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Molecular Brain. 2019 Mar 18;12(1):22
University of British Columbia. Graduate Program in Neuroscience
Djavad Mowafaghian Centre for Brain Health
The Author(s).
Sheppard, Paul A. S.
Choleris, Elena
Galea, Liisa A. M.
It is well established that estrogens affect neuroplasticity in a number of brain regions. In particular, estrogens modulate and mediate spine and synapse formation as well as neurogenesis in the hippocampal formation. In this review, we discuss current research exploring the effects of estrogens on dendritic spine plasticity and neurogenesis with a focus on the modulating factors of sex, age, and pregnancy. Hormone levels, including those of estrogens, fluctuate widely across the lifespan from early life to puberty, through adulthood and into old age, as well as with pregnancy and parturition. Dendritic spine formation and modulation are altered both by rapid (likely non-genomic) and classical (genomic) actions of estrogens and have been suggested to play a role in the effects of estrogens on learning and memory. Neurogenesis in the hippocampus is influenced by age, the estrous cycle, pregnancy, and parity in female rodents. Furthermore, sex differences exist in hippocampal cellular and molecular responses to estrogens and are briefly discussed throughout. Understanding how structural plasticity in the hippocampus is affected by estrogens and how these effects can influence function and be influenced by other factors, such as experience and sex, is critical and can inform future treatments in conditions involving the hippocampus.
REVIEW Open AccessStructural plasticity of the hippocampus inresponse to estrogens in female rodentsPaul A. S. Sheppard1, Elena Choleris2 and Liisa A. M. Galea1*AbstractIt is well established that estrogens affect neuroplasticity in a number of brain regions. In particular, estrogensmodulate and mediate spine and synapse formation as well as neurogenesis in the hippocampal formation. In thisreview, we discuss current research exploring the effects of estrogens on dendritic spine plasticity and neurogenesiswith a focus on the modulating factors of sex, age, and pregnancy. Hormone levels, including those of estrogens,fluctuate widely across the lifespan from early life to puberty, through adulthood and into old age, as well as withpregnancy and parturition. Dendritic spine formation and modulation are altered both by rapid (likely non-genomic)and classical (genomic) actions of estrogens and have been suggested to play a role in the effects of estrogens onlearning and memory. Neurogenesis in the hippocampus is influenced by age, the estrous cycle, pregnancy, and parityin female rodents. Furthermore, sex differences exist in hippocampal cellular and molecular responses to estrogens andare briefly discussed throughout. Understanding how structural plasticity in the hippocampus is affected by estrogensand how these effects can influence function and be influenced by other factors, such as experience and sex, is criticaland can inform future treatments in conditions involving the hippocampus.Keywords: Neurogenesis, dendritic spines, sex differences, memory, depression, stress, aging, pregnancy, parityIntroductionNumerous investigations in animals and humans havefound sex differences in brain and behaviour [1]. Whilethe underlying impetus of these differences is complexand multi-faceted, differences in sex steroid hormones,particularly estrogens, appear to be of clinical and ex-perimental importance [2]. The manifestation, occur-rence, and/or severity of brain disorders such asAlzheimer’s disease (AD), autism spectrum disorders,depression, and schizophrenia show differences betweenthe sexes [3–7]. Furthermore, many of these same disor-ders show sex differences in severity of hippocampus-dependent cognitive symptoms, with greater severity infemales with AD [6] and depression [8–11], but greaterseverity in males with schizophrenia [7]. Cognitive dis-turbances are likely influenced by disruption to synapticplasticity in the hippocampus and other regions. Thesedifferences are influenced, in part, by estrogens inwomen, but less is known on whether estrogens mayimpact these disorders in men [12–14]. In middle-agedand aged women, treatment with exogenous17β-estradiol – the most bioactive, abundant, and widelyexpressed of the circulating estrogens in most mammals[15] – may reduce the risk of AD [16], lessen the sever-ity of symptoms of depression [17] or schizophrenia[18], and improve cognition in postmenopausal women[19, 20]. Understanding how estrogens can influence thebrain and behaviour is crucial to the development ofsex-targeted treatments for brain diseases.The hippocampus is a brain structure with profoundstructural and functional plasticity evident across thelifespan in humans and rodents. The integrity of thehippocampus is implicated in learning and memory,anxiety, and stress regulation (e.g. [21, 22]). Further-more, the hippocampus is implicated in disease statesthat result in cognitive dysfunction and synaptic func-tion that exhibit sex differences (e.g. autism [5, 23]),schizophrenia [24], depression [25–27], suggestingstudying the influence of hormones on hippocampusmay inform development of targeted and sex-specifictreatments and therapies [5, 28–30].© The Author(s). 2019 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.* Correspondence: liisa.galea@ubc.ca1Department of Psychology, Graduate Program in Neuroscience, DjavadMowafaghian Centre for Brain Health, University of British Columbia,Vancouver, BC V6T 1Z3, CanadaFull list of author information is available at the end of the articleSheppard et al. Molecular Brain (2019) 12:22 https://doi.org/10.1186/s13041-019-0442-7Within the hippocampus, changes in dendritic spinenumber, length, type, and shape may affect neurotrans-mission and, subsequently, behaviour through modula-tion of synapses in predominantly glutamatergicneurons. Neurogenesis – the process of proliferation,migration, differentiation, and survival to maturity ofnovel neurons – allows for new neurons to be integratedinto hippocampal networks and modify hippocampalfunction [31] (Fig. 1c). Both dendritic spine changes[32–34] and neurogenesis [31, 35] exhibit sex differ-ences, respond to estrogens, and allow the hippocampusto maintain plasticity throughout adulthood. Under-standing how sex and/or estrogens can affect structuralplasticity of the hippocampus is crucial to understandingthe functional outcomes of these modifications and topotential future treatments for disorders with hippocam-pal dysfunction (such as AD, depression, and schizo-phrenia). Beyond the differences between the sexes,circulating levels of estrogens in females vary by age andreproductive status [36], during pregnancy and partur-ition [37], and long after reproductive experience [38].As a result, effects of exogenous estrogens (e.g. fromhormone therapies) may also be modulated by thesefactors but are not always taken into account in theliterature.Estrogens and estrogen receptors: A short primerEstrogens can act on estrogen receptors (ERs) withinthe region to elicit changes in structure and function.ERα, ERβ, and the G protein-coupled estrogen recep-tor 1 (GPER1) are found in multiple areas of thebrain, including the hippocampus, and are expressedin varying densities in both sexes [15, 39–41]. Allthree receptors are found in the dorsal and ventralhorns of the hippocampus and within the CA1, CA2,CA3, and dentate gyrus, and are located in the nu-cleus and at extranuclear sites such as the dendrites[39, 40]. It should be noted that estrogens can be se-creted from the ovaries in females and from adiposetissue in both sexes [42], whereas androgens are se-creted from testes in males and from adipose tissueand adrenal cortex in both sexes [43]. However, it isalso important to note that estrogens can be synthe-sized de novo from cholesterol in both sexes in thebrain or be converted from testosterone via aroma-tase [42].Fig. 1 Hippocampal regions, strata, and neurogenesis. a Diagram of the major divisions of the hippocampus. Red box shows region depicted inB. Yellow box shows region depicted in C. b Image of Golgi-Cox stained hippocampal CA1 neurons from OVX female mouse, captured using 10xobjective. Stratum oriens ~40-60% the length of basal dendrite. Stratum radiatum ~30-50% the length of the apical dendrite. Lacunosum-moleculare ~80-100% the length of the apical dendrite. c Diagram depicting the stages of adult neurogenesis in the dentate gyrus. DG, dentategyrus; SO, stratum oriens; SR, stratum radiatum; LM, (stratum) lacunosum-moleculareSheppard et al. Molecular Brain (2019) 12:22 Page 2 of 17The majority of neuroendocrine research has exploredthe effects of 17β-estradiol because it is the most bio-active of the endogenous estrogens in pre-menopausalwomen [44]. To the best of our knowledge, contribu-tions of estrone and estriol to the formation and modu-lation of dendritic spines have not been investigated,though these estrogens may be neuroprotective in cer-tain disease and neurological states (e.g. [45–49]). Whileestrone and estriol are less bioactive than estradiol, theireffects on dendritic spines require future investigation,especially with regards to pregnancy (when circulatingestriol levels increase greatly as a result of placental pro-duction [50]) and post-menopause (when 17β-estradiollevels decline more so than estrone levels leading to es-trone becoming the most abundant of the estrogens[51]), periods in which hippocampal dendritic spinenumbers are increased [52, 53] and decreased (typicallyinvestigated via ovariectomy) [32, 54–56], respectively. Itshould further be mentioned that this review does notcover the effects of phytoestrogens (weak estrogensfound in plants) or endocrine disruptors such asbisphenol-A on dendritic spine density or neurogenesis;however, there is emerging evidence that phytoestrogensmay affect these types of hippocampal plasticity [57–63].In this review, we will discuss how estrogens canaffect structural plasticity of the hippocampus, den-dritic spine morphology and neurogenesis, with the me-diating and modulating factors of sex, age, parity, andpregnancy in females.Estrogens and dendritic spinesDendritic spines are small, membranous protrusionsfrom the dendrites of neurons. These structures expressmany different receptors on their surface and serve asthe primary recipients of excitatory synaptic input in themammalian central nervous system as 90% of excitatorysynapses occur on dendritic spines [64, 65]. The plasti-city of dendritic spines has been suggested to play a rolein motivation, memory, and learning [32, 66]; particu-larly, the growth of novel spines and morphologicalchanges of pre-existing spines can mediate long-termmemory formation [67]. Regional differences exist indendritic spine density (i.e. the number of spines perunit length of dendrite), from highly spiny regions suchas the hippocampus and cortex to spine sparse regionssuch as the hypothalamus [32]. Within the hippocam-pus, spine changes in response to effectors (activity,drugs, surgery, compounds, etc.) can vary dependent onregion of the hippocampus (e.g. dentate gyrus, CA3,CA1). For instance, orchidectomy in male rats increasesdendritic arborization (the degree of branching of thedendrites) in CA3 pyramidal neurons with no effect onthe CA1 dendritic arbor [68]. These subregional differ-ences can also be sex specific. For example, an acutestressor in male rats increased apical CA1 dendriticspine density but decreased it in proestrous females [69].Thus, it is important to keep in mind that there arelikely to be regional and sex differences in response tofactors such as sex hormones.Dendritic spines fall into subtypes based predomin-antly on shape, from stubby, mushroom-shaped maturespines to long, thin, immature spines lacking any sort ofsynaptic terminal enlargement [70, 71]. Although per-haps too simplistic, it has been suggested that thinspines are the “learning” spines while mushroom spinesare the “memory” spines [72, 73]. In this model, thin,learning spines are amenable to experience-inducedmodifications that lead to the formation of new memor-ies. These experience-induced modifications drive thematuration of thin spines into the more stable mushroomand stubby spines that hold synapses. Unfortunately, manystudies investigate the density of dendritic spines but failto report on spine shape (e.g. [74–78]). There is some de-bate on the functional significance of these two measures,that is, whether spine number is as important to behav-iour as the maturation of spines. It is also hotly contestedand debated what the best method of visualization andcategorization of spines should entail [72, 73].It has been known for decades that changes in circu-lating estrogens alter dendritic spine density in variousbrain regions in female rodents [52, 79–83], includingthe hippocampus [54, 55] (Table 1). Across the 4-5 dayestrous cycle of the rat, apical CA1 dendritic spine dens-ity fluctuates by approximately 30%, with the highestdensities coinciding with phases of high circulating es-trogens [32, 55]. Ovariectomy (OVX) decreases thedensity of apical CA1 dendritic spines [54]. This can bereversed by treatment with exogenous estradiol benzoate(EB) [84]. The effect of estradiol, both EB and17β-estradiol (which metabolizes more rapidly than EB[85]), to increase dendritic spines in apical dendrites ofCA1 pyramidal neurons was observed within 24 hours,peaked at 2-3 days, and then gradually declined over thenext 7 days [85]. Progesterone treatment, given subse-quent to estradiol, served to rapidly increase spine dens-ity between 2-6 hours following treatment in OVX rats[85]. Dendritic spine density fell rapidly to baseline levelsthereafter [85]. These findings indicate that ovarian hor-mones can modulate dendritic spine density. Intri-guingly, there are reported differences in hippocampalvolume across the menstrual cycle in women, with men-ses phase associated with lower volume than the preovu-latory surge [86–88]; but see [89] an effect that isechoed across the estrous cycle in mice [90]. It is tempt-ing to speculate that changes in spines may contribute tothese alterations in volume but more studies need to beconducted. Of interest, functional activation patterns arealso altered across the estrous cycle in rodents [91], andSheppard et al. Molecular Brain (2019) 12:22 Page 3 of 17with menstrual cycle [88, 92, 93] and exogenous estradiol[94] in women, suggesting that ovarian hormones modu-late brain activity. Altered activation and volume changesacross the menstrual cycle in women could be caused bythe modulation of spine and synapse dynamics, dendriticarchitecture, and/or neurogenesis in the hippocampus.Table 1 Summary of the effects of estrogens on hippocampal dendritic spine densityReference Model ResultsWoolley et al.,1990Intact female rats CA1 dendritic spine density fluctuates by approx. 30% across estrous cycle;highest densities when circulating estrogens are highest [50]Gould et al.,1990Intact and OVX female rats OVX decreases CA1 dendritic spine density [49]Woolley &McEwen, 1992OVX female rats 2 subcutaneous (s.c.) injections of EB (given 24h apart) reverse CA1 dendritic spine densitydecreases from OVX within 48h following second injection [51]Woolley &McEwen, 1993OVX female rats S.c. EB or 17β-estradiol increases CA1 pyramidal neuron apical dendritic spine density within 24h,peaked at 2-3d, declines over 7d; s.c. progesterone following 17β-estradiol further increased spinedensity for 2-6h but then levels fell quickly to baseline [52]Leranthet al., 2003Intact and GDX male rats GDX reduces CA1 spine synapse density; s.c. testosterone proprionate increases CA1 spinesynapse density in intact males after 2d of treatment; s.c. dihydrotestosterone but not 17β-estradiol increased CA1 spine synapse density in GDX males after 2d of treatment [55]MacLuskyet al., 2004Intact male rats Increases in CA1 dendritic spine density driven by s.c. testosterone are not via aromatization oftestosterone to estrogens [56]MacLuskyet al., 2005OVX female rats S.c. 17β-estradiol increases CA1 spine synapse density within 30min and 4.5h; s.c. 17α-estradiolincreases CA1 spine synapse density within 30min [63]Tsurugizawaet al., 2005Ex vivo hippocampalslices from male rats2h bath in 17β-estradiol or ERα agonist decreased CA3 dendritic excrescence thorns [95]Kinsleyet al., 2006Intact, pregnant, lactating,and OVX female ratsPregnant and lactating rats had greater CA1 dendritic spine density than nulliparous intact rats;nulliparous proestrus intact rats had greater CA1 dendritic spine density than nulliparous diestrusor estrus intact rats; OVX rats given hormonal treatment to mimic pregnancy (17β-estradiol andprogesterone via Silastic implant) had greater CA1 dendritic spine density than OVX controls[135]Murakamiet al., 2006Ex vivo hippocampalslices from male ratsIncreased CA1 stratum oriens or lacunosum-moleculare dendritic spine density following 2h bathin 17β-estradiol or ERα agonist [64]Wallaceet al., 2006Intact and OVX femalerats7wks post-surgery, OVX rats had decreased CA1, but not CA3, dendritic spines compared tointact rats [136]Mukai et al., 2007 Ex vivo hippocampalslices from male ratsIncreased CA1 stratum radiatum dendritic spine density following 2h bath in 17β-estradiolor ERα agonist [65]Phan et al., 2011 OVX female mice S.c. ERα agonist increased CA1 spine density within 40min; s.c. ERβ agonist decreased spinedensity and increased spine length within 40min [38]González-Burgoset al., 2012Intact male rats Injection of tamoxifen or raloxifene (route not specified) increased CA1 dendritic spine density;tamoxifen increased thin- and stubby-type spines whereas raloxifene increased thin-,stubby-, and wide-type spines [93]Phan et al., 2012 OVX female mice S.c. 17β-estradiol increased CA1 dendritic spine length within 40min [39]Velázquez-Zamoraet al., 2012OVX female rats Twice daily treatment (s.c.) with EB increased CA1 dendritic spine density at 3d, but not 10d [125]Gaboret al., 2015OVX female mice S.c. GPER1 agonist increased CA1 dendritic spine density within 40min [41]Phanet al., 2015Ex vivo hippocampal slicesfrom female mice17β-estradiol or ERα agonist increased CA1 dendritic spine density within 30min of bathapplication [40]Jacomeet al., 2016GDX male rats Acute s.c. injection of 17β-estradiol or T increased CA1, but not DG, dendritic spine density30min or 2h following treatment [59]Tuscheret al., 2016OVX female mice Intrahippocampal 17β-estradiol increased CA1 basal and apical dendritic spine density within30min or 2h of treatment; intracerebroventricular 17β-estradiol increased CA1 basal and apicaldendritic spine density within 2h via ERK and mTOR pathways [42]Mendellet al., 2017Intact and OVX female rats,intact and GDX male ratsProestrus intact females had greater CA1 apical dendritic spine densities than metestrus intact orOVX females; proestrus intact females had greater CA3 apical dendritic spine densities than OVXfemales; GDX males had increased CA3 dendritic branching than intact males; OVX had minimaleffects on dendritic branching [32]OVX, ovariectomized; GDX, gonadectomized; EB, estradiol benzoate; ER, estrogen receptor; GPER1, G-protein-coupled estrogen receptor 1; s.c., subcutaneousSheppard et al. Molecular Brain (2019) 12:22 Page 4 of 17In addition to the influence of estrogens in females,dendritic spines in the CA1 region also fluctuate inmales with hormones. Interestingly, long-term changesin dendritic spine density in this region is driven by tes-tosterone [95], but not by aromatization of testosteroneto estradiol [96]. Similarly, androgens, but not estrogens,also upregulate neurogenesis in the dentate gyrus ofadult males [97, 98], as reviewed in a latter section (Es-trogens and neurogenesis). Gonadectomized male ratshave reduced CA1 dendritic spine density when com-pared with intact males, which is recovered by testoster-one propionate or dihydrotestosterone treatment, butnot 17β-estradiol, for 2 days [95, 99]. Testosterone or di-hydrotestosterone rapidly (within 2h) increased in CA1pyramidal neuron dendritic spine density in ex vivo hip-pocampal slices from adult male rats [100]. Similarly, inex vivo hippocampal slices from adult male rats, a 2hbath in 17β-estradiol (1nM) increased dendritic spinedensity in the strata oriens, radiatum, andlacunosum-moleculare of the CA1 [101, 102]. In malerats, both testosterone and 17β-estradiol in vivo alsorapidly increased dendritic spine density in the CA1 re-gion, but not in the dentate gyrus, 30 minutes or 2 hoursfollowing treatment [103]. Collectively, these findingssuggest that estrogens increase dendritic spines in malesonly via rapid mechanisms of action, whereas androgensincrease spines both rapidly and long-term. Differencesbetween long-term and rapid effects of steroid hor-mones, especially estrogens, have been of increasinginterest in recent years [33, 34, 104–106].Acute, exogenous 17β-estradiol or EB substantially(i.e. as much as 50%) increases dendritic spine andsynapse density in both rapid and longer timeframesin the CA1 region of the hippocampus of female ro-dents [74–78, 84, 101–103, 107]. Woolley and McE-wen [84] initially found that losses in dendritic spinedensity following OVX in female rats can be over-come through two 10μg subcutaneous injections ofestradiol benzoate (EB; given 24h apart) when evalu-ated 48h following the second injection. More rapideffects of estrogens have since been observed. Within4.5h of 17β-estradiol treatment in OVX female rats(45μg/kg; a dose previously found to enhance visualand place memory [108]), spine synapse density inthe CA1 was significantly increased [107]. Within 30minutes, either 17β-estradiol (45 or 60μg/kg) or17α-estradiol (15 or 45μg/kg) increased spine synapsedensity in the same model [107]. In OVX femalemice, a single subcutaneous injection of 17β-estradiol(1.5, 2, or 3μg/kg) increased dendritic spine density inCA1 stratum radiatum, but not lacunosum-molecularewithin 40 minutes [75] (see Fig. 1 for hippocampalsubregions). Treatment of 17β-estradiol directly intothe hippocampus of female mice (30 minutes or 2hfollowing 5μg/hemisphere) [78] or to ex vivo hippo-campal slices from female mice (50nM for 20-30 mi-nutes, equivalent to the intrahippocampal dose thatfacilitated social recognition, object recognition, andobject placement in a separate set of mice in thesame study [6.81pg/hemisphere]) [76] rapidly in-creased CA1 dendritic spine density. It is importantto note here that the contribution of these novelspines to behaviour is unknown. Experiments utilizingin vivo estrogen administration almost exclusively(one exception is [109]) used behaviourally naïve ani-mals. Whether these spines are utilized in behaviouror are modulated by behaviour remains, as of yet, tobe determined. While estrogens affect a number ofbehaviours [105, 110, 111], the next section will focuson their effects on hippocampus-dependent learningand memory.Estrogens in the hippocampus: Learning and memoryWhile a causal link between the physiological (e.g. in-crease in dendritic spine density) and behavioural (e.g.facilitation of short-term social recognition memory) hasyet to be proven, many of these effects occur withinsimilar timeframes. Estrogens rapidly increase synapsedensity both in vivo [107] and in vitro [112, 113], suggest-ing that pre-synaptic input (i.e. synaptic transmission toestrogen-treated neurons) may also be involved in the17β-estradiol mediated changes (impairments or enhance-ments) in learning and memory that have beenobserved within the same rapid timeframe (e.g. [75,76, 108, 114–122]). Learning and memory (see [123]for disambiguation of these terms) are not a singularprocess but are comprised of several steps includingencoding, storage, and retrieval of information [72].In brief, typically, learning is considered to be the ac-quisition or encoding of information to memory,whereas memory could be considered the storage andretrieval of information [123]. Memory can be dividedinto many different subtypes (e.g. episodic and se-mantic memory, declarative and non-declarativememory) and there are many reviews written on thesubject (e.g. [124, 125]). One way we find it useful tocategorize memory is working versus reference mem-ory. Reference memory is considered long-term mem-ory for events or stimuli that stay stable over time[126], whereas working memory can be defined astrial-unique information to guide prospective action[127, 128]. Reference memory relies more on the dor-sal hippocampus [129, 130] while working memoryrelies more on the ventral hippocampus (and pre-frontal cortex) [129–132]. Different tasks that rely onthe integrity of the hippocampus can influence refer-ence and working memory to different degrees and,not surprisingly, estrogens can have differentSheppard et al. Molecular Brain (2019) 12:22 Page 5 of 17influences on these different types of learning andmemory. We illustrate a number of tasks mentionedin this review that are used to assess different formsof learning and memory in Fig. 2. It is important tonote that there are different versions of the tasksshown in Fig. 2 and, thus, the descriptions are notexhaustive. A thorough discussion of different formsof memory and how the hippocampus may be in-volved is beyond the scope of this review, but we dir-ect the readers to excellent reviews on this subject[133–136].Crucially, 17β-estradiol given during consolidation/storage can improve memory of a reference memorytask of object recognition or object placement memoryFig. 2 Overview of behavioural tasks affected by estrogens and mentioned in this review. a Object recognition, b) social recognition, and c)object placement tasks take advantage of rodents’ innate preference for novelty. In each of task, a test rodent is presented with stimuli (typicallytwo) to explore during training. Upon test, one stimulus is replaced with a novel stimulus (object/social recognition) or moved to a novellocation. d In conditioned place preference, an animal is rewarded in one of two distinguishable contexts. A probe trial then explores the amountof time spent in the two contexts. e In the social transmission of food preferences, a “demonstrator” animal consumes a novel flavoured diet.They are then paired with an “observer” for an interaction period in which the observer will smell the novel flavoured diet on the demonstrator’sbreath. When given a choice between the flavoured diet smelled on the demonstrator’s breath and another novel diet (both diets are novel tothe observer), an animal with intact social learning will prefer the demonstrator’s diet. f In the win-shift version of the radial arm maze, rodentsare placed in the maze and allowed to enter only a subset of the arms in order to receive rewards. Upon test phases, all arms are open, butrodents are only rewarded at the termini of formerly un-baited arms. Entries into previously baited arms are reference memory errors, whereas re-entry into arms entered during the test phase are working memory errors. Similarly, g) in the working/reference memory radial arm maze task,rodents are repeatedly rewarded in the same arms. Entries into never-baited arms are reference memory errors, whereas re-entries are workingmemory errors. h In the Morris water maze, an animal learns to swim to a hidden platform to escape. Probe trials then evaluate the amount oftime the animal spends swimming in the quadrant previously containing the platformSheppard et al. Molecular Brain (2019) 12:22 Page 6 of 17(tasks that can involve the dorsal hippocampus) 24-48 hafter 17β-estradiol exposure [115–117, 119, 122]. Otherstudies examining performance in the spatial workingreference/memory version or working memory win-shiftversion of the radial arm maze (hippocampus-dependenttasks) show facilitated acquisition at lower doses of EBor impaired acquisition at higher doses of EB [118, 137].Performance in other spatial memory tasks show a similardose response in performance with 17β-estradiol in bothhumans [138] and rodents [139–141]. In addition, sys-temic or intrahippocampal administration of 17β-estradiol15 minutes prior to training in an object, social, or placerecognition task facilitated performance when tested 40minutes later in OVX female mice [74–76]. It is clear that17β-estradiol can facilitate or impair various aspects ofworking and reference memory dependent on dose,course of treatment, when during encoding, consolidation,and/or retrieval 17β-estradiol is given, and the type of task(e.g. what brain areas are recruited during the task). Taskperformance may be influenced by 17β-estradiol’s effectson synaptic plasticity, including influence on dendriticspines, the putative structural and integral compartmentsof learning/memory within the synapse.Estrogens and “two-step wiring plasticity”The combination of 17β-estradiol increasing spines andenhancing memory suggested the idea of “two-step wir-ing plasticity” (also known as “sample and hold” theory[142]; see [66] for a thorough explanation). Briefly, inStep 1, acute application of 17β-estradiol to culturedcortical neurons from embryonic day 18 rats (mixed sex[personal communications]) led to a rapid, transient in-crease in the density of dendritic spines in an extracellu-lar signal-regulated protein kinase (ERK)-dependentmanner, along with the presence of silent synapses (i.e.synapses where the postsynaptic membrane contains fewalpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid (AMPA)-type glutamate receptors) [112]. Followingthis, in Step 2, when N-methyl-D-aspartate (NMDA) re-ceptors were activated, the increases in dendritic spinedensity and silent synapse number persisted up to 24hours [112]. NMDA receptor activation was necessaryfor dendritic spine increases to persist. While this effectwas investigated in cultured embryonic cortical neurons,rapid “two-step wiring plasticity” may be a mechanismby which estrogens can exert their enhancing effects onlearning in other brain regions in adults (e.g. [114]).That is, estrogens may affect learning by priming neu-rons to form lasting connections by first creating silentsynapses and increasing dendritic spine density (Step 1)– likely through actin cytoskeleton dynamics [66] and denovo protein synthesis [106, 143–145] – followed bystimulation (Step 2), leading these neurons to undergolong-term potentiation (LTP) [146, 147]. In this way,novel synapses are formed selectivel by exposure to es-trogens. Only when silent synapses are present andwhen the neuron is activated (receives stimulation) dothose synapses that get utilized in the neuron’s activitydevelop into their fully functioning forms (Fig. 3). How-ever, other potential explanations exist for the mecha-nisms behind the effects of estrogens on learning,including those that may or may not involve changes todendritic spine density (e.g. glutamate receptor shuttlingand/or stabilization [148]). Through what mechanismsestrogens affect learning and memory, and whethernovel dendritic spines and/or LTP are involved, requiresfurther investigation.Estrogens do not always improve memory or LTPAs noted above, estrogens do not always enhance learn-ing and memory. OVX female mice given 17β-estradiolvia drinking water for 5 weeks improved object recogni-tion memory but impaired spatial reference memory atthe middle physiological dose [149]. Similarly, chronictreatment with high doses of EB impaired (whereas lowdoses facilitated) spatial working memory in radial armmaze [118] and conditioned place-preference [150] inOVX female rats. Further, acute administration of highdoses of 17β-estradiol and progesterone can also impairperformance in the standard reference memory versionof Morris water maze [151]. There is agreement in thehuman literature as well, with high endogenous levels of17β-estradiol associated with poorer performance onspatial tasks [138] and cognitive function (assessed usingthe Montreal Cognitive Assessment scale [152]) and highexogenous 17β-estradiol impairing recognition memory[94]. It is important to acknowledge that estradiol leads tocurvilinear influence on hippocampal-dependent perform-ance, with low and high levels impairing but a mediumdose improving performance on a variety of tasks.Estradiol also can have dramatically different effects onLTP as well, dependent on dose and region. For example,proestrus was associated with increased hippocampal LTPin the Schaffer collateral-stratum radiatum (CA1) pathwayin adult female rats [153]. A recent study shows that in exvivo hippocampal slices from adult female mice,17β-estradiol (15 minutes) reduced CA1 miniature excita-tory postsynaptic current frequency and firing in responseto AMPA [76]. However, when EB is given in longer time-lines (2 in vivo injections, 24 hours apart), in ex vivo hip-pocampal slices from OVX female rats, excitatory synaptictransmission in the CA1 was potentiated through in-creases in presynaptic vesicular glutamate release [154].These findings collectively suggest that 17β-estradiol cantransiently decrease excitation in the CA1 but increase ex-citation over longer timeframes. Differences in timing(rapid [15 min] vs longer-term [48 h]), route of adminis-tration (subcutaneous injection, implant, intercranialSheppard et al. Molecular Brain (2019) 12:22 Page 7 of 17infusion, in vitro bath application, etc.), and experimentalmodel (species, sex, in vivo, ex vivo, in vitro, etc.) betweenstudies may underlie these, and other, between-study dif-ferences. For instance, in the above electrophysiology ex-periments, decreased firing resulted from application ofestradiol to ex vivo hippocampal slices concurrent tomeasurement [76, 102], whereas in vivo treatment withEB 2 days prior to sacrifice and measurement resulted inan increase in synaptic transmission [154]. Here, differ-ences in timing and/or model may underlie the opposingeffects. Similarly, the rapid effects of estrogens involveintracellular signalling which may or may not lead to gen-omic products [33], whereas longer-term actions of estro-gens, such as those in studies using chronic hormonetreatments, may involve both genomic actions of estrogens(classical and non-classical) and ongoing, non-genomic,rapid effects. It is important to consider these factors asthey may make comparing the results of different studiesdifficult.There are important considerations when observing theeffects of estrogens on LTP and LTD. Finding an appropri-ate tetanus can be difficult, as hippocampal excitabilityand seizure threshold increase with high 17β-estradiol.For example, the hippocampus is more prone to seizureduring proestrus (high circulating estrogens [153, 155]) orfollowing chronic high-dose 17β-estradiol replacement(dorsal, but not ventral hippocampal seizures [156]). Fur-thermore, the hippocampus can be hyperexcitable follow-ing systemic administration of EB [157] and there aredose-dependent seizure risk associations found in womenwith epilepsy [158]. Additionally, there has been muchdiscussion about the lack of statistical power in manyneuroscience studies [159]. Contradictory findings insimilar experiments could be driven by inadequatesample sizes. Researchers are urged to consider statis-tical power when planning future experiments, espe-cially when sex or hormonal differences are involved,for example, often estrous cycle analyses are under-powered due to subdividing an already small samplesize [1, 2]. However, it is equally important is to con-sider all the variables in the experiment (see [160]),given that tetanus, region of the hippocampus, age,and experience matter for LTP outcomes. As such, allaspects must be considered and the LTP and estro-gens story must not be generalized when multipleareas or stimulation paradigms are used. Careful con-trol of experimental parameters (e.g. consistency andcontrol of experimental conditions, such as cuechoice in spatial tasks) is adequate to maintain statis-tical power in neuroscience research [160].Fig. 3 Suggested non-genomic, intracellular mechanisms driving dendritic spine changes and neurogenesis by estrogens. We hypothesize thatestrogens bind to estrogen receptors (membrane bound or intracellular) which go on to activate cell signalling pathways, including, but notlimited to the ERK, PI3K, JNK, and/or mTOR pathways. Cross-talk between these pathways is common. These have downstream effects on anumber of intracellular mechanisms, including protein synthesis and actin polymerization. Through actin polymerization and protein synthesis,novel spines or “silent” synapses are created, which can become mature synapses following neuronal activity. If unused, the novel spines do notmature and are instead re-internalized. Other intracellular mechanisms, such as epigenetic or post-translational protein modifications andmediation of neurotransmitters and/or receptors, are likely also involved. The contributions of cell signalling pathways and other intracellularmechanisms in the effects of estrogens on neurogenesis remain to be exploredSheppard et al. Molecular Brain (2019) 12:22 Page 8 of 17As suggested earlier, the effects of estrogens on behav-iour are often dose dependent and follow an invertedU-shape dose response curve with intermediate dosesshowing the greatest effects [161] (e.g. [76, 77, 94, 114,149, 162]). Similar dose response curves have been ob-served in the rapid effects of estrogens on dendriticspines [74, 76]. As such, investigations into the effects ofestrogens on either behaviour or cellular morphologyshould take dose response into consideration. Further-more, longer term exposure to estrogens can similarlyhave dose dependent responses on learning and mem-ory, with low levels of 17β-estradiol enhancing spatialworking memory and high levels of estradiol impairingspatial working and reference memory [150, 163, 164].Studies have also shown that, whereas there is dosedependent facilitation in contextual fear conditioning by17β- and 17α-estradiol, estrone results in dosedependent impairments in contextual fear conditioning[165]. Thus, it is important to keep in mind that thenumber of injections, dose, and type of estrogen(s) uti-lized along with the type of memory task investigatedand when during acquisition or retrieval estrogens aregiven, are critical to the learning outcomes.Molecular mechanisms of spine changesThe contributions of the different subtypes of ERs to themodulation of dendritic spines are not yet fully under-stood. Increases in apical and basal pyramidal neuronspine density were found within 2 hours of administra-tion of ERα agonist PPT in the CA1 hippocampus ofmale rats, while ERβ agonist DPN did not produce sucheffects [101]. Twenty-four hours following treatmentwith mixed agonist-antagonist selective estrogen recep-tor modulators, raloxifene and tamoxifen, male rats hadhigher CA1 dendritic spine densities than vehicle treatedcontrols [166]. Tamoxifen increased thin- andstubby-type spines over controls and mushroom-typespines over both vehicle and raloxifene treated males,whereas raloxifene treated males showed increases inthin-, stubby-, and wide-type spines over control males[166]. Within 40 minutes of systemic administration,17β-estradiol [75], PPT [74], or GPER1 agonist G-1 [77]in young adult OVX female mice increased dendritic spinedensity in the stratum radiatum of the CA1 hippocampus,with PPT also increasing dendritic spine density in thelacunosum-moleculare [74]. In all, ERα and the GPER1seem to drive the effects of estrogens in this region,whereas other regions show more involvement from ERβ(e.g. the cortex [112] and the medial amygdala [114]).While the link between changes in dendritic spinesand behaviour has not been causally demonstrated inthese studies, many of the same doses of these estrogensand ER agonists that increased dendritic spine densityalso facilitated short-term social recognition, sociallearning, object recognition, and/or object placementmemory in a separate group of OVX female mice in thesame timeline (40-45 minutes) as spine changes [33, 34,74–77, 114, 167]. Conversely, systemic administration ofDPN impaired social recognition, facilitated object place-ment, did not affect object recognition performance inOVX female mice, and decreased dendritic spine densityand length in the lacunosum-moleculare [74]. In ex vivohippocampal slices, 17β-estradiol and PPT, but not DPN,rapidly increased spine density in the stratum radiatumand stratum oriens subregions of the CA1 [76]. FemaleOVX mice administered a memory-improving dose of17β-estradiol into the dorsal hippocampus had increasedbasal and apical dendritic spine density in CA1 pyramidalneurons 30 minutes and 2 hours following hormone treat-ment [78]. Furthermore, a memory-improving dose of in-tracerebroventricular 17β-estradiol similarly increasedbasal and apical dendritic spine density in CA1 pyramidalneurons within 2 hours in an ERK- and mammalian targetof rapamycin (mTOR)-dependent fashion [78]. Furtherstudy is required to conclusively determine the involve-ment of estrogen-facilitated dendritic spine changes inlearning and memory.The majority of studies have utilized behaviourally-naïveanimals when examining spinogenesis. Interestingly, be-havioural training (Morris Water Maze) interfered withEB-facilitated increases in CA1 spine density [109]. Simi-larly, more recent investigations have found a lack of CA1dendritic spine density increases in animals treated with17β-estradiol prior to acquisition in a rapid short-term so-cial recognition memory testing (Sheppard & Choleris,unpublished results). One potential explanation is that es-tradiol treatment is increasing overall spine number, but,upon activation or experience, only a subset of spines, per-haps those involved in the learning, persists. Further in-vestigation into whether novel spines produced following17β-estradiol treatment remain, mature, or are utilized inbehaviour is required.Intriguingly, in the CA3 region of the hippocampus,there are distinct spines called thorny excrescences thatare the postsynaptic synapses from the mossy fiber inputsfrom granule cells in the dentate gyrus [168]. In hippo-campal slices from adult male rats, 1nM 17β-estradiol for2h decreased CA3 excrescence thorns [169]. This decreasewas blocked by AMPAR, but not NMDAR, antagonismand MAPK signalling inhibition [169]. ERα is believed todrive this decrease as PPT, but not DPN produced a simi-lar effect and ERα was present at CA3 mossy fibre termi-nals [169]. Notably, CA3 dendritic spine density does notvary across the estrous cycle [54, 55]. Ovariectomized fe-male rats had decreased dendritic spine density in prox-imal, medial, and distal regions of the apical dendrites ofpyramidal neurons in the CA1, whereas the CA3 had de-creases in proximal and distal regions only, whenSheppard et al. Molecular Brain (2019) 12:22 Page 9 of 17compared with gonadally intact females in proestrus, ahigh 17β-estradiol phase of the estrous cycle [68]. Femalesin metestrus also had reduced spine density in the medialregion of the CA1 when compared to those in proestrus[68]. Interestingly, orchidectomy in males significantly in-creased dendritic branching in the CA3 whereas OVX infemales had minimal effects on the dendritic arbor [68].Although the CA1 is more often studied, there are clearlysex differences in the effects of sex hormones on CA3dendritic spines and arborization that require furtherinvestigation.Of particular interest in dendritic spine modulation isthe actin cytoskeleton [67] – a dynamic network of actinprotein filaments and associated actin binding proteins– which is highly plastic and serves structural roles inmany cell types [67]. A number of studies have foundthe actin cytoskeleton to be pivotal in the formation,elimination, motility, stability, size, and shape of den-dritic spines (e.g. [170–173]). Estrogens have been foundto affect the remodeling of the actin cytoskeleton (Fig. 3)by rapidly stimulating the RhoA/ROCK (RhoA kinase)pathway and activating Rac/p21-activated kinase (PAK)signalling in neurons [174–177]. Furthermore, intrahip-pocampal administration of latrunculin A, an inhibitorof actin polymerization (the process by which globularactin [G-actin] units combine to form filamentous actin[F-actin]), blocked the rapid GPER1-mediated enhance-ments of long-term object and spatial memory consolida-tion in OVX mice [178]. As such, effects on the pathwaysaffecting the actin cytoskeleton dynamics within dendritesare a potential mechanism by which estrogens facilitatelearning and memory on a rapid timescale.In addition to remodeling of the actin cytoskeleton, pro-tein synthesis has been implicated as a critical factor inchanges to dendritic spine morphology [143, 179], as wellas in learning and memory (e.g. [180–189]). The enlarge-ment and stabilization of dendritic spines requires synthe-sis of new proteins, and specific subsets of mRNAs areactively transported to and stored in neuronal dendrites inorder for local protein synthesis to be synapse- orspine-specific [143]. It has been known since the 1960sthat estrogens increase protein synthesis [190, 191].Through their classical, genomic actions, estrogens, viadimerized ERs binding to estrogen response elements ontarget genes, regulate gene transcription and subsequentprotein synthesis [192]. Additionally, recent evidencesuggests that local protein synthesis (i.e. the synthesisof novel proteins from mRNA stored in the dendrites,independent of gene transcription) may underlie manyof the effects of estrogens on dendritic spines, bothlong-term and rapidly [34, 193, 194].In the hippocampus and in cultured hippocampal pyr-amidal neurons, estradiol (either EB [195–197] or17β-estradiol [174, 194, 198]) alters synaptic proteinexpression in vivo [195–197] and in vitro [174, 194,197]. In the CA1 dorsal hippocampus of male rats, EB,PPT, and DPN increased post-synaptic density protein95 (PSD-95) – a post-synaptic scaffolding protein – andAMPA-type glutamate receptor subunit GluR1, withDPN also increasing GluR2 and decreasing GluR3 [195].Following 2 days of EB treatment in OVX female rats,pre-synaptic markers synaptophysin (vesicular protein)and syntaxin (pre-synaptic membrane-bound protein)and post-synaptic marker spinophilin (spine homeostasisprotein) were significantly increased in the CA1 [196].Interestingly, OVX female rats show an increase in spi-nophilin 2 days following EB treatment, whereas levelsare decreased in gonadectomized males [198]. OVX fe-male rats injected twice daily with 10μg of EB had in-creased CA1 dendritic spine density at 3 days, but not10 days, with increases of synaptophysin expression atboth timepoints [199]. Similarly, spinophilin was in-creased in primary hippocampal cultures from embry-onic day 18 rat embryos (sex not discussed) 24 hoursfollowing EB treatment in a CaMKII-dependent manner[197]. In the CA3 of OVX female rats, synaptophysinwas increased in response to high and middle doses ofestrone (10 and 1μg, respectively) and low dose17β-estradiol (0.3μg) in conjunction with contextual fearconditioning, without these increases in synaptophysincorrelating with cognition [165].In a well-established in vitro model system of differen-tiated NG108-15 neurons, Akama & McEwen [200]found that PSD-95 protein, but not mRNA, levels wereincreased rapidly following 17β-estradiol treatment in anAkt-dependent manner suggesting that, in these cells,17β-estradiol was eliciting an increase in translation,which was independent of DNA transcription. Enhancedconsolidation of longer-term object recognition memory(tested 48h post-training) by intrahippocampal adminis-tration of 17β-estradiol may require local synthesis ofproteins as mTOR is rapidly activated by ERK and Aktsignalling cascades leading to phosphorylation of transla-tion initiation proteins eukaryotic initiation factor4E-binding protein (4E-BP1) and p70 ribosomal S6 kin-ase (S6K) and is required for 17β-estradiol-facilitatedmemory enhancements [117]. Similarly, mTOR is rapidlyactivated (phosphorylated) in a calpain-dependent man-ner 15 minutes following acute 17β-estradiol treatmentto ex vivo hippocampal slices [174]. Expression ofactivity-regulated cytoskeleton-associated protein (Arc),a protein known to be rapidly translated in response toactivity, was also up-regulated in these slices and theseeffects may depend upon GPER1 signalling and not ERαor β [174]. Collectively, this evidence suggests that in-creases in spine density and synapse formation in thehippocampus may involve a 17β-estradiol-triggered pro-tein synthesis, often in a dendrite-localized fashion (Fig.Sheppard et al. Molecular Brain (2019) 12:22 Page 10 of 173). However, novel protein synthesis is not required forthe rapid 17β-estradiol-facilitated formation of new den-dritic spines in cultured cortical neurons (from embry-onic day 18 rats; mixed sex [personal communications])[112]. It is unclear whether protein synthesis, mediated bya mTOR pathway, is required for the maturation andstabilization of novel spines in this region or whether ex-periment model (in vitro vs. in vivo) accounts for differ-ences in results [106, 113, 194]. Thus, further investigationinto whether protein synthesis is necessary for increases inhippocampal dendritic spine number, either rapidly orover longer timeframes, is warranted (Fig. 3).Estrogens and neurogenesisEstrogens not only modulate dendritic spines but also thebirth and survival of new neurons in the dentate gyrus(for review, see [35]). There have been a few reviews spe-cifically on this topic and the reader is directed to thesereviews for a more in-depth discussion [31, 35, 201].Briefly, the process of neurogenesis involves a number ofsteps leading to mature neurons (Fig. 1c). First, neuralprogenitor cells that reside in the subgranular zone in thedentate gyrus undergo asymmetrical proliferation. Thedaughter cells then can differentiate into neurons, glia, orprogenitor cell types. If the cell fate is that of a neuronalphenotype, the cell migrates a small distance into thegranule cell layer. Eventually, the new neuron will ex-press mature neuronal proteins (~2-3 weeks in ratsand ~4 weeks in mice), establish synaptic connectionswith CA3 neurons (and within the DG), and becomeelectrophysiologically active [202, 203]. Estrogens caninfluence neurogenesis by acting on any of these pro-cesses, resulting in either a net increase or decreasein levels of new mature neurons.It bears mentioning that there are some studies thatquestion the extent of adult neurogenesis in the hippo-campus of humans. A recent paper by Sorrells and col-leagues [204] cast doubt on the presence of adulthippocampal neurogenesis in humans, although claimsof near-absent neurogenesis in humans [205, 206] andnon-human primates [207, 208] have been made before.This was followed shortly thereafter by a paper byBoldrini and colleagues [209] which reached the oppos-ite conclusions. Using multiple methods – bromodeox-yuridine [210], doublecortin [211], and 14C dating [212]– numerous studies show evidence for hippocampalneurogenesis in humans, but, as in rodents, there areprecipitous declines in levels of neurogenesis with age[213]. Flaws in the design of the Sorrells et al study havebeen discussed [214], but, briefly, the actual numbers ofDCX+PSA-NCAM cells are not given and PSA-NCAMis not exclusive to the dentate gyrus or to new neurons[214]. The majority of studies observe low, but detect-able, levels of neurogenesis in adult humans [214]. Otherstudies have suggested immunohistological methodsunderestimate the numbers of new neurons in humanhippocampus [209, 214] and the data using 14C datingsuggests much greater levels of neurogenesis exist in thehuman brain than was previously believed. As our reviewfocuses on experimental animal studies, we direct readersto these papers for discussion on the existence and extentof adult hippocampal neurogenesis [204, 209, 214–217]).Research indicates that estrogens rapidly upregulate cellproliferation within 30 minutes [218] a time-frame similarto that observed for the rapid increase in dendritic spines.However, with prolonged exposure to EB (48 h), a decreasein cell proliferation is observed [219, 220]. This biphasic ef-fect is most likely due to the homeostatic nature of neuro-genesis [221, 222] but also to the ability of 17β-estradiol toupregulate adrenal steroids, as adrenalectomy eliminatesthe downregulation of cell proliferation in the dentategyrus 48 h later [223]. ERα and ERβ agonists upregulatecell proliferation in adult female rats [224]; however, theability of 17β-estradiol to increase cell proliferation is notdependent on GPER1 or NMDAR activation [224–226].The upregulation of neurogenesis with ovarian hormonesis also seen across the estrous cycle, with female rats show-ing the highest levels of cell proliferation during proestrus[227, 228] (but see [229]). Estrogens do not appear to altercell fate/differentiation but do influence survival of newneurons, although this latter effect depends upon the typeof estrogen, whether estrogens are administered through-out the survival period, and/or whether animals perform acognitive task [230–232]. In short, 15 days of EB can de-crease survival of new neurons independent of the influ-ence on cell proliferation [232]. However, if 17β-estradiolis given right before administration of bromodeoxyuridine– a thymidine analog used to identify proliferating cells –an increase in survival of new neurons is seen in rats thathave also undergone water maze training [231]. In con-trast, rats given estrone showed a decrease in survival ofnew neurons [231]. These findings indicate that not all es-trogens increase neurogenesis in the hippocampus. Intri-guingly, spatial training and age influence how Premarin, ahormone therapy comprised of 50% estrone sulphate and0.1% estradiol sulphate, increases neurogenesis [230, 233].Premarin increases survival of new neurons in radial-mazetrained rats but not in cage controls [230]. In middle-agednulliparous or primiparous rats (i.e. rats who have nevergiven birth to a litter and rats who have had one litter, re-spectively), lower doses of Premarin decreased survival ofnew neurons in rats that were also trained in the MorrisWater Maze [233]. Recent work also suggests thatlong-term exposure to estradiol, but not DPN or PPT, in-creases survival of new neurons in the hippocampus of fe-male mice [234], suggesting either the involvement ofother ERs (e.g. GPER1) or ER-independent effects of estro-gens to influence neurogenesis under chronic conditions.Sheppard et al. Molecular Brain (2019) 12:22 Page 11 of 17Much of the work in this area has been conducted inyoung adult female rodents [218–220, 223–234], butthere are a few studies examining middle-age and olderfemales. Curiously, in middle-aged nulliparous females,estrogens lose their ability to increase cell proliferation,but estrone, 17α- and 17β-estradiol all increase cell pro-liferation in multiparous middle-aged female rats [235].More work is needed to determine how age and parityaffect estrogens’ abilities to modulate neurogenesis.A few studies conducted in males so far suggest that es-tradiol does not influence the survival of new neurons, butthat both testosterone and dihydrotestosterone increasesurvival of new neurons [97, 100] via interactions with theandrogen receptor [236]. The ability of dihydrotestoster-one to enhance hippocampal neurogenesis in males de-pends on age, as the effect is seen in young, but notmiddle-aged, males [98]. However, Ormerod and col-leagues [220] showed that 5 days of exposure to estradiolincreased survival of new neurons in male meadow voles,at a time when new neurons are extending their axons inboth cage control and voles trained in the Morris WaterMaze. This suggests that estradiol can have survival pro-moting effects in males at specific time points during mat-uration of new neurons, but more work needs to be donein this area and/or explore species differences. One fieldthat has been neglected is the trajectory of spine forma-tion on new neurons in the dentate gyrus and/or in theCA3 region, the synaptic target of the new neurons. Thisis a field ripe for investigation.ConclusionThe plasticity of the hippocampus that allows for changesand adaptability also makes the hippocampus susceptibleto disease and disorder [28]. The literature we review heredemonstrates that estrogens can modulate structural plas-ticity within the hippocampus. A variety of factors, includ-ing sex, age, dose, hormonal state, and reproductivehistory, can influence the effects of estrogens on hippo-campal plasticity. Understanding the complex interplay ofthese factors and estrogens in healthy brains is essential todetermining how dysregulation occurs, progresses, andmanifests in disease states. A preponderance of researchhas examined how estrogens affect structural plasticity infemale rodents. It is crucial that future studies investigateboth sexes, and do so appropriately [1, 2, 237], as manybrain disorders show marked sex differences [2]. Addition-ally, more studies are needed that study estrogens’ effectsacross age and experience, with the understanding that ex-periences in one sex may be very different than the other(i.e. motherhood, lactation). Only by understanding thecomplex, multi-faceted nature of estrogens on hippocam-pal plasticity can we hope to develop targeted therapies tocombat disorders affecting the hippocampus and improvequality of life for those afflicted.Abbreviations4E-BP1: Eukaryotic initiation factor 4E-binding protein; AMPA: Alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; BrdU: Bromodeoxyuridine;CaMKII: Ca2+/calmodulin-dependent protein kinase II;DPN: Diarylproprionitrile; EB: Estradiol benzoate; ER: Estrogen receptor;ERK: Extracellular signal-regulated protein kinase; GDX: Gonadectomy;GPER1: G-protein-coupled estrogen receptor 1; LTD: Long term depression;LTP: Long term potentiation; mTOR: Mammalian target of rapamycin;NMDA: N-methyl-D-aspartate; OVX: Ovariectomy; PAK: p21-activated kinase;PPT: Propyl pyrazole triol; ROCK: Rho-associated protein kinaseAcknowledgementsNot applicable.FundingThe writing of this review was supported by the University of BritishColumbia Faculty of Arts and the University of Guelph College of Social andApplied Human Sciences. The authors’ empirical work described wassupported by grants to LAMG from Canadian Institutes for Health Research(MOP102568) and Natural Sciences and Engineering Research Council ofCanada (203596-13) and to EC from the Natural Sciences and EngineeringResearch Council of Canada (400212).Availability of data and materialsNot applicable.Authors’ contributionsPrimary draft by PASS. Neurogenesis section by LAMG. Revisions by PASS,LAMG, and EC, amended by PASS. All authors have read and approved thefinal version.Ethics approval and consent to participateNot applicable.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Department of Psychology, Graduate Program in Neuroscience, DjavadMowafaghian Centre for Brain Health, University of British Columbia,Vancouver, BC V6T 1Z3, Canada. 2Department of Psychology & NeuroscienceProgram, University of Guelph, Guelph, ON N1G 2W1, Canada.Received: 2 January 2019 Accepted: 11 March 2019References1. Choleris E, Galea LAM, Sohrabji F, Frick KM. Sex differences in the brain:implications for behavioral and biomedical research. Neurosci Biobehav Rev.2018;85:126–45. https://doi.org/10.1016/j.neubiorev.2017.07.005.2. Galea LAM, Frick KM, Hampson E, Sohrabji F, Choleris E. 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Neurogenesis
dendritic spines
sex differences
memory
depression
stress
aging
pregnancy
parity
Structural plasticity of the hippocampus in response to estrogens in female rodents
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