in [1]). For this reason, PPD maybe considered a form of early life adversity. The adverseeffects of untreated PPD include increased risk for de-pression among adolescent boys and girls ([2]—propor-tion of children of mothers with depression [3]— incomparison to children of mothers with no history ofdepression), propensity for violent behavior ([4] —incomparison to children of mothers without depression),and lower IQ scores ([5] —meta-analysis). However,treating PPD is complicated by the poorly understoodconsequences of neonatal exposure to prescribed anti-depressants such as selective serotonin reuptake inhibi-tors (SSRIs). In some studies, there are either minimalor positive effects of maternal SSRI exposure observedin children. For example, neonatal SSRI exposure hadminimal impact on body weight [6] and enhanced lan-guage development in comparison to no exposure toSSRIs [7]. Additionally, children with neonatal SSRIexposure exhibited fewer behavior problems (hyper-activity and inattention) than children of mothers withuntreated depression [8]. However, maternal SSRI usehas been linked to delayed psychomotor developmentin infants [9], increased internalizing behavior in chil-dren (i.e., behaviors predisposing anxiety and depres-sion; [10]), and a higher risk for autism spectrumdisorders in children [11]. These findings may be con-sistent with preclinical findings from our laboratorythat maternal postpartum fluoxetine (FLX) exposure in-creased anxiety-like behavior in young adult male off-spring [12]. However, as in the clinical literature,preclinical research has yielded mixed results regardingmaternal SSRI exposure on offspring outcome depend-ing on whether a model of concurrent maternal depres-sion was used, sex of the offspring studied, and ageexamined (reviewed in [13]). To this end, this studyaims to contribute a better understanding of howmaternal SSRI exposure in a rat model of PPD affectsmale and female development (specifically hippocampalneurogenesis) at three different ages.The hippocampus is highly sensitive to the effectsof stress and stress hormones (i.e., glucocorticoids)throughout the lifespan, including during early devel-opment (reviewed in [14]). After parturition, postnatalhippocampal neurogenesis (from birth until weaning;approximately 21 days) is necessary to develop thehippocampus into its fully matured form. In fact, 85%of granule cells forming the dentate gyrus are bornduring this postnatal period [15]. After this developmentalperiod, the structural matrix of the dentate gyrus isformed, but the subgranular zone of the dentate gyruscontinues to generate new neurons throughout the life-span. Different forms of early life adversity can affectneurogenesis in the dentate gyrus during the postnatalperiod (maternal deprivation; [16]), adolescence (prenatalstress; [17]), and adulthood (maternal deprivation; [18,19]). Doublecortin (DCX) is an endogenous, microtubule-associated protein important for neuronal migration [23]that is most highly expressed early in development andprogressively tapers off throughout development and intoadulthood. Early life adversity can disrupt this pattern ofexpression across the lifespan.Given the well-established sex differences in stress re-sponses (reviewed in [22]), it is perhaps not surprisingthat sex is an important factor in mediating the effectsof early life adversity on hippocampal neurogenesis. Forexample, an acute bout of maternal deprivation (24 hon postnatal day 3) increased the density of DCX-expressing cells in pre-adolescent male rats but de-creased it in pre-adolescent female rats [16]. However,by adulthood, this paradigm of maternal deprivationdecreased the density of immature neurons in male rats[18] but had no significant effect in females, suggestingthat density of DCX-expressing cells had recovered infemales [19]. However, longer periods of maternal separ-ation (3 h/day) for the first two postnatal weeks transi-ently reduce DCX-positive cells at the end of maternalseparation in male rat pups [20]. These findings indicatethat early adversity via maternal deprivation had age-and sex-specific influences on neurogenesis throughoutdevelopment, particularly in males. Notably, early lifeadversity does not always lead to a suppressive effect onneurogenesis but rather can alter the time course ofneurogenesis over the lifespan in dynamic ways. How-ever, a singular bout of maternal deprivation moreclosely models acute and severe neglect and does notmodel the voluntary and diminished quality of maternalcare observed with PPD. PPD is associated with pro-longed periods of disengaged maternal care, which in-cludes neutral affect and withdrawal from the infant andsometimes negative maternal care, which includes nega-tive affect and hostility directed to the infant (reviewedin [21]). The maternal neglect modeled by maternal sep-aration/deprivation [16, 19, 20] therefore does not ap-proximate the prolonged diminished quality of maternalcare that occurs in PPD but rather, represents abruptcessation of maternal care. Thus, one of the goals of thepresent study is to examine how postnatal adversity rele-vant to PPD (i.e., sustained reductions in maternal careand higher maternal glucocorticoid levels) affects hippo-campal neurogenesis from post-weaning to adult stagesof development in both sexes.Gobinath et al. Biology of Sex Differences  (2017) 8:20 Page 2 of 13To investigate the effects of PPD on offspring develop-ment and neurogenesis, we used a rodent model of PPD.In this model, dams are treated daily with high levels ofcorticosterone (CORT) to induce a PPD-like phenotype,thus capitalizing on the well-established relationship be-tween glucocorticoids and depression, including peri-natal depression (reviewed in [14]). Treating postpartumrats with CORT consistently increases time spent awayfrom the nest and reduces time spent nursing withoutcompletely absolutely depriving the pups of any mater-nal care [23–25]. Although other models of depressionexist in the literature, such as chronic unpredictablestress, these paradigms applied in the postpartumwould either force the dam to be away from her pups(making it difficult to distinguish the effects of maternalseparation from maternal “depression”). Or, if pupswere kept with the dam during stress exposure, thiswould directly inflict stress on the pups themselves(making it difficult to distinguish the effects of directpostnatal stress from maternal “depression”). Unlikethese models, the CORT-induced model of PPD in-duces depressive-like behavior with minimal separationof the dams from the offspring (<1 min to perform in-jections) and results in the dam voluntarily withdrawingfrom her offspring as well as higher levels of CORT inthe milk [25, 38], which mimic key features of PPD inwomen (reviewed in [21]). When examining the off-spring outcome, maternal postpartum CORT decreasedhippocampal cell proliferation in males, but not fe-males, just after weaning [24]. By adolescence, however,maternal postpartum CORT did not significantly affectsurvival of new cells produced at weaning in either sex[24]. However, whether these early reductions in cellproliferation perturbed neurogenesis (differentiationinto new neurons) at the time of weaning or later in lifewere not determined. The present study aims to ad-dress this gap by examining how maternal CORTexposure affects density of immature neurons in thehippocampus after weaning as well as in adolescenceand adulthood in both sexes.In contrast to the body of research examining develop-mental stress and its effects on the hippocampus, thereis limited research evaluating how developmental FLXexposure affects the hippocampus. Treating dams withFLX in the postpartum reversed the suppressive effect ofprenatal stress on hippocampal DCX-expressing cells inboth adolescent male and female offspring [17]. How-ever, this interaction between prenatal stress and post-partum FLX exposure did not persist to adulthood asmaternal postpartum FLX decreased number of DCX-expressing cells in offspring also exposed to prenatalstress, particularly in the males [29]. We recently re-ported that FLX given to the dam during the postpartumperiod increased density of DCX-expressing cells in thedorsal hippocampus of adult male offspring but not inadult female offspring [12]. It remains unclear, however,whether maternal postpartum FLX, either alone or incombination with CORT alters hippocampal neurogen-esis across development in a rodent model relevant toPPD. To investigate this, we administered high CORT todams to induce a depression-like phenotype [24, 25, 27,28] as well as FLX to model antidepressant treatment ofpostpartum CORT in dams [28]. While there has beenconsiderable investigation of how stress affects hippo-campal neurogenesis in the early developmental periods(prenatal and postnatal) as well as in later ages (adulthoodand aging), relatively little is known about how hippocam-pal neurogenesis proceeds through pre-adolescent andadolescent time periods. Moreover, how developmentalexposure to CORT and/or FLX affects the neurogenic tra-jectory in the hippocampus is also poorly understood.Thus, we investigated male and female offspring afterweaning (pre-adolescence), in adolescence, and in adult-hood. We hypothesized maternal postpartum CORT andFLX would alter the time course of hippocampal neuro-genesis throughout development differently in males andfemales, and that both treatments could potentiallyinteract such that FLX may prevent disruptions thatarise following maternal postpartum CORT exposure.More specifically, we predicted that males would bemore sensitive to CORT and FLX than females, giventhe established literature demonstrating that males aremore vulnerable to early life adversity in a variety ofendpoints (reviewed in [14]).MethodsAnimalsThirty-two adult female Sprague-Dawley rats (2–3 monthsold) and 16 adult male Sprague-Dawley rats (2–3 monthsold, Charles River) were initially housed in same-sexpairs with aspen chip bedding in the Centre for DiseaseModeling at University of British Columbia. Rats weremaintained in a 12:12 h light/dark cycle (lights on at7:00 am) and given rat chow (Jamieson’s Pet FoodDistributors Ltd, Delta, BC, Canada) and tap water adlibitum. All protocols were in accordance with ethicalguidelines set by Canada Council for Animal Care andwere approved by the University of British ColumbiaAnimal Care Committee.Breeding proceduresFor breeding, two females and one male were paireddaily between 5:00 and 7:00 pm. Females were vaginallylavaged each morning between 7:30 and 9:30 am. Uponidentification of sperm in the lavage sample, femaleswere considered pregnant, weighed, and single housedinto clean cages with autoclaved paper towels and anenrichment tube.Gobinath et al. Biology of Sex Differences  (2017) 8:20 Page 3 of 13Maternal treatments1 day after birth (birth day = postnatal day 0), all litterswere culled to 5 males and 5 females. If there were notenough males or females in one litter, pups were cross-fostered from a dam that gave birth the same day. Ifthere were not enough pups available to support a fivemale and five female litters, then dams maintained asex-skewed or smaller litters (this happened twice withboth being in the CORT/saline group). Dams were ran-domly assigned to one of four treatment groups: (1) oil/saline; (2) oil/FLX; (3) CORT/saline; (4) CORT/FLX.Beginning on postpartum day 2, dams received dailyinjections of either subcutaneous CORT (40 mg/kg) orsesame oil (1 ml/kg). Dams also received a secondinjection of either intraperitoneal FLX (10 mg/kg) orsaline (1 ml/kg). Injections occurred daily for 22 con-secutive days. The effects of maternal postpartumCORT/saline on depressive-like behavior and maternalbehavior were verified in the dam, and data about theeffects of maternal postpartum CORT and FLX onserum CORT levels in dams as well as body mass ofdams and pre-weaning offspring have been publishedseparately [28]. Dams received both injections in suc-cession between 11am and 2 pm.Drug preparationAn emulsion of CORT (Sigma-Aldrich, St. Louis, MO,USA) was prepared every 2–3 days by mixing CORTwith ethanol and then adjusting with sesame oil to yielda final concentration of 40 mg/ml of CORT in oil with10% ethanol. The dose was chosen because it reliablyinduces a depressive-like phenotype in dams, disruptsmaternal care, and affects offspring development [23,24]. To control for CORT, vehicle injections consistedof 10% ethanol in sesame oil (referred to as “oil”). FLX(Sequoia Research Products, Pangbourne, UK) was pre-pared every 2–3 days by dissolving in dimethyl sulfox-ide (DMSO; Sigma Aldrich) and adjusted with 0.9%saline to yield a final concentration of 10 mg/ml FLX insaline with 10% DMSO. This dose of FLX was chosenbased on work illustrating that this dose increasedbrain derived neurotrophic factor and cell proliferationin the hippocampus and amygdala after 21 days of in-jections in both male and female rodents [30]. To con-trol for FLX, vehicle injections consisted of 10% DMSOin 0.9% saline.Offspring tissue collectionFor the pre-adolescent offspring, pups remained group-housed with litter mates until perfusion. For the ado-lescent and adult offspring, pups were weaned onpostnatal day 24 and pair-housed with an unrelated,same-sex cage mate whose mother received the sametreatment. Besides weekly cage changing, offspringremained undisturbed until perfusion. Based on thefour maternal treatments described above, rats wereused from each of the following groups were utilizedat pre-adolescence, adolescence, and adult time points(n = 124): male oil/saline offspring, n = 5–7; male oil/FLX offspring, n = 5; male CORT/saline offspring, n =5; male CORT/FLX offspring, n = 5; female oil/salineoffspring, n = 5; female oil/FLX offspring, n = 5; femaleCORT/saline offspring, n = 5; female CORT/FLX off-spring, n = 5.Pre-adolescent offspring were perfused on postnatalday 31. Adolescent offspring were perfused on postnatalday 42 because this time point is considered to be mid-adolescence [31–33]. Adult offspring were perfused onpostnatal day 69. On the day of perfusion, rats wereweighed and then given an overdose of Euthanyl (so-dium pentobarbital). Rats were perfused with 60 mlcold 0.9% saline followed by 120 ml cold 4% parafor-maldehyde. Brains were extracted and post-fixed using4% paraformaldehyde overnight at 4 °C. Brains werethen transferred to 30% sucrose in phosphate buffer at4 °C until they sank to the bottom. Brains were rapidlyfrozen with dry ice, were sectioned using a freezingmicrotome (Leica, Richmond Hill, ON, Canada) at40 μm, and were collected in series of 10. Sections werestored in antifreeze (ethylene glycol/glycerol; Sigma)and were stored at −20 °C until processing. For an over-view of experimental procedures, refer to Fig. 1.Fig. 1 Timeline of experiment. (not to scale)Gobinath et al. Biology of Sex Differences  (2017) 8:20 Page 4 of 13DCX immunohistochemistrySections were rinsed 5 × 10 min in 0.1 M phosphate-buffered saline (PBS), were treated with 0.3% hydrogenperoxide in dH2O for 30 min, and were incubated at 4 °C in primary antibody solution: 1:1000, goat anti-DCX(Santa Cruz Biotechnology, Santa Cruz, CA, USA) with0.04% Triton-X in PBS, and 3% normal rabbit serum for24 h. Sections were then rinsed 5 × 10 min in 0.1 M PBSand were transferred to a secondary antibody solutionwith 1:500, rabbit anti-goat (Vector Laboratories, Burling-ton, ON, Canada) in 0.1 M PBS for 24 h at 4 °C. Then,sections were washed 5 × 10 min in 0.1 M PBS and wereincubated in ABC complex (ABC Elite Kit; 1:1000; Vector)for 4 h. Sections were then washed in 0.175 M sodiumacetate buffer 2 × 2 min. Finally, sections were developedusing diaminobenzidine in the presence of nickel (DABPeroxidase Substrate Kit, Vector), mounted on slides, anddried. Sections were then dehydrated and coverslippedwith Permount (Fisher Scientific).DCX-expressing cells were quantified in 3 dorsal sec-tions (−2.76 to −4.68 mm below bregma) and 3 ventralsections (−5.52 to −6.60 mm below bregma) using the ×40objective using an Olympus CX22LED brightfield micro-scope. Areas of these sections were quantified usingImageJ (NIH, Bethesda, MD, USA) and were used fordensity calculations (number of cells per mm2).Data analysesData were analyzed using repeated measures ANOVAwith hippocampal region (dorsal, ventral) as the within-subject factor and age, sex, maternal postpartum CORT,and maternal postpartum FLX as between-subject fac-tors. Newman-Keuls tests were conducted for post-hoccomparisons which controls for multiple pair-wise com-parisons in a step-wise fashion. Because we had hypoth-eses that sex, CORT, and FLX would interact, a prioricomparisons were conducted and subjected to Bonfer-roni corrections. All data were analyzed using Statisticasoftware (v. 9, StatSoft, Inc., Tulsa, OK, USA). All effectswere considered statistically significant if p ≤ 0.05.Results and discussionOur statistical analysis was a comprehensive five-wayANOVA which generated 31 possible main effects andinteractions. Of these possibilities, ten main and inter-acting effects were statistically significant, with threemain effects (age, sex, and region), four two-way interac-tions (age × sex, age × CORT, region × age, area × CORT),two three-way interactions (region × CORT × FLX, andregion × age × CORT), and finally the four-way interaction(region × age × sex × CORT). There was also a trend fora four-way interaction (region × age × sex × FLX) andlimited comparisons were conducted. These significantinteractions are summarized in Table 1.Maternal postpartum CORT altered the density ofDCX-expressing cells depending on age, sex, andhippocampal sub-region (interaction between region,age, sex, and maternal postpartum CORT)Maternal postpartum CORT decreased the density ofDCX-expressing cells in the dorsal hippocampus of pre-adolescent males in comparison to oil [p < 0.001, Cohen’sd = 0.83; area, age, sex, and maternal postpartum CORTinteraction: F (2, 98) = 4.59, p = 0.01; Fig. 2a). Amongoil-exposed offspring, pre-adolescent males had a greaterdensity of DCX-expressing cells in comparison to pre-adolescent females in dorsal hippocampus (p < 0.001,Cohen’s d = 1.37). Maternal postpartum CORT exposureprevented this sex difference in pre-adolescent offspring(p = 0.06; Fig. 2a, b). Further, maternal postpartum CORTincreased the density of DCX-expressing cells in thedorsal hippocampus of both adolescent male and femaleoffspring compared with oil (males: p = 0.003, Cohen’s d =2.18; females: p = 0.023, Cohen’s d = 1.98; Fig. 2a, b). Inour prior study [12] we observed that maternal postpar-tum CORT, regardless of FLX, decreased density of dorsalDCX-expressing cells in female offspring, and an a prioricomparison revealed the same result in this dataset (p =0.019, Cohen’s d = 0.91). Maternal postpartum CORTsignificantly increased the density of DCX-expressingcells in the ventral hippocampus of adolescent malesTable 1 Summary of statistical interactionsSignificant effects from omnibus ANOVA p valueInteraction between region, age, sex, and maternal postpartum CORTDorsal hippocampus Pre-adolescent ♂: oil > CORT p < 0.001♀: oil vs. CORT n.s.Adolescent ♂: oil < CORT p= 0.03♀: oil < CORT p = 0.02Adult ♂: oil vs. CORT n.s.♀: oil > CORT p = 0.02Ventral hippocampus Pre-adolescent ♂: oil vs. CORT n.s.♀: oil vs. CORT n.s.Adolescent ♂: oil < CORT p = 0.003♀: oil vs. CORT n.s.Adult ♂: oil vs. CORT n.s.♀: oil vs. CORT n.s.Interaction between region, age, sex, and maternal postpartum FLXDorsal hippocampus Pre-adolescent ♂: saline vs. FLX n.s.♀: saline < FLX p = 0.003Interaction between region, maternal postpartum CORT, and FLXDorsal hippocampus CORT/saline > CORT/FLX p = 0.035Oil/FLX > CORT/FLX p = 0.041Ventral hippocampus Oil/FLX < CORT/FLX p = 0.032CORT corticosterone, FLX fluoxetine, n.s., non-significant. Significant comparisonsare in italicsGobinath et al. Biology of Sex Differences  (2017) 8:20 Page 5 of 13compared with oil (p = 0.003, Cohen’s d = 1.35; Fig. 2c)but not in females (p = 0.95; Fig. 2d).Density of DCX-expressing cells declined frompre-adolescence to adolescence except in the ventralhippocampus of CORT-exposed females (interactionbetween region, age, sex, and maternal postpartum CORT)The density of DCX-expressing cells in the dorsal hippo-campus decreased from pre-adolescence to adolescenceregardless of sex or CORT exposure (p’s < 0.04, Cohen’sd = 0.66–3.31; Fig. 2a, b). In the ventral hippocampus ofmales, the density of DCX-expressing cells decreasedfrom pre-adolescence to adolescence in oil- and CORT-exposed rats (p’s < 0.04, Cohen’s d = 0.86–1.97; Fig. 2c).In females, the density of DCX-expressing cells in theventral hippocampus did not change significantly frompre-adolescence to adolescence in oil- or CORT-exposedrats (p’s > 0.08; Fig. 2d). There were no other significantmain effects or interactions.Maternal postpartum CORT prevented the increasein density of DCX-expressing cells from adolescenceto adulthood in the dorsal hippocampus (interactionbetween region, age, sex, and maternal postpartumCORT)The density of DCX-expressing cells in the dorsalhippocampus increased from adolescence to adult-hood in oil-exposed males (p = 0.046, Cohen’s d =1.75) and females (p < 0.001, Cohen’s d = 2.71). Thisage-related increase, however, was not present inCORT-treated males (p = 0.92) or females (p = 0.84).The density of DCX-expressing cells in the ventralhippocampus decreased from adolescence to adult-hood in CORT-exposed males (p < 0.001, Cohen’s d =3.07), but not oil-exposed males (p = 0.26). The dens-ity of DCX-expressing cells in the ventral hippocam-pus decreased from adolescence to adulthood in oil-exposed females (p = 0.009; Cohen’s d = 1.95), but notCORT-exposed females (p = 0.17).Fig. 2 Mean + SEM density of DCX-expressing cells/mm2 in A–D. a In dorsal hippocampus, maternal postpartum CORT decreased the density ofDCX-expressing cells in pre-adolescent males and increased it in adolescent males compared with oil. Males of oil-treated dams also had a greaterdensity of DCX-expressing cells compared with females of oil-treated dams. b In the dorsal hippocampus of adolescent females, maternal postpartumCORT increased the density of DCX-expressing cells compared with oil. However, in adulthood, maternal postpartum CORT decreased the densityof DCX-expressing cells in females. c In the ventral hippocampus of adolescent males, maternal postpartum CORT increased the density ofDCX-expressing cells compared with oil. d In the ventral hippocampus of females, maternal postpartum CORT did not significantly alter thedensity of DCX-expressing cells. @p < 0.05, males vs. females; *p < 0.05, oil vs. CORT; n = 5–7/sex/groupGobinath et al. Biology of Sex Differences  (2017) 8:20 Page 6 of 13Maternal postpartum FLX decreased the density of DCX-expressing cells in dorsal hippocampus of pre-adolescentfemale but not male offspring (interaction betweenregion, age, sex, and maternal postpartum FLX)A priori comparisons revealed that maternal postpartumFLX decreased the density of DCX-expressing cells incomparison to saline in the dorsal hippocampus of pre-adolescent females (p = 0.003, Cohen’s d = 0.58; Fig. 3b)but not males [p = 0.45; area, age, sex, and maternal post-partum FLX interaction: F (2, 98) = 2.74; p = 0.069; Fig. 3a].Additionally, among offspring exposed to maternal post-partum saline, pre-adolescent males had a greater densityof DCX-expressing cells than pre-adolescent females inthe dorsal hippocampus (p = 0.008, Cohen’s d = 0.47).Maternal postpartum FLX prevented the increase indensity of DCX-expressing cells from adolescence toadulthood in dorsal hippocampus of females (interactionbetween region, age, sex, and maternal postpartum FLX)In the dorsal hippocampus, density of DCX-expressingcells increased from adolescence to adulthood amongsaline-exposed females (p = 0.003, Cohen’s d = 1.36) butnot FLX-exposed females (p = 0.273). In the ventralhippocampus, density of DCX-expressing cells decreasedsimilarly in offspring regardless of sex or FLX exposure(p’s <0.01, Cohen’s d = 1.23–2.48). No other comparisonswere statistically significant after performing Bonferronicorrections.Maternal postpartum CORT and FLX decreased thedensity of DCX-expressing cells in dorsal hippocampus,but increased it in ventral hippocampus (interactionbetween region, CORT, and FLX)Regardless of age and sex, maternal postpartum CORTand FLX decreased the density of DCX-expressing cellsin the dorsal hippocampus compared with CORT alone(p = 0.035, Cohen’s d = 0.41) and with FLX alone [p =0.041, Cohen’s d = 0.36; area, CORT, and FLX interaction:F (1, 98) = 13.787, p = 0.003; Fig. 4a]. In the ventral hippo-campus, the combination of maternal postpartum CORTand FLX increased the density of DCX-expressing cellscompared to FLX exposure alone (p = 0.032, Cohen’sd = 0.44; Fig. 4b).Males weighed more than females in adolescence andadulthoodMale offspring weighed more than female offspring inadolescence (p < 0.001, Cohen’s d = 2.03) and adulthood(p < 0.001, Cohen’s d = 5.58) but not as pre-adolescents(p = 0.532; interaction between age and sex: F (2, 85) =105.78; p < 0.001; Table 2). There were no other signifi-cant main effects of or interactions between age, sex,maternal postpartum CORT, or maternal postpartumFLX (all p’s > 0.21).DiscussionHere, we show that maternal postpartum CORT andFLX affected density of DCX-expressing cells in malesand females differently from pre-adolescence to earlyadulthood and that the dorsal hippocampus was moresensitive than the ventral hippocampus to these mater-nal treatments. Consistent with our hypothesis, maternalpostpartum CORT predominantly affected males early inlife such that it reduced the density of dorsal DCX-expressing cells in pre-adolescent males and increaseddensity of dorsal DCX-expressing cells in adolescentmales as well as females. On the other hand, maternalpostpartum FLX predominantly affected females earlierin life as it decreased density of DCX-expressing cellsin pre-adolescent females in the dorsal hippocampusFig. 3 Mean + SEM density of DCX-expressing cells/mm2 in a, b. a Maternal postpartum FLX did not significantly alter the density of DCX-expressingcells in male offspring. b In pre-adolescent female offspring, maternal postpartum FLX decreased the density of DCX-expressing cells in thedorsal hippocampus compared with SAL. There were no other significant effects of sex, CORT, or FLX in ventral hippocampus. *p < 0.05, salinevs. FLX; n = 5–7/sex/groupGobinath et al. Biology of Sex Differences  (2017) 8:20 Page 7 of 13and attenuated the age-related increase in density ofDCX-expressing cells from adolescence to adulthood.Regardless of age and sex, maternal postpartum CORTand FLX decreased density of DCX-expressing cells indorsal hippocampus and increased density of DCX-expressing cells in ventral hippocampus. Furthermore,maternal postpartum CORT reduced the density ofDCX-expressing cells in adult females, consistent withprevious findings [12]. Collectively, these findings revealthat maternal postpartum CORT and FLX can impactdensity of DCX-expressing cells earlier in the lifespan inmales and females whereas the combination of CORTand FLX may have more general effects on density ofDCX-expressing cells regardless of age and sex.Maternal postpartum CORT decreased density of DCX-expressing cells in pre-adolescent males and adultfemales but increased density of DCX-expressing cellsin adolescent offspringMaternal postpartum CORT decreased density of DCX-expressing cells in the dorsal hippocampus of pre-adolescent male but not female offspring. By adolescence,maternal postpartum CORT generally enhanced density ofDCX-expressing cells in both sexes (sub-region differencesare further discussed below). However, by adulthood,the effect of maternal postpartum CORT was no longerapparent in males but it reduced density of DCX-ex-pressing cells in females. This extends previous workwith this model which found that maternal postpartumCORT diminished hippocampal cell proliferation only inpre-adolescent males but not in females whereas mater-nal postpartum CORT did not affect survival of thesecells produced post-weaning [24]. The detrimental effectof maternal postpartum CORT on density of DCX-expressing cells in males is in line with broad findingsthat males are more susceptible to adverse outcomesafter perinatal complications and to neurodevelopmentaldisorders such as autism spectrum disorder (reviewed in[14, 34, 35]). Further, this CORT-induced reduction inneurogenesis is in line with findings that postnatal stressis associated with reductions in hippocampal neurogenesisand plasticity [18, 19, 36]. This reduction in neurogenesismay be related to disruption of the stress hyporesponsiveperiod, an important period in postnatal developmentcharacterized by low levels of endogenous glucocorticoidlevels which promotes optimal neural development [37].Maternal postpartum CORT treatment can disrupt thisperiod of quiescent glucocorticoid activity either indirectlyvia decreased maternal care [23, 28] or directly via in-creased CORT levels in the brain, serum, and stomachmilk of the offspring [38]. Either mechanism could reduceneurogenesis after weaning. However, little is knownabout sex differences in the stress hyporesponsive period.There is some evidence that adrenocorticotropic hormoneis capable of eliciting CORT secretion in female pups butnot male pups during the stress hyporesponsive period[39, 40]. Additionally, female rat pups (20 days old) havehigher basal CORT levels but blunted cold stress-inducedFig. 4 Mean + SEM density of DCX-expressing cells/mm2 in a, b. a Maternal postpartum CORT and FLX decreased the density of DCX-expressingcells in the dorsal hippocampus compared with CORT only and FLX only. b In the ventral hippocampus, maternal postpartum CORT and FLXincreased the density of DCX-expressing cells in comparison to maternal postpartum FLX only. *p < 0.05. CORT/FLX vs. CORT only or FLXonly; n = 5–7/sex/groupTable 2 Body mass (g) ± SEM. Males had a greater body massthan females in both adolescence and adulthood but not aspre-adolescentsPre-adolescent Adolescent AdultMale–oil/SAL 122.2 ± 0.8 250.0 ± 7.3* 524.7 ± 12.6@Male–oil/FLX 130.7 ± 9.0 248.2 ± 8.0* 529.4 ± 20.3@Male–CORT/SAL 118.7 ± 10.4 236.0 ± 5.9* 543.3 ± 24.8@Male–CORT/FLX 112.6 ± 9.2 234.6 ± 17.5* 553.0 ± 38.3@Female–oil/SAL 118.4 ± 1.5 195.8 ± 5.3 307.7 ± 10.2Female–oil/FLX 120.0 ± 2.6 159.0 ± 24.1 300.0 ± 10.8Female–CORT/SAL 111.0 ± 6.1 186.4 ± 10.1 327.0 ± 16.0Female–CORT/FLX 106.0 ± 10.2 190.4 ± 5.5 308.0 ± 13.7*p < 0.05, adolescent males vs. adolescent females; @p < 0.05, adult males vs.adult femalesGobinath et al. Biology of Sex Differences  (2017) 8:20 Page 8 of 13CORT levels than males [41]. However, it is not clear howthese sex differences in ontogeny of the HPA axis are re-lated to hippocampal neurogenesis. It should be notedthat although pre-adolescent females did not exhibitany changes in density of DCX-expressing cells, it re-mains possible that other measures of neurogenesisand/or plasticity were altered after maternal postpar-tum CORT exposure.Interestingly, we found that maternal postpartumCORT increased density of DCX-expressing cells inadolescent offspring. In general, chronic stress or gluco-corticoid exposure reduces hippocampal neurogenesis[42], but most of these studies have been conducted inrodents shortly after birth or in adulthood. Relative toeither of these time points, there is a substantial gap inour understanding of neurogenesis in adolescence.Neurogenesis reaches peak levels in the rat dentate gyruson postnatal day 6 and declines with age [43]. However,the relationship between the cells produced post-weaningand the cells that continually regenerate later in life hasyet to be fully elucidated. One possible explanation for theincrease in adolescent density of DCX-expressing cells isthat it is a compensatory mechanism for a loss in plasticityafter maternal postpartum CORT exposure to ultimatelynormalize density of DCX-expressing cells by adulthoodunder cage control conditions. Alternatively, neurogenesiscontinues outside of the dentate gyrus during puberty inthe prefrontal cortex, nucleus accumbens, anteroventralperiventricular nucleus, medial amygdala, and sexually di-morphic nucleus [44, 45]. Thus, another possible explan-ation is that the effect of maternal postpartum CORTincreasing density of DCX-expressing cells in adolescenceis part of a system-wide change in neurogenesis that willultimately contribute to altered brain development. Fur-thermore, synaptic pruning is a critical developmentalprocess that occurs throughout the brain throughout de-velopment including adolescence. It is important to notethat a reduction in synaptic plasticity is a normal and ne-cessary component to brain maturation. Thus, we cautionagainst interpreting that the enhancing effect of maternalpostpartum CORT on offspring density of DCX-expressing cells is favorable or beneficial for brain devel-opment because it is possible that maternal postpartumCORT disturbed this important culling process and re-sulted in aberrant density of DCX-expressing cells. Or,as discussed above, increased density of DCX-expressingcells could be a compensatory mechanism to promotedensity of DCX-expressing cells during adolescence afterit was reduced in pre-adolescence. Alternatively, the op-posing effects between pre-adolescence and adolescencemay be influenced by the different housing conditions aspre-adolescent subjects were group-housed and adoles-cent subjects were pair-housed. There is some evidencethat group housing versus isolation can influenceneurogenesis in middle-aged rats [46] but not youngadult male mice [47]. Nonetheless, housing differencesbetween pre-adolescence and adolescence may be acontributing factor to the observed differences betweenthese ages. Regardless of housing conditions, adoles-cence is a critical developmental period that deservesfurther research.Maternal postpartum CORT decreased the density ofDCX-expressing cells in dorsal hippocampus of adult fe-males but did not affect density of DCX-expressing cellsin adult males. This observation in adult females is con-sistent with our prior study [12] which examined adultmale and female offspring and changes in neurogenesisafter a battery of behavioral tests and exposure to dexa-methasone. Thus, despite the repeated behavioral andendocrine challenges, present and prior studies indicatethat maternal postpartum CORT reduced neurogenesisin adult females regardless of basal conditions (thepresent study) or challenging conditions (i.e., stress and/or novelty; [12]). Given the relationship between neuro-genesis in the hippocampus and depression [48], thedecreased neurogenesis in adult females exposed tomaternal postpartum CORT may be related to the in-creased basal levels of serum CORT observed in adultfemale but not male offspring in this model [26]. Indeed,reductions in hippocampal neurogenesis have beenmechanistically linked to abnormalities in the HPAaxis at least in male mice [49]. This connection betweenendocrine and neural endophenotypes of depressionmay partly explain the propensity for depression in girlsof mothers with depression [50]. Although the functionalsignificance of reduced neurogenesis in dorsal hippo-campus is not clear, this observation does indicate thatfemale offspring are vulnerable to the effects of maternalpostpartum CORT, and, unlike male offspring, manifestlater in life. Collectively, these findings emphasize bothpre-adolescence and adolescence as critical periods formaternal postpartum CORT effects on density of DCX-expressing cells in male offspring whereas the effects ofmaternal postpartum CORT on female neurogenesisemerge later in life during adolescence and adulthood.Maternal postpartum FLX decreased density of DCX-expressing cells in pre-adolescent femalesMaternal postpartum FLX decreased density of DCX ex-pressing cells in dorsal hippocampus of pre-adolescentfemales, although this finding had only a medium effectsize. This is particularly interesting because our previousfindings indicated that males were more vulnerable thanfemales to the effects of maternal postpartum FLX treat-ment in terms of anxiety-like behavior and HPA axisdysregulation [12]. However, our present findings indi-cate that females are also vulnerable to the effects of ma-ternal postpartum FLX early in life and that these effectsGobinath et al. Biology of Sex Differences  (2017) 8:20 Page 9 of 13manifest differently than in males. This female-specificvulnerability to maternal SSRI exposure early in develop-ment has also been observed in clinical research with ma-ternal SSRI exposure reducing reelin expression inumbilical cord serum in female infants but not in male in-fants [51]. Based on the current state of research, themechanism explaining early female vulnerability to mater-nal fluoxetine exposure is unclear. A lower dose of mater-nal postpartum FLX (5 mg/kg; s.c.) delays pubertal onsetin female rats [55] and increases sexual behavior in adultfemale rats [57]. Thus, maternal postpartum FLX can im-pact development of female endocrine physiology whichcould alter hippocampal plasticity. It should be noted thatdifferent studies using a lower dose of FLX (5 mg/kg;s.c.) in dams found that maternal postpartum FLX hasno effect on density of DCX-expressing cells in males orfemales at weaning [56], in adolescence [17], or in adult-hood ([58]; only males examined). This suggests thatonly higher doses of FLX alter density of DCX-expressing cells in pre-adolescent offspring. Althoughthe mechanism underlying how different doses of mater-nal postpartum FLX account for endocrine disturbancesand hippocampal neurogenesis is not clear, maternalpostpartum FLX can impact neurogenesis in pre-adolescent female offspring and highlights that bothsexes need to be studied in this field of research.Maternal postpartum CORT and FLX together decreaseddensity of DCX-expressing cells in dorsal but increaseddensity of DCX-expressing cells in the ventral hippocampusin male and female offspringMaternal postpartum FLX also potentiated the effects ofmaternal postpartum CORT, demonstrating that devel-opmental FLX can interact with a model relevant forPPD to affect offspring density of DCX-expressing cells.This finding also underscores the importance of studyingthe effects of antidepressant exposure within a diseasemodel. Maternal postpartum CORT and concurrentFLX increased density of DCX-expressing cells in theventral hippocampus. This bolstering effect of maternalpostpartum FLX is in line with numerous studies ob-serving treatment of adult rats with FLX increasesneurogenesis [59, 60]. Interestingly, maternal postpar-tum CORT and concurrent FLX also resulted in adecreased density of dorsal DCX-expressing cells.Although treating adult rodents with FLX typically in-creases hippocampal neurogenesis, the present studyutilized a different route of FLX exposure (i.e., via themother during postnatal development) which affectsthe brain differently than adult exposure.This effect of maternal postpartum CORT and concur-rent FLX reducing density of DCX-expressing cells indorsal hippocampus is different from [12] which foundthat maternal postpartum CORT/FLX yielded opposingeffects in the dorsal hippocampus of males and femalesundergoing behavioral testing. In our previous study[12], after a battery of behavioral tests and exposure todexamethasone, maternal postpartum CORT and FLXincreased dorsal density of DCX-expressing cells in adultmales, and this increase was not observed in the presentstudy. The difference in the methods and results be-tween the present and prior studies indicate that neuro-genesis varies from basal conditions (the present study)to challenging conditions (i.e., stress and/or novelty;[12]) particularly in males. DCX is expressed for up to21 days after new neurons are produced [52], and thebehavioral testing and dexamethasone exposure mayhave interacted with developmental exposure to CORT/FLX to affect the number of DCX-expressing cells. Fur-thermore, other studies demonstrate that experience,such as Morris water maze or radial arm maze training,alters measures of hippocampal plasticity that are notobserved in cage controls ([53, 54], respectively). Col-lectively, this suggests that some of the effects of mater-nal postpartum CORT/FLX exposure on offspringhippocampal neurogenesis may not necessarily resolveby adulthood, but rather emerge after a challenge tothe system (i.e., behavioral testing and/or dexametha-sone exposure) as shown in our previous study. Thesefindings indicate that concurrent maternal postpartumCORT and FLX will impact neurogenesis differently de-pending on experience with perhaps a greater impact inmales than females. This set of observations has note-worthy functional implications regarding what maternalantidepressant use means within the context of mater-nal postpartum stress/depression. In considering use ofrat models, it should be noted that the first 10 days ofthe postpartum period are equivalent to the third tri-mester [61, 62]. Nonetheless, it would be important forfuture studies to characterize the behavioral implica-tions of maternal postpartum FLX exposure in bothsexes at different time points.Dorsal versus ventral hippocampus: maternal postpartumCORT and/or FLX affect density of immature neuronsrespond differently depending on sub-regionIn the present study, we found that neurogenesis in thedorsal hippocampus was more sensitive to maternaltreatments with CORT or FLX than in the ventralhippocampus and that when concurrent of both drugshad opposing effects in dorsal and ventral hippocampusregardless of age or sex. The hippocampus is a heteroge-neous structure with differences along the dorsal-ventralhippocampal axis in terms of function, gene expression,and neurotransmission (reviewed in [63]). The dorsal-ventral axis of the hippocampus is present even at day ofbirth [64] although its function is best understood in theadult brain. Generally, dorsal hippocampus is associatedGobinath et al. Biology of Sex Differences  (2017) 8:20 Page 10 of 13with learning and spatial navigation, and the ventralhippocampus is associated with stress regulation andaffective behavior (reviewed in [63]). However, thesefunctional roles are not exclusive in each pole of thehippocampus as dorsal hippocampus has been impli-cated in anxiety-behavior [65] and ventral hippocampushas been implicated in memory [66].Interestingly, maternal postpartum CORT and FLXspecifically (albeit independently) affected dorsal but notventral hippocampus in the pre-adolescent offspring. Inthe adolescent offspring, maternal postpartum CORTaffected the density of DCX-expressing cells in both dor-sal and ventral hippocampus. However, in adult males,neither maternal postpartum CORT nor FLX alone sig-nificantly altered density of DCX-expressing cells in thedorsal or ventral hippocampus. Thus, one possibility isthat the effects of maternal CORT and FLX treatmenton ventral hippocampus were apparent under conditionswhen the HPA axis was in the process of maturing. In-deed, HPA axis reaches full maturity between P42 andP49 [33]. Thus, the effects in ventral hippocampus dens-ity of DCX-expressing cells alterations being present inadolescence may be reflective of maternal exposure toCORT and/or FLX interacting with the immature stressand gonadal hormone systems. As previously discussed,Gobinath et al. [12] found that maternal postpartumCORT alone and maternal postpartum FLX alone in-creased density of DCX-expressing cells, and this in-crease was selectively in the dorsal hippocampus ofadult male rats. The functional implications of maternalpostpartum CORT and FLX in pre-adolescent and ado-lescent offspring on behavior and neurogenesis are cur-rently unknown, but these data indicate that outcomesduring these earlier stages may be different than thoseseen in adulthood. Furthermore, our results indicate thatthe neurogenic potential of the dentate gyrus is alteredwith maternal postpartum exposure to CORT or FLX inboth males and females at different stages in develop-ment, potentially influencing sex differences in risk forpsychiatric disease at different ages.ConclusionsCollectively, these findings highlight that males and fe-males are differentially vulnerable at different time pe-riods during development to the effects of maternalpostpartum CORT and/or maternal postpartum FLX.Maternal postpartum CORT decreased the density ofDCX-expressing cells in pre-adolescent males but in-creased it in both adolescent males and females. Mater-nal postpartum FLX decreased the density of DCX-expressing cells in the dorsal hippocampus of pre-adolescent females but not males. As we have notedpreviously, maternal postpartum CORT decreased thedensity of DCX-expressing cells in the dorsalhippocampus of adult female but not male offspring.However, maternal postpartum FLX did not signifi-cantly affected adult offspring of either sex, suggestingthat the effects present earlier in life were resolved byadulthood at least under cage control conditions. Incontrast, the combination of maternal postpartumCORT and FLX together decreased the density of dorsalDCX-expressing cells and increased it in the ventralhippocampus regardless of age or sex. Thus, the com-bination of maternal postpartum CORT and FLX al-tered the density of DCX-expressing cells regardless ofage and sex whereas each treatment independently im-pacted hippocampal density of DCX-expressing cellsearlier in life depending on sex. These findings yieldimportant implications for maternal antidepressant usein treating PPD and developmental outcome and high-light that early postnatal environments can differen-tially affect both sexes.AbbreviationsCORT: Corticosterone; DCX: Doublecortin; FLX: Fluoxetine; P: Postnatal day;PPD: Postpartum depression; SAL: SalineAcknowledgementsThe authors would like to thank Lucille Hoover, Nikki Kitay, Paula Duarte-Guterman, Robin Richardson, and Christine Ausman for their assistance andcontributions throughout the experiment.FundingThis work was funded by a CIHR operating grant to LAMG (IGO-103692)and a Coast Capital Depression Fund to JLW and LAMG. The findings andconclusions of this manuscript do not necessarily represent the views ofthe Canadian Institutes of Health Research or Coast Capital.Availability of data and materialsThe datasets generated and/or analyzed during the current study areavailable from the corresponding author on reasonable request.Authors’ contributionsARG contributed to the study conception and experimental design, conductedthe immunohistochemistry, performed the data collection (quantification ofdoublecortin expression), statistical analysis, and drafted the manuscript. JLWassisted with study conception and experimental design and assisted withperforming the immunohistochemistry and critical revision of the manuscript.CC and SL assisted with experimental design, assisted with performing theimmunohistochemistry, and provided critical revision of the manuscript. LAMGcontributed to the study conception and experimental design, supervised, andhelped with statistical analysis, data interpretation, and critical revision of themanuscript. All authors read and approved the final manuscript.Authors’ informationNot applicable.Competing interestsThe authors declare that they have no competing interests.Consent for publicationNot applicable.Ethics approval and consent to participateAll protocols were in accordance with ethical guidelines set by CanadaCouncil for Animal Care and were approved by the University of BritishColumbia Animal Care Committee.Gobinath et al. Biology of Sex Differences  (2017) 8:20 Page 11 of 13Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Program in Neuroscience, University of British Columbia, 2215 WesbrookMall, Vancouver, BC V6T 1Z3, Canada. 2Department of Psychology, Universityof British Columbia, 2136 West Mall, Vancouver, BC V6T 1Z4, Canada. 3Centrefor Brain Health, University of British Columbia, 2215 Wesbrook Mall,Vancouver, BC V6T 1Z3, Canada. 4Present Address: Department ofPsychology, University at Albany, State University of New York, 1400Washington Ave., Albany, NY 12222, USA.Received: 13 February 2017 Accepted: 25 May 2017References1. Brummelte S, Galea LA. Postpartum depression: etiology, treatment andconsequences for maternal care. Horm Behav. 2016;77:153–66.2. Pilowsky DJ, Wickramaratne PJ, Rush AJ, Hughes CW, Garber J, Malloy E,King CA, Cerda G, Sood AB, Alpert JE, et al. 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J Neurosci. 1993;13:3916–25.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Gobinath et al. Biology of Sex Differences  (2017) 8:20 Page 13 of 13


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