Sex differences are reported in hippocampal plasticity, cognition, and in a number of disorders that target the integrity of the hippocampus. For example, meta-analyses reveal that males outperform females on hippocampus-dependent tasks in rodents and in humans, furthermore women are more likely to experience greater cognitive decline in Alzheimer’s disease and depression, both diseases characterized by hippocampal dysfunction. The hippocampus is a highly plastic structure, important for processing higher order information and is sensitive to the environmental factors such as stress. The structure retains the ability to produce new neurons and this process plays an important role in pattern separation, proactive interference, and cognitive flexibility. Intriguingly, there are prominent sex differences in the level of neurogenesis and the activation of new neurons in response to hippocampus-dependent cognitive tasks in rodents. However, sex differences in spatial performance can be nuanced as animal studies have demonstrated that there are task, and strategy choice dependent sex differences in performance, as well as sex differences in the subregions of the hippocampus influenced by learning. This review discusses sex differences in pattern separation, pattern completion, spatial learning, and links between adult neurogenesis and these cognitive functions of the hippocampus. We emphasize the importance of including both sexes when studying genomic, cellular, and structural mechanisms of the hippocampal function.
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McPherson S, Back C, Buckwalter JG, Cummings JL. Gender-related cognitive deficits in Alzheimer’s disease. Int Psychogeriatr. 1999;11:117–22.
Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998;88:1337–42.
Gutiérrez-Lobos K, Scherer M, Anderer P, Katschnig H. The influence of age on the female/male ratio of treated incidence rates in depression. BMC Psychiatry. 2002;2:3.
Irvine K, Laws KR, Gale TM, Kondel TK. Greater cognitive deterioration in women than men with Alzheimer’s disease: a meta analysis. J Clin Exp Neuropsychol. 2012;34:989–98.
Hy LX, Keller DM. Prevalence of AD among whites: a summary by levels of severity. Neurology. 2000;55:198–204.
Leung A, Chue P. Sex differences in schizophrenia, a review of the literature. Acta Psychiatr Scand Suppl. 2000;401:3–38.
Mossaheb N, Kaufmann RM, Schlögelhofer M, Aninilkumparambil T, Himmelbauer C, Gold A, et al. The impact of sex differences on odor identification and facial affect recognition in patients with schizophrenia spectrum disorders. Front Psychiatry. 2018;9:1–8.
Nicoletti A, Vasta R, Mostile G, Nicoletti G, Arabia G, Iliceto G, et al. Gender effect on non-motor symptoms in Parkinson’s disease: are men more at risk? Park Relat Disord. 2017;35:69–74.
Szewczyk-Krolikowski K, Tomlinson P, Nithi K, Wade-Martins R, Talbot K, Ben-Shlomo Y, et al. The influence of age and gender on motor and non-motor features of early Parkinson’s disease: initial findings from the Oxford Parkinson Disease Center (OPDC) discovery cohort. Park Relat Disord. 2014;20:99–105.
Cereda E, Cilia R, Klersy C, Siri C, Pozzi B, Reali E, et al. Dementia in Parkinson’s disease: is male gender a risk factor? Park Relat Disord. 2016;26:67–72.
Han M, Huang XF, Chen DC, Xiu MH, Hui L, Liu H, et al. Gender differences in cognitive function of patients with chronic schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2012;39:358–63.
De Vries GJ. Minireview: sex differences in adult and developing brains: compensation, compensation, compensation. Endocrinology. 2004;145:1063–8.
Becker JB, Koob GF. Sex Differences in Animal Models: Focus on Addiction. Pharmacol Rev. 2016;68:242–63.
Christie BR, Cameron HA. Neurogenesis in the adult hippocampus. Hippocampus. 2006;16:199–207.
Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn aM, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4:1313–7.
Neves G, Cooke SF, Bliss TVP. Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat Rev Neurosci. 2008;9:65–75.
McEwen BS. Redefining neuroendocrinology: epigenetics of brain-body communication over the life course. Front Neuroendocrinol. 2018;49:8–30.
Whitlock JR, Heynen AJ, Shuler MG, Bear MF. Learning induces long-term potentiation in the hippocampus. Science 2006;313:1093–7.
Artola A, Frijtag JCVon, Fermont PCJ, Gispen WH, Schrama LH, Kamal A, et al. Long-lasting modulation of the induction of LTD and LTP in rat hippocampal CA1 by behavioural stress and environmental enrichment. Eur J Neurosci. 2006;23:261–72.
Hunsaker MR, Kesner RP. The operation of pattern separation and pattern completion processes associated with different attributes or domains of memory. Neurosci Biobehav Rev. 2013;37:36–58.
Zhang JQ, Cai WQ, Zhou DS, Su BY. Distribution and differences of estrogen receptor beta immunoreactivity in the brain of adult male and female rats. Brain Res. 2002;935:73–80.
Feng Y, Weijdegård B, Wang T, Egecioglu E, Fernandez-Rodriguez J, Huhtaniemi I, et al. Spatiotemporal expression of androgen receptors in the female rat brain during the oestrous cycle and the impact of exogenous androgen administration: a comparison with gonadally intact males. Mol Cell Endocrinol. 2010;321:161–74.
Mitterling KL, Spencer JL, Dziedzic N, Shenoy S, McCarthy K, Waters EM, et al. Cellular and subcellular localization of estrogen and progestin receptor immunoreactivities in the mouse hippocampus. J Comp Neurol. 2010;518:2729–43.
Mogi K, Takanashi H, Nagasawa M, Kikusui T. Sex differences in spatiotemporal expression of AR, ERα, and ERβ mRNA in the perinatal mouse brain. Neurosci Lett. 2015;584:88–92.
McEwen BS, Weiss JM, Leslie SS. Selective retention of corticosterone by limbic structures in rat brain. Nature. 1968;220:911–2.
Mocuilewsky M, Raynaud JP. Evidence for a specific mineralocorticoid receptor pituitary and brain. J Steroid Biochem. 1980;12:309–14.
Aronsson M, Fuxe K, Dong Y, Agnati LF, Okret S. Localization of glucocorticoid receptor mRNA in the male rat brain by in situ Hybridization. Proc Natl Acad Sci USA. 1988;85:9331–5.
Wang Q, Heerikhuize JVan, Aronica E, Kawata M, Seress L, Joels M, et al. Glucocorticoid receptor protein expression in human hippocampus; stability with age. Neurobiol Aging. 2013;34:1662–73.
Owen D, Matthews SG. Glucocorticoids and sex-dependent development of brain glucocorticoid and mineralocorticoid receptors. Endocrinology. 2003;144:2775–84.
Ruigrok ANV, Salimi-Khorshidi G, Lai M-C, Baron-Cohen S, Lombardo MV, Tait RJ, et al. A meta-analysis of sex differences in human brain structure. Neurosci Biobehav Rev. 2014;39:34–50.
Tan A, Ma W, Vira A, Marwha D, Eliot L. The human hippocampus is not sexually-dimorphic: meta-analysis of structural MRI volumes. Neuroimage. 2016;124:350–66. Meta-analysis showing that sex differences in the volume of the hippocampus are explained by total brain volume differences between the sexes
Tamnes CK, Bos MGN, van de Kamp FC, Peters S, Crone EA. Longitudinal development of hippocampal subregions from childhood to adulthood. Dev Cogn Neurosci. 2018;30:212–22.
Colle R, Segawa T, Chupin M, Tran Dong MN, Hardy P, Falissard B, et al. Early life adversity is associated with a smaller hippocampus in male but not female depressed in-patients: a case-control study. BMC Psychiatry. 2017;17:71.
Lisofsky N, Mårtensson J, Eckert A, Lindenberger U, Gallinat J, Kühn S. Hippocampal volume and functional connectivity changes during the female menstrual cycle. Neuroimage. 2015;118:154–62. This study demonstrate the dynamics of female hippocampal volume and functional connectivity, in which increase of estradiol leads to an increase of hippocampal volume
Hoekzema E, Barba-Müller E, Pozzobon C, Picado M, Lucco F, García-García D, et al. Pregnancy leads to long-lasting changes in human brain structure. Nat Neurosci. 2017;20:287–96. One of the first studies to show long-term changes to the brain, including the hippocampus, after pregnancy, and that these reductions in grey matter were associated with positive parenting outcomes, indicating that more is not always better
Wnuk A, Korol DL, Erickson KI. Estrogens, hormone therapy, and hippocampal volume in postmenopausal women. Maturitas. 2012;73:186–90.
Goto M, Abe O, Miyati T, Inano S, Hayashi N, Aoki S, et al. 3 Tesla MRI detects accelerated hippocampal volume reduction in postmenopausal women. J Magn Reson Imaging. 2011;33:48–53.
Everaerd D, Gerritsen L, Rijpkema M, Frodl T, Van Oostrom I, Franke B, et al. Sex modulates the interactive effect of the serotonin transporter gene polymorphism and childhood adversity on hippocampal volume. Neuropsychopharmacology. 2012;37:1848–55.
Lord C, Buss C, Lupien SJ, Pruessner JC. Hippocampal volumes are larger in postmenopausal women using estrogen therapy compared to past users, never users and men: A possible window of opportunity effect. Neurobiol Aging. 2008;29:95–101.
Persson J, Spreng RN, Turner G, Herlitz A, Morell A, Stening E, et al. Sex differences in volume and structural covariance of the anterior and posterior hippocampus. Neuroimage. 2014;99:215–25.
Sacher J, Neumann J, Okon-Singer H, Gotowiec S, Villringer A. Sexual dimorphism in the human brain: evidence from neuroimaging. Magn Reson Imaging. 2013;31:366–75.
Scheinost D, Finn ES, Tokoglu F, Shen X, Papademetris X, Hampson M, et al. Sex differences in normal age trajectories of functional brain networks. Hum Brain Mapp. 2015;36:1524–35.
Zhang C, Cahill ND, Arbabshirani MR, White T, Baum SA, Michael AM. Sex and Age Effects of Functional Connectivity in Early Adulthood. Brain Connect. 2016;6:700–13. This is the first study showing sex and age effects on the whole brain functional connectivity with resting-state functional MRI. This study demonstrated that men’s and women’s brains are differently organized compared to young adults and the functional organization changes differently between the sexes with age
Ingalhalikar M, Smith A, Parker D, Satterthwaite TD, Elliott MA, Ruparel K, et al. Sex differences in the structural connectome of the human brain. Proc Natl Acad Sci. 2014;111:823–8.
Joel D, Berman Z, Tavor I, Wexler N, Gaber O, Stein Y, et al. Sex beyond the genitalia: the human brain mosaic. Proc Natl Acad Sci. 2015;112:15468–73.
Filippi M, Valsasina P, Misci P, Falini A, Comi G, Rocca MA. The organization of intrinsic brain activity differs between genders: a resting-state fMRI study in a large cohort of young healthy subjects. Hum Brain Mapp. 2013;34:1330–43.
Gobinath AR, Choleris E, Galea LA. Sex, hormones, and genotype interact to influence psychiatric disease, treatment, and behavioral research. J Neurosci Res. 2017a;95:50–64.
Glezerman M. Yes, there is a female and a male brain: morphology versus functionality. Proc Natl Acad Sci. 2016;113:E1971–E1971.
Baxter LC, Saykin AJ, Flashman LA, Johnson SC, Guerin SJ, Babcock DR, et al. Sex differences in semantic language processing: a functional MRI study. Brain Lang. 2003;84:264–72.
Kansaku K, Yamaura A, Kitazawa S. Sex differences in lateralization revealed in the posterior language areas. Cereb Cortex. 2000;10:866–72.
Sneider JT, Sava S, Rogowska J, Yurgelun-Todd DA. A preliminary study of sex differences in brain activation during a spatial navigation task in healthy adults. Percept Mot Skills. 2011;113:461–80.
Grön G, Wunderlich AP, Spitzer M, Tomczak R, Riepe MW. Brain activation during human navigation:gender-different neural networks as substrate performance. Nat Neurosci. 2000;3:404–8.
Kolb B, Stewart J. Changes in the neonatal gonadal hormonal environment prevent behavioral sparing and alter cortical morphogenesis after early frontal cortex lesions in male and female rats. Behav Neurosci. 1995;109:285–94.
Padurariu M, Ciobica A, Mavroudis I, Fotiou D, Baloyannis S. Hippocampal neuronal loss in the Ca1 and Ca3 areas of Alzheimer’. S Dis Patients. 2012;24:152–8.
Kerchner GA, Deutsch GK, Zeineh M, Dougherty RF, Saranathan M, Rutt BK. Hippocampal CA1 apical neuropil atrophy and memory performance in Alzheimer’s disease. Neuroimage. 2012;63:194–202.
Sabuncu M, Desikan R. The dynamics of cortical and hippocampal atrophy in Alzheimer disease. Arch Neurol. 2011;68:1040–8.
Henneman WJP, Sluimer JD, Barnes J, Van Der Flier WM, Sluimer IC, Fox NC, et al. Hippocampal atrophy rates in Alzheimer disease: added value over whole brain volume measures. Neurology. 2009;72:999–1007.
Martínez-Pinilla E, Ordóñez C, Del Valle E, Navarro A, Tolivia J. Regional and gender study of neuronal density in brain during aging and in Alzheimer’s disease. Front Aging Neurosci. 2016;8:213.
Koran MEI, Wagener M, Hohman TJ. Sex differences in the association between AD biomarkers and cognitive decline. Brain Imaging Behav. 2017;11:205–13.
Sohn D, Shpanskaya K, Lucas JE, Petrella JR, Saykin AJ, Tanzi RE, et al. Sex differences in cognitive decline in subjects with high likelihood of mild cognitive impairment due to Alzheimer’s disease. Sci Rep. 2018;8:1–9.
Burke SL, Hu T, Fava NM, Li T, Rodriguez MJ, Schuldiner KL, et al. Sex differences in the development of mild cognitive impairment and probable Alzheimer’s disease as predicted by hippocampal volume or white matter hyperintensities. J Women Aging. 2018;10:1–25.
Caldwell JZK, Berg JL, Cummings JL, Banks SJ, Alzheimer’s Disease Neuroimaging Initiative. Moderating effects of sex on the impact of diagnosis and amyloid positivity on verbal memory and hippocampal volume. Alzheimers Res Ther. 2017;9:72.
Rummel J, Epp JR, Galea LAM. Estradiol does not influence strategy choice but place strategy choice is associated with increased cell proliferation in the hippocampus of female rats. Horm Behav. 2010;58:582–90.
Tanapat P, Hastings NB, Reeves AJ, Gould E. Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J Neurosci. 1999;19:5792–801.
Qiu LR, Germann J, Spring S, Alm C, Vousden DA, Palmert MR, et al. Hippocampal volumes differ across the mouse estrous cycle, can change within 24h, and associate with cognitive strategies. Neuroimage. 2013;83:593–8.
Warren SG, Humphreys AG, Juraska JM, Greenough WT. LTP varies across the estrous cycle: enhanced synaptic plasticity in proestrus rats. Brain Res. 1995;703:26–30.
Good M, Day M, Muir JL. Cyclical changes in endogenous levels of oestrogen modulate the induction of LTD and LTP in the hippocampal CA1 region. Eur J Neurosci. 1999;11:4476–80.
Woolley CS, Gould E, Frankfurt M, McEwen BS. Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J Neurosci. 1990;10:4035–9.
Tada H, Koide M, Ara W, Shibata Y, Funabashi T, Suyama K, et al. Estrous cycle-dependent phasic changes in the stoichiometry of hippocampal synaptic AMPA receptors in rats. PLoS ONE. 2015;10:e0131359.
Mendell AL, Atwi S, Bailey CDC, McCloskey D, Scharfman HE, MacLusky NJ. Expansion of mossy fibers and CA3 apical dendritic length accompanies the fall in dendritic spine density after gonadectomy in male, but not female, rats. Brain Struct Funct. 2017;222:587–601.
Gould E, Woolley CS, Frankfurt M, McEwen BS. Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood. J Neurosci. 1990b;10:1286–91. An early study indicating that phase of estrous cycle influence spine density in the CA1 region of the hippocampus
Juraska JM, Fitch JM, Washburne DL. The dendritic morphology of pyramidal neurons in the rat hippocampal CA3 area. II. Eff Gend Environ Brain Res. 1989;479:115–9.
Galea LA, McEwen B, Tanapat P, Deak T, Spencer R, Dhabhar F. Sex differences in dendritic atrophy of CA3 pyramidal neurons in response to chronic restraint stress. Neuroscience. 1997;81:689–97.
Gould E, Westlind-Danielsson A, Frankfurt M, McEwen BS. Sex differences and thyroid hormone sensitivity of hippocampal pyramidal cells. J Neurosci. 1990a;10:996–1003.
Shors TJ, Chua C, Falduto J. Sex differences and opposite effects of stress on dendritic spine density in the male versus female hippocampus. J Neurosci. 2001a;21:6292–7.
Juraska JM, Fitch JM, Henderson C, Rivers N. Sex differences in the dendritic branching of dentate granule cells following differential experience. Brain Res. 1985;333:73–80. This is the first study demonstrating sex differences in the morphology of dentate granule neurons in response to environmental.
Maccari S, Krugers HJ, Morley-Fletcher S, Szyf M, Brunton PJ. The consequences of early-life adversity: neurobiological, behavioural and epigenetic adaptations. J Neuroendocrinol. 2014;26:707–23.
Loi M, Mossink JC, Meerhoff GF, Den Blaauwen JL, Lucassen PJ, Joëls M. Effects of early-life stress on cognitive function and hippocampal structure in female rodents. Neuroscience. 2017;342:101–19.
Guadagno A, Wong TP, Walker CD. Morphological and functional changes in the preweaning basolateral amygdala induced by early chronic stress associate with anxiety and fear behavior in adult male, but not female rats. Prog Neuropsychopharmacol Biol Psychiatry. 2018;81:25–37.
Maren S, Oca BDe, Fanselow MS. Sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats: positive correlation between LTP and contextual learning. Brain Res. 1994;661:25–34.
Monfort P, Gomez-Gimenez B, Llansola M, Felipo V. Gender differences in spatial learning, synaptic activity, and long-term potentiation in the hippocampus in rats: molecular mechanisms. ACS Chem Neurosci. 2015;6:1420–7.
Yang DW, Pan B, Han TZ, Xie W. Sexual dimorphism in the induction of LTP: Critical role of tetanizing stimulation. Life Sci. 2004;75:119–27.
Harte-Hargrove LC, Varga-Wesson A, Duffy AM, Milner TA, Scharfman HE. Opioid receptor-dependent sex differences in synaptic plasticity in the hippocampal mossy fiber pathway of the adult rat. J Neurosci. 2015;35:1723–38.
Qi X, Zhang K, Xu T, Yamaki VN, Wei Z, Huang M, et al. Sex differences in long-term potentiation at temporoammonic-CA1 synapses: potential implications for memory consolidation. PLoS ONE. 2016;11:1–18. This is the first study demonstrating that sex differences in AMPA/NMDA receptor composition influences on the sex differences in late-LTP of the CA1 pyramidal neurons.
Tan M, Tan U. Sex difference in susceptibility to epileptic seizures in rats: importance of estrous cycle. J Neurosci. 2001;108:175–91.
Terasawa E, Timiras PS. Electrical activity during the estrous cycle of the rat: cyclic changes in limbic structures. Endocrinology. 1968;83:207.
Oberlander JG, Woolley CS. 17-estradiol acutely potentiates glutamatergic synaptic transmission in the hippocampus through distinct mechanisms in males and females. J Neurosci. 2016;36:2677–90. This is the first study elucidating the cellular mechanism of enhancing effects of estradiol on neural excitability of the hippocampal neurons, in which estradiol enhances long-term potentiation through different estrogen receptors between males and females.
Scharfman HE, MacLusky NJ. Sex differences in hippocampal area CA3 pyramidal cells. J Neurosci Res. 2017;95:563–75.
Scharfman HE. Hyperexcitability in combined entorhinal/hippocampal slices of adult rat after exposure to brain-derived neurotrophic factor. J Neurophysiol. 1997;78:1082–95.
Scharfman HE, Mercurio TC, Goodman JH, Wilson MA, MacLusky NJ. Hippocampal excitability increases during the estrous cycle in the rat: a potential role for brain-derived neurotrophic factor. J Neurosci. 2003;23:11641–52.
Duarte-Guterman P, Yagi S, Chow C, Galea LAM. Hippocampal learning, memory, and neurogenesis: effects of sex and estrogens across the lifespan in adults. Horm Behav. 2015;74:37–52.
Nakashiba T, Cushman JD, Pelkey KA, Renaudineau S, Buhl DL, McHugh TJ, et al. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell. 2012;149:188–201. The first study with determining the age of adult-born neurons dependent roles for pattern separation and pattern completion in male mice.
Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature. 2011;476:458–61.
Clelland CD, Choi M, Romberg C, Clemenson GD, Fragniere A, Tyers P, et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science. 2009;325:210–3. One of the first studies to show that adult neurogenesis in the hippocampus was required for pattern separation.
Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E. Neurogenesis in the adult is involved in the formation of trace memories. Nature. 2001b;410:372–6.
Denny CA, Burghardt NS, Schachter DM, Hen R, Drew MR. 4- To 6-week-old adult-born hippocampal neurons influence novelty-evoked exploration and contextual fear conditioning. Hippocampus. 2012;22:1188–201.
Drew MR, Denny CA, Hen R. Arrest of adult hippocampal neurogenesis in mice impairs single- but not multiple-trial contextual fear conditioning. Behav Neurosci. 2010;124:446–54.
Akers KG, Akers KG, Martinez-canabal A, Restivo L, Yiu AP, De Cristofaro A, et al. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science. 2014;344:598–602. The first direct evidence that adult neurogenesis in the hippocampus was related to forgetting.
Kitamura T, Saitoh Y, Takashima N, Murayama A, Niibori Y, Ageta H, et al. Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell. 2009;139:814–27.
Epp JR, Silva Mera R, Köhler S, Josselyn SA, Frankland PW. Neurogenesis-mediated forgetting minimizes proactive interference. Nat Commun. 2016;7:10838.
Snyder JS, Hong NS, McDonald RJ, Wojtowicz JM. A role for adult neurogenesis in spatial long-term memory. Neuroscience. 2005;130:843–52. This is an important study as it indicates that reducing neurogenesis in the dentate gyrus of male rats does not impair Morris Water Maze acquisition or immediate memory, but four weeks later, the rats were impaired in retention of spatial memory. Most studies do not examine long-term memory so this was a pivotal finding adding more information to how new neurons contribute to spatial memory.
Garthe A, Roeder I, Kempermann G. Mice in an enriched environment learn more flexibly because of adult hippocampal neurogenesis. Hippocampus. 2016;26:261–71.
Kalm M, Karlsson N, Nilsson MKL, Blomgren K. Loss of hippocampal neurogenesis, increased novelty-induced activity, decreased home cage activity, and impaired reversal learning one year after irradiation of the young mouse brain. Exp Neurol. 2013;247:402–9.
Seib DR, Chahley E, Princz-Lebel O, Snyder JS. Intact memory for local and distal cues in male and female rats that lack adult neurogenesis. PLoS ONE. 2018;13:e0197869.
Sliwowska JH, Barker JM, Barha CK, Lan N, Weinberg J, Galea LAM. Stress-induced suppression of hippocampal neurogenesis in adult male rats is altered by prenatal ethanol exposure. Stress. 2010;13:301–13.
Uban KA, Sliwowska JH, Lieblich S, Ellis LA, Yu WK, Weinberg J, et al. Prenatal alcohol exposure reduces the proportion of newly produced neurons and glia in the dentate gyrus of the hippocampus in female rats. Horm Behav. 2010;58:835–43.
Galea LAM, McEwen BS. Sex and seasonal differences in the rate of cell proliferation in the dentate gyrus of adult wild meadow voles. Neuroscience. 1999;89:955–64.
Westenbroek C, Den Boer JA, Veenhuis M, Ter Horst GJ. Chronic stress and social housing differentially affect neurogenesis in male and female rats. Brain Res Bull. 2004;64:303–8.
Yagi S, Chow C, Lieblich SE, Galea LAM. Sex and strategy use matters for pattern separation, adult neurogenesis, and immediate early gene expression in the hippocampus. Hippocampus. 2016;101:87–101. This study is the first study demonstrating sex differences favouring male rats in the spatial pattern separation and in adult neurogenesis, in a learning strategy dependent manner.
Falconer EM, Galea LAM. Sex differences in cell proliferation, cell death and defensive behavior following acute predator odor stress in adult rats. Brain Res. 2003;975:22–36. One of the earliest studies to indicate a sex differences in neurogenesis in response to stress in adult rodents.
Spritzer MD, Panning AW, Engelman SM, Prince WT, Casler AE, Georgakas JE, et al. Seasonal and sex differences in cell proliferation, neurogenesis, and cell death within the dentate gyrus of adult wild-caught meadow voles. Neuroscience. 2017;360:155–65.
Lagace DC, Fischer SJ, Eisch AJ. Gender and endogenous levels of estradiol do not influence adult hippocampal neurogenesis in mice. Hippocampus. 2007;17:175–80.
Amrein I, Slomianka L, Poletaeva II, Bologova NV, Lipp HP. Marked species and age-dependent differences in cell proliferation and neurogenesis in the hippocampus of wild-living rodents. Hippocampus. 2004;14:1000–10.
Tzeng W-Y, Chen L-H, Cherng CG, Tsai Y-N, Yu L. Sex differences and the modulating effects of gonadal hormones on basal and the stressor-decreased newly proliferative cells and neuroblasts in dentate gyrus. Psychoneuroendocrinology. 2014;42:24–37.
Lee TTY, Wainwright SR, Hill MN, Galea LAM, Gorzalka BB. Sex, drugs, and adult neurogenesis: sex-dependent effects of escalating adolescent cannabinoid exposure on adult hippocampal neurogenesis, stress reactivity, and amphetamine sensitization. Hippocampus. 2014;24:280–92.
Barker JM, Galea LAM. Repeated estradiol administration alters different aspects of neurogenesis and cell death in the hippocampus of female, but not male, rats. Neuroscience. 2008;152:888–902.
Dalla C, Papachristos EB, Whetstone AS, Shors TJ. Female rats learn trace memories better than male rats and consequently retain a greater proportion of new neurons in their hippocampi. Proc Natl Acad Sci USA. 2009;106:2927–32. The first study to indicate that sex differences in learning was related to sex differences in the impact of that learning on neurogenesis in the hippocampus.
Hillerer KM, Neumann ID, Couillard-Despres S, Aigner L, Slattery DA. Sex-dependent regulation of hippocampal neurogenesis under basal and chronic stress conditions in rats. Hippocampus. 2013;23:476–87.
Swift-Gallant A, Duarte-Guterman P, Hamson DK, Ibrahim M, Monks DA, Galea LAM. Neural androgen receptors affect the number of surviving new neurons in the adult dentate gyrus of male mice. J Neuroendocrinol. 2018;e12578:https://doi.org/10.1111/jne.12578.
Hamson DK, Wainwright SR, Taylor JR, Jones BA, Watson NV, Galea LAM. Androgens increase survival of adult-born neurons in the dentate gyrus by an androgen receptor-dependent mechanism in male rats. Endocrinology. 2013;154:3294–304.
Mahmoud R, Wainwright SR, Galea LAM. Sex hormones and adult hippocampal neurogenesis: Regulation, implications, and potential mechanisms. Front Neuroendocrinol. 2016;41:129–52.
Kambo JS, Galea LAM. Activational levels of androgens influence risk assessment behaviour but do not influence stress-induced suppression in hippocampal cell proliferation in adult male rats. Behav Brain Res. 2006;175:263–70.
Naninck EFG, Hoeijmakers L, Kakava-Georgiadou N, Meesters A, Lazic SE, Lucassen PJ, et al. Chronic early life stress alters developmental and adult neurogenesis and impairs cognitive function in mice. Hippocampus. 2015;25:309–28.
Gobinath AR, Workman JL, Chow C, Lieblich SE, Galea LA. Maternal postpartum corticosterone and fluoxetine differentially affect adult male and female offspring on anxiety-like behavior, stress reactivity, and hippocampal neurogenesis. Neuropharmacology. 2016;101:165–78.
Gobinath AR, Workman JL, Chow C, Lieblich SE, Galea LAM. Sex-dependent effects of maternal corticosterone and SSRI treatment on hippocampal neurogenesis across development. Biol Sex Differ. 2017b;8:1–13.
Oomen CA, Girardi CEN, Cahyadi R, Verbeek EC, Krugers H, Joëls M, et al. Opposite effects of early maternal deprivation on neurogenesis in male versus female rats. PLoS ONE. 2009;4:e3675.
Barha CK, Brummelte S, Lieblich SE, Galea LAM. Chronic restraint stress in adolescence differentially influences hypothalamic-pituitary-adrenal axis function and adult hippocampal neurogenesis in male and female rats. Hippocampus. 2011;21:1216–27.
Gobinath AR, Mahmoud R, Galea LAM. Influence of sex and stress exposure across the lifespan on endophenotypes of depression: focus on behavior, glucocorticoids, and hippocampus. Front Neurosci. 2015;9:1–18.
Chow C, Epp JR, Lieblich SE, Barha CK, Galea LAM. Sex differences in neurogenesis and activation of new neurons in response to spatial learning and memory. Psychoneuroendocrinology. 2013;38:1236–50. One of first studies to examine sex differences in immediate early gene expression in new neurons in association with learning ability.
Epp JR, Spritzer MD, Galea LAM. Hippocampus-dependent learning promotes survival of new neurons in the dentate gyrus at a specific time during cell maturation. Neuroscience. 2007;149:273–85.
Lawton CA. Gender differences in way-finding strategies: relationship to spatial ability and spatial anxiety. Sex Roles. 1994;30:765–79.
Silverman I, Choi J. Non-Euclidean navigational strategies of women: compensatory response or evolved dimorphism? Evol Psychol. 2006;4:75–84.
Dabbs JM, Chang E-L, Strong RA, Milun R. Spatial ability, navigation strategy, and geographic knowledge among men and women. Evol Hum Behav. 1998;19:89–98.
Korol DL, Malin EL, Borden KA, Busby RA, Couper-Leo J. Shifts in preferred learning strategy across the estrous cycle in female rats. Horm Behav. 2004;45:330–8. One of first studies examining sex difference and effect of estrous cycle on learning strategy of rats.
Grissom EM, Hawley WR, Hodges KS, Fawcett-Patel JM, Dohanich GP. Biological sex influences learning strategy preference and muscarinic receptor binding in specific brain regions of prepubertal rats. Hippocampus. 2013;23:313–22.
Hawley WR, Grissom EM, Barratt HE, Conrad TS, Dohanich GP. The effects of biological sex and gonadal hormones on learning strategy in adult rats. Physiol Behav. 2012;105:1014–20.
Maguire EA, Burgess N, Donnett JG, Frackowiak RSJ, Maguire EA, Burgess N, et al. Knowing where and getting there: a human navigation network. Science. 2017;280:921–4.
McDonald RJ, White NM. A triple dissociation of memory systems: hippocampus, amygdala, and dorsal striatum. Behav Neurosci. 1993;107:3–22.
Iaria G, Petrides M, Dagher A, Pike B, Bohbot VD. Cognitive strategies dependent on the hippocampus and caudate nucleus in human navigation: variability and change with practice. J Neurosci. 2003;23:5945–52.
Andersen NE, Dahmani L, Konishi K, Bohbot VD. Eye tracking, strategies, and sex differences in virtual navigation. Neurobiol Learn Mem. 2012;97:81–9.
Galea LAM, Kimura D. Sex differences in route-learning. Personal Individ Differ. 1993;14:53–65.
Williams CL, Barnett AM, Meck WH. Organizational effects of early gonadal secretions on sexual differentiation in spatial memory. Behav Neurosci. 1990;104:84–97.
Cherney ID, Brabec CM, Runco DV. Mapping out spatial ability: sex differences in way-finding navigation. Percept Mot Skills. 2008;107:747–60.
Spritzer MD, Fox EC, Larsen GD, Batson CG, Wagner BA, Maher J. Testosterone influences spatial strategy preferences among adult male rats. Horm Behav. 2013;63:800–12.
Keeley RJ, Tyndall AV, Scott GA, Saucier DM. Sex difference in cue strategy in a modified version of the Morris water task: correlations between brain and behaviour. PLoS ONE. 2013;8:e69727.
Moradpour F, Naghdi N, Fathollahi Y, Javan M, Choopani S, Gharaylou Z. Pre-pubertal castration improves spatial learning during mid-adolescence in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2013;46:105–12.
Yagi S, Drewczynski D, Wainwright SR, Barha CK, Hershorn O, Galea LAM. Sex and estrous cycle differences in immediate early gene activation in the hippocampus and the dorsal striatum after the cue competition task. Horm Behav. 2017;87:69–79.
Linn MC, Petersen AC. Emergence and characterization of sex differences in spatial ability: a meta-analysis. Soc Res Child Dev. 2016;56:1479–98.
Voyer D, Voyer S, Bryden MP. Magnitude of sex differences in spatial abilities: a meta-analysis and consideration of critical variables. Psychol Bull. 1995;117:250–70.
Jonasson Z. Meta-analysis of sex differences in rodent models of learning and memory: a review of behavioral and biological data. Neurosci Biobehav Rev. 2005;28:811–25.
Chamizo VD, Artigas AA, Sansa J, Banterla F. Gender differences in landmark learning for virtual navigation: the role of distance to a goal. Behav Process. 2011;88:20–6.
Button KS, Ioannidis JP, Mokrysz C, Nosek BA, Flint J, Robinson ES, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci. 2013;14:365–76.
Hvoslef-Eide M, Nilsson SR, Saksida LM, Bussey TJ. Cognitive translation using the rodent touchscreen testing approach. Curr Top Behav Neurosci. 2016;28:423–47.
Perrot-Sinal TS, Kostenuik MA, Ossenkopp KP, Kavaliers M. Sex differences in performance in the Morris water maze and the effects of initial nonstationary hidden platform training. Behav Neurosci. 1996;110:1309–20.
Beiko J, Lander R, Hampson E, Boon F, Cain DP. Contribution of sex differences in the acute stress response to sex differences in water maze performance in the rat. Behav Brain Res. 2004;151:239–53.
Engelmann M, Ebner K, Landgraf R, Wotjak CT. Effects of Morris water maze testing on the neuroendocrine stress response and intrahypothalamic release of vasopressin and oxytocin in the rat. Horm Behav. 2006;50:496–501.
Galea LA, Kavaliers M, Ossenkopp KP, Hampson E. Gonadal hormone levels and spatial learning performance in the Morris water maze in male and female meadow voles, Microtus pennsylvanicus. Horm Behav. 1995;29:106–25.
Barha CK, Pawluski JL, Galea LAM. Maternal care affects male and female offspring working memory and stress reactivity. Physiol Behav. 2007;92:939–50.
Bayer J, Gläscher J, Finsterbusch J, Schulte LH, Sommer T. Linear and inverted U-shaped dose-response functions describe estrogen effects on hippocampal activity in young women. Nat Commun. 2018;9:1220.
Hampson E. Estrogen-related variations in human spatial and articulatory-motor skills. Psychoneuroendocrinology. 1990;15:97–111. One of the first studies to show a double dissociation in cognitive performance across the menstrual cycle during menses and the pre-ovulatory surge, in a number of tasks. Hampson found spatial performance improved but fine motor skills worsened during menses while the reverse pattern was observed during the pre-ovulatory surge.
Viau V, Meaney MJ. Basal and stress hypothalamic pituitary adrenal activity in cycling and ovariectomized steroid treated rats. Endocrinology. 1992;131:1261–9.
Bowman RE, Zrull MC, Luine VN. Chronic restraint stress enhances radial arm maze performance in female rats. Brain Res. 2001;904:279–89.
Wood GE, Shors TJ. Stress facilitates classical conditioning in males, but impairs classical conditioning in females through activational effects of ovarian hormones. Proc Natl Acad Sci. 1998;95:4066–71.
Luine V. Sex differences in chronic stress effects on memory in rats. Stress. 2002;5:205–16.
Hodes GE, Pfau ML, Purushothaman I, Ahn HF, Golden SA, Christoffel DJ, et al. Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress. J Neurosci. 2015;35:16362–76. This is the first study indicating that elucidating the association between transcriptome analysis in the nucleus accumbens and sex differences in stress vulnerability.
Arnold AP, Lusis AJ. Understanding the sexome: measuring and reporting sex differences in gene systems. Endocrinology. 2012;153:2551–5.
Labonté B, Engmann O, Purushothaman I, Menard C, Wang J, Tan C, et al. Sex-specific transcriptional signatures in human depression. Nat Med. 2017;23:1102–11. This is a comprehensive transcriptome analysis elucidating sex differences in the gene expression in human brains with major depressive disorder.
Mangold CA, Wronowski B, Du M, Masser DR, Hadad N, Bixler GV, et al. Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging. J Neuroinflamm. 2017;14:141.
Guebel DV, Torres NV. Sexual dimorphism and aging in the human hyppocampus: identification, validation, and impact of differentially expressed genes by factorial microarray and network analysis. Front Aging Neurosci. 2016;8:229.
Hanamsagar R, Alter MD, Block CS, Sullivan H, Bolton JL, Bilbo SD. Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity. Glia. 2017;65:1504–20.
Bundy JL, Vied C, Nowakowski RS. Sex differences in the molecular signature of the developing mouse hippocampus. BMC Genom. 2017;18:1–17.
Vied C, Ray S, Badger CD, Bundy JL, Arbeitman MN, Nowakowski RS. Transcriptomic analysis of the hippocampus from six inbred strains of mice suggests a basis for sex-specific susceptibility and severity of neurological disorders. J Comp Neurol. 2016;524:2696–710.
Guzowski JF, Setlow B, Wagner EK, McGaugh JL. Experience-dependent gene expression in the rat hippocampus after spatial learning: a comparison of the immediate-early genes Arc, c- fos, and zif268. J Neurosci. 2001;21:5089–98.
Jones MW, Errington ML, French PJ, Fine A, Bliss TV, Garel S, et al. A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat Neurosci. 2001;4:289–96.
Wisden W, Errington ML, Williams S, Dunnett SB, Waters C, Hitchcock D, et al. Differential expression of immediate early genes in the hippocampus and spinal cord. Neuron. 1990;4:603–14.
Douglas RM, Dragunow M, Robertson HA. High-frequency discharge of dentate granule cells, but not long-term potentiation, induces c-fos protein. Brain Res. 1988;464:259–62.
Penke Z, Morice E, Veyrac A, Gros A, Chagneau C, Samson N et al. Plasticity and long-term spatial recognition memory Zif268 / Egr1 gain of function facilitates hippocampal synaptic plasticity and long-term spatial recognition memory. Phil Trans R Soc B Biol Sci. 2014;369:20130159.
Petersohn D, Schoch S, Brinkmann DR, Thiel G. The human synapsin II gene promoter: possible role for the transcription factors zif268/EGR-1, polyoma enhancer activator 3, and AP2. J Biol Chem. 1995;270:24361–9.
Moser MB, Moser EI, Forrest E, Andersen P, Morris RG. Spatial learning with a minislab in the dorsal hippocampus. Proc Natl Acad Sci. 1995;92:9697–701.
Lonergan ME, Gafford GM, Jarome TJ, Helmstetter FJ. Time-dependent expression of arc and Zif268 after acquisition of fear conditioning. Neural Plast. 2010;2010:8–11. This is one of few study reporting time courses of immediate early genes Arc and zif268 protein expression, which indicates zif268 expression reaches the peak earlier than Arc protein expression.
Barros VN, Mundim M, Galindo LT, Bittencourt S, Porcionatto M, Mello LE. The pattern of c-Fos expression and its refractory period in the brain of rats and monkeys. Front Cell Neurosci 2015;9:1–8.
Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen H-U. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res. 2012;21:169–84.
Breslau N, Davis GC, Andreski P, Peterson EL, Schultz LR. Sex differences in posttraumatic stress disorderr. Arch Gen Psychiatry. 1997;54:1044–8.
Meulders A, Vansteenwegen D, Vlaeyen JWS. Women, but not men, report increasingly more pain during repeated (un)predictable painful electrocutaneous stimulation: evidence for mediation by fear of pain. Pain. 2012;153:1030–41.
Keiser AA, Turnbull LM, Darian MA, Feldman DE, Song I, Tronson NC. Sex differences in context fear generalization and recruitment of hippocampus and amygdala during retrieval. Neuropsychopharmacology. 2017;42:397–407. This study demonstrates that the hippocampus and amygdala compete with each other during fear related memory retrieval, and sex modulates the competition between the two regions.
Lynch JJ, Cullen PK, Jasnow AM, Riccio DC. Sex differences in the generalization of fear as a function of retention intervals. Learn Mem. 2013;20:628–32.
Gresack JE, Schafe GE, Orr PT, Frick KM. Sex differences in contextual fear conditioning are associated with differential ventral hippocampal extracellular signal-regulated kinase activation. Neuroscience. 2009;159:451–67.
Matsuda S, Matsuzawa D, Ishii D, Tomizawa H, Sutoh C, Shimizu E. Sex differences in fear extinction and involvements of extracellular signal-regulated kinase (ERK). Neurobiol Learn Mem. 2015;123:117–24.
Voulo ME, Parsons RG. Response-specific sex difference in the retention of fear extinction. Learn Mem. 2017;24:245–51.
Barker JM, Galea LA. Males show stronger contextual fear conditioning than females after context pre-exposure. Physiol Behav. 2010;99:82–90.
Gruene TM, Flick K, Stefano A, Shea SD, Shansky RM. Sexually divergent expression of active and passive conditioned fear responses in rats. A study showing that female rats show distinctly different active responses to fear memory, unlike male rats. eLife 2015;4:e11352.
Chen LS, Tzeng WY, Chuang JY, Cherng CG, Gean PW, Yu L. Roles of testosterone and amygdaloid LTP induction in determining sex differences in fear memory magnitude. Horm Behav. 2014;66:498–508.
Gruene TM, Roberts E, Thomas V, Ronzio A, Shansky RM. Sex-specific neuroanatomical correlates of fear expression in prefrontal-amygdala circuits. Biol Psychiatry. 2015;78:186–93.
Barha CK, Hsiung G-YR, Best JR, Davis JC, Eng JJ, Jacova C, et al. Sex difference in aerobic exercise efficacy to improve cognition in older adults with vascular cognitive impairment: secondary analysis of a randomized controlled. Trial J Alzheimer’s Dis. 2017;60:1–13.
Varma VR, Tang X, Carlson MC. Hippocampal sub-regional shape and physical activity in older adults. Hippocampus. 2016;26:1051–60.
Nieuwenhuis S, Forstmann BU, Wagenmakers EJ. Erroneous analyses of interactions in neuroscience: a problem of significance. Nat Neurosci. 2011;14:1105–7.
Research described from LAMG laboratory was funded by operating grants from Natural Sciences and Engineering Council of Canada (NSERC) (203596-13) and Canadian Institutes for Health Research (CIHR) MOP102568. SY gratefully acknowledges support from the Killam Doctoral Scholarship through the University of British Columbia.
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Molecular Brain (2019)