{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T05:06:02Z","timestamp":1791608762989,"version":"4.3.4"},"reference-count":150,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Brain sex neurosteroids have been attracted much attention, because the brain itself can synthesizes a sufficient amount of sex neurosteroids independent of circulating sex steroids. Local synthesis and action of neuro-estrogen [such as neuro-estradiol (nE2)] and neuro-androgen [such as neuro-testosterone (nT) and neuro-dihydrotestosterone (nDHT)] have become recognized as key factors in modulation of synaptic plasticity, cognitive performance, and protection of aging dependent decline of neurological functions. Unlike circulating sex steroids, these locally synthesized sex neurosteroids can directly and rapidly modulate neuronal synapses and induce potent effects on learning and memory. The properties of local neurocrine systems are significantly different from those of classical neuroendocrine systems dependent on the hypothalamic\u2013pituitary-gonadal axis. For example, in the hippocampus, not only neuro-androgen (nT and nDHT) but also nE2 have higher concentrations than testis-derived circulating androgen (T and DHT) and ovary-derived circulating E2 (cir-E2). In addition, male nE2 concentration is higher than female nE2 at both adult stage and newborn stage during which brain masculinization occurs. Over the past decades, numerous experimental results and interpretations of sex neurosteroids have been shown. However, in several cases, these results and interpretations are mutually conflicting, and a unified understanding has not yet been achieved. Therefore, we here deeply discuss several critical and important issues toward solving complex problems to understand. We focus the following issues. First (A) Local synthesis of nE2, nT and nDHT, with particular attention to their concentrations, synthesis pathways and sex differences in rodents. Higher nE2 concentration in male hippocampus than in female in adult stage. Then (B) Comparison of modulation of long-term potentiation (LTP) by nE2 and nDHT. Stimulatory effects of nE2 on LTP which are mediated by membrane estrogen receptor ER and protein kinase signaling. Inhibitory effects of nDHT on LTP which are mediated by membrane androgen receptor AR. Third (C) Both nE2 and nDHT show the same rapid increases in dendritic spines. Their effects on spinogenesis are very different from their effects on LTP. Fourth (D) Rapid effects of nE2 and nT on cognitive behavior. Male signaling pathway may be more complex than female signaling pathway. Finally (E) Aging-dependent cognitive decline which is dependent on decrease of nT in male and nE2 in female. T-replacement therapy of male patients shows improvement in spatial cognitive decline. E2-replacement therapy improves female cognitive decline.<\/jats:p>","DOI":"10.3389\/fncel.2025.1695565","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T15:26:56Z","timestamp":1769614016000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Local synthesis and function of neuro-estrogen and neuro-androgen: impact on the hippocampus-related cognition and neuronal plasticity"],"prefix":"10.3389","volume":"19","author":[{"given":"Suguru","family":"Kawato","sequence":"first","affiliation":[{"name":"Department of Biophysics and Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo","place":["Tokyo, Japan"]},{"name":"Department of Cognitive Neuroscience, Faculty of Pharma-Science, Teikyo University","place":["Tokyo, Japan"]},{"name":"Department of Urology, Graduate School of Medicine, Juntendo University","place":["Tokyo, Japan"]},{"name":"Department of Biosciences, College of Humanities and Sciences, Nihon University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Hojo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Saitama Medical University","place":["Saitama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika","family":"Soma","sequence":"additional","affiliation":[{"name":"Department of Cognitive Neuroscience, Faculty of Pharma-Science, Teikyo University","place":["Tokyo, Japan"]},{"name":"Department of Urology, Graduate School of Medicine, Juntendo University","place":["Tokyo, Japan"]},{"name":"Department of Biosciences, College of Humanities and Sciences, Nihon University","place":["Tokyo, Japan"]},{"name":"Department of Anatomy and Neurobiology, Nippon Medical School","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeo","family":"Horie","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Medicine, Juntendo University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Biosciences, College of Humanities and Sciences, Nihon University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Ogiue-Ikeda","sequence":"additional","affiliation":[{"name":"Department of Cognitive Neuroscience, Faculty of Pharma-Science, Teikyo University","place":["Tokyo, Japan"]},{"name":"Department of Urology, Graduate School of Medicine, Juntendo University","place":["Tokyo, Japan"]},{"name":"Department of Biosciences, College of Humanities and Sciences, Nihon University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"8071","DOI":"10.1073\/pnas.141215898","article-title":"Different modes of hippocampal plasticity in response to estrogen in young and aged female rats","volume":"98","author":"Adams","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"CD010783","DOI":"10.1002\/14651858.CD010783.pub2","article-title":"Mini-mental state examination (MMSE) for the detection of Alzheimer's disease and other dementias in people with mild cognitive impairment (MCI)","volume":"2015","author":"Arevalo-Rodriguez","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"100335","DOI":"10.1016\/j.coemr.2022.100335","article-title":"Synthesis and impact of neuroestradiol on hippocampal neuronal networks","volume":"24","author":"Azcoitia","year":"2022","journal-title":"Curr. Opin. Endocr. Metab. Res."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"5280","DOI":"10.1073\/pnas.96.9.5280","article-title":"Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway","volume":"96","author":"Bach","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.tins.2006.03.004","article-title":"Is brain estradiol a hormone or a neurotransmitter?","volume":"29","author":"Balthazart","year":"2006","journal-title":"Trends Neurosci."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1037\/h0077579","article-title":"Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat","volume":"93","author":"Barnes","year":"1979","journal-title":"J. Comp. Physiol. Psychol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1002\/hipo.450020413","article-title":"Region-specific age effects on AMPA sensitivity: electrophysiological evidence for loss of synaptic contacts in hippocampal field CA1","volume":"2","author":"Barnes","year":"1992","journal-title":"Hippocampus"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1101\/lm.3.2-3.124","article-title":"Functional integrity of NMDA-dependent LTP induction mechanisms across the lifespan of F-344 rats","volume":"3","author":"Barnes","year":"1996","journal-title":"Learn. Mem."},{"key":"ref9","first-page":"1","article-title":"Neurosteroids: of the nervous system, by the nervous system, for the nervous system","volume":"52","author":"Baulieu","year":"1997","journal-title":"Recent Prog. Horm. Res."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"4089","DOI":"10.1073\/pnas.95.8.4089","article-title":"Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids","volume":"95","author":"Baulieu","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.3390\/ijms25031377","article-title":"Locally synthetized 17-beta-estradiol reverses amyloid-beta-42-induced hippocampal long-term potentiation deficits","volume":"25","author":"Bellingacci","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"3602","DOI":"10.1073\/pnas.97.7.3602","article-title":"The tyrosine kinase and mitogen-activated protein kinase pathways mediate multiple effects of estrogen in hippocampus","volume":"97","author":"Bi","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.2147\/CIA.S61760","article-title":"Cognitive effects of testosterone and finasteride administration in older hypogonadal men","volume":"9","author":"Borst","year":"2014","journal-title":"Clin. Interv. Aging"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1016\/j.steroids.2008.11.013","article-title":"Membrane estrogen receptors activate metabotropic glutamate receptors to influence nervous system physiology","volume":"74","author":"Boulware","year":"2009","journal-title":"Steroids"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1002\/cne.901020206","article-title":"Organization of the cerebral cortex. III. A study of aging in the human cerebral cortex","volume":"102","author":"Brody","year":"1955","journal-title":"J. Comp. Neurol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/nrn1809","article-title":"Neural plasticity in the ageing brain","volume":"7","author":"Burke","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"13357","DOI":"10.1523\/JNEUROSCI.2718-07.2007","article-title":"Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice","volume":"27","author":"Carroll","year":"2007","journal-title":"J. Neurosci."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.brainres.2010.10.009","article-title":"Sex differences in beta-amyloid accumulation in 3xTg-AD mice: role of neonatal sex steroid hormone exposure","volume":"1366","author":"Carroll","year":"2010","journal-title":"Brain Res."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"2278","DOI":"10.1016\/j.psyneuen.2013.04.016","article-title":"Comparison of plasma and cerebrospinal fluid levels of neuroactive steroids with their brain, spinal cord and peripheral nerve levels in male and female rats","volume":"38","author":"Caruso","year":"2013","journal-title":"Psychoneuroendocrinology"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"R99","DOI":"10.1530\/EJE-15-0262","article-title":"THERAPY OF ENDOCRINE DISEASE: testosterone supplementation and body composition: results from a meta-analysis study","volume":"174","author":"Corona","year":"2016","journal-title":"Eur. J. Endocrinol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"9","DOI":"10.5534\/wjmh.200017","article-title":"Testosterone deficiency and risk of cognitive disorders in aging males","volume":"39","author":"Corona","year":"2021","journal-title":"World J. Mens Health"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/0197-4580(93)90009-Z","article-title":"Age-related alterations in potentiation in the CA1 region in F344 rats","volume":"14","author":"Deupree","year":"1993","journal-title":"Neurobiol. Aging"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0006-8993(91)90164-Q","article-title":"Spatial performance correlates with in vitro potentiation in young and aged Fischer 344 rats","volume":"554","author":"Deupree","year":"1991","journal-title":"Brain Res."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"376","DOI":"10.3389\/fncel.2015.00376","article-title":"Neo-synthesis of estrogenic or androgenic neurosteroids determine whether long-term potentiation or depression is induced in hippocampus of male rat","volume":"9","author":"Di Mauro","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1111\/ejn.13455","article-title":"Different synaptic stimulation patterns influence the local androgenic and estrogenic neurosteroid availability triggering hippocampal synaptic plasticity in the male rat","volume":"45","author":"Di Mauro","year":"2017","journal-title":"Eur. J. Neurosci."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"110664","DOI":"10.1016\/j.exger.2019.110664","article-title":"Testosterone administration increases synaptic density in the gyrus dentatus of old mice independently of physical exercise","volume":"125","author":"Fattoretti","year":"2019","journal-title":"Exp. Gerontol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1016\/0197-4580(91)90071-Q","article-title":"Increase in perforant path quantal size in aged F-344 rats","volume":"12","author":"Foster","year":"1991","journal-title":"Neurobiol. Aging"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1152\/jn.1999.81.2.925","article-title":"17beta-estradiol enhances NMDA receptor-mediated EPSPs and long-term potentiation","volume":"81","author":"Foy","year":"1999","journal-title":"J. Neurophysiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/nrn2788","article-title":"Protein palmitoylation in neuronal development and synaptic plasticity","volume":"11","author":"Fukata","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1146\/annurev.psych.48.1.339","article-title":"The use of animal models to study the effects of aging on cognition","volume":"48","author":"Gallagher","year":"1997","journal-title":"Annu. Rev. Psychol."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"101102","DOI":"10.1016\/j.yfrne.2023.101102","article-title":"Neuroestradiol and neuronal development: not an exclusive male tale anymore","volume":"71","author":"Garcia-Segura","year":"2023","journal-title":"Front. Neuroendocrinol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1002\/agm2.12152","article-title":"Utility of a shortened Hasegawa dementia scale revised questionnaire to rapidly screen and diagnose Alzheimer's disease","volume":"4","author":"Gong","year":"2021","journal-title":"Aging Med."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.1523\/JNEUROSCI.10-04-01286.1990","article-title":"Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood","volume":"10","author":"Gould","year":"1990","journal-title":"J. Neurosci."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.neuroscience.2011.06.078","article-title":"Neural 17\u03b2-estradiol facilitates long-term potentiation in the hippocampal CA1 region","volume":"192","author":"Grassi","year":"2011","journal-title":"Neuroscience"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1093\/ajcn\/nqab253","article-title":"Cognitive response to testosterone replacement added to intensive lifestyle intervention in older men with obesity and hypogonadism: prespecified secondary analyses of a randomized clinical trial","volume":"114","author":"Gregori","year":"2021","journal-title":"Am. J. Clin. Nutr."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1038\/73980","article-title":"Brain activation during human navigation: gender-different neural networks as substrate of performance","volume":"3","author":"Gr\u00f6n","year":"2000","journal-title":"Nat. Neurosci."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1002\/cne.10837","article-title":"Estrogen increases the number of spinophilin-immunoreactive spines in the hippocampus of young and aged female rhesus monkeys","volume":"465","author":"Hao","year":"2003","journal-title":"J. Comp. Neurol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"11465","DOI":"10.1073\/pnas.0704757104","article-title":"Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex","volume":"104","author":"Hao","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"2571","DOI":"10.1523\/JNEUROSCI.3440-05.2006","article-title":"Estrogen alters spine number and morphology in prefrontal cortex of aged female rhesus monkeys","volume":"26","author":"Hao","year":"2006","journal-title":"J. Neurosci."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1152\/physrev.00036.2014","article-title":"Estrogen effects on cognitive and synaptic health over the Lifecourse","volume":"95","author":"Hara","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1210\/jcem.86.2.7219","article-title":"Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore longitudinal study of aging","volume":"86","author":"Harman","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref42","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2014.12.056","article-title":"Estradiol rapidly modulates synaptic plasticity of hippocampal neurons: involvement of kinase networks","volume":"1621","author":"Hasegawa","year":"2015","journal-title":"Brain Res."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.brainres.2014.12.011","article-title":"Rapid increase of spines by dihydrotestosterone and testosterone in hippocampal neurons: dependence on synaptic androgen receptor and kinase networks","volume":"1621","author":"Hatanaka","year":"2015","journal-title":"Brain Res."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/1477-7525-1-15","article-title":"The aging males' symptoms (AMS) scale: update and compilation of international versions","volume":"1","author":"Heinemann","year":"2003","journal-title":"Health Qual. Life Outcomes"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1073\/pnas.2630225100","article-title":"Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017alpha and P450 aromatase localized in neurons","volume":"101","author":"Hojo","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"5106","DOI":"10.1210\/en.2009-0305","article-title":"Comparison between hippocampus-synthesized and circulation-derived sex steroids in the hippocampus","volume":"150","author":"Hojo","year":"2009","journal-title":"Endocrinology"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3389\/fendo.2011.00043","article-title":"Hippocampal synthesis of sex steroids and corticosteroids: essential for modulation of synaptic plasticity","volume":"2","author":"Hojo","year":"2011","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"183","DOI":"10.3389\/fendo.2018.00183","article-title":"Neurosteroids in adult Hippocampus of male and female rodents: biosynthesis and actions of sex steroids","volume":"9","author":"Hojo","year":"2018","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"Article S4","DOI":"10.4172\/2157-7536.S4-002","article-title":"Neurosteroid synthesis in adult female rat hippocampus, including androgens and allopregnanolone","author":"Hojo","year":"2014","journal-title":"J. Steroids Hormon. Sci."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1507\/endocrj.EJ22-0604","article-title":"The impact of testosterone in men's health","volume":"70","author":"Ide","year":"2023","journal-title":"Endocr. J."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1111\/iju.15160","article-title":"Summary of the clinical practice manual for late-onset hypogonadism","volume":"30","author":"Ide","year":"2023","journal-title":"Int. J. Urol."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1210\/en.2015-1959","article-title":"Gonadal hormones rapidly enhance spatial memory and increase hippocampal spine density in male rats","volume":"157","author":"Jacome","year":"2016","journal-title":"Endocrinology"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"104550","DOI":"10.1016\/j.psyneuen.2019.104550","article-title":"Testosterone replacement causes dose-dependent improvements in spatial memory among aged male rats","volume":"113","author":"Jaeger","year":"2020","journal-title":"Psychoneuroendocrinology"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1552","DOI":"10.1523\/JNEUROSCI.1897-18.2018","article-title":"Latent sex differences in molecular signaling that underlies excitatory synaptic potentiation in the hippocampus","volume":"39","author":"Jain","year":"2019","journal-title":"J. Neurosci."},{"key":"ref55","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0037-22.2022","article-title":"Ultrasensitive quantification of multiple estrogens in songbird blood and microdissected brain by LC-MS\/MS","volume":"9","author":"Jalabert","year":"2022","journal-title":"eNeuro"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"149","DOI":"10.3389\/fncir.2013.00149","article-title":"Female hippocampal estrogens have a significant correlation with cyclic fluctuation of hippocampal spines","volume":"7","author":"Kato","year":"2013","journal-title":"Front. Neural Circuits"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/S0076-6879(02)57682-5","article-title":"Histological and metabolism analysis of P450 expression in the brain","volume":"357","author":"Kawato","year":"2002","journal-title":"Methods Enzymol."},{"key":"ref58","doi-asserted-by":"publisher","DOI":"10.1101\/2025.08.17.670749","article-title":"Age-related decline of synaptic plasticity is regulated by neuro-androgen and neuro-estrogen in normal aging of hippocampus","author":"Kawato","year":"","journal-title":"bioRxiv"},{"key":"ref59","doi-asserted-by":"publisher","DOI":"10.1101\/2025.01.27.25321222","article-title":"Testosterone replacement therapy ameliorates spatial cognitive function in age related hypogonadism (LOH) patients: analysis with a virtual three-dimensional maze","author":"Kawato","year":"","journal-title":"medRxiv"},{"key":"ref60","doi-asserted-by":"publisher","DOI":"10.1101\/2025.08.13.670028","article-title":"Rethinking synthesis and function of neuro-estrogen and neuro-androgen in the hippocampus: some methodological problems and possible solutions","author":"Kawato","year":"","journal-title":"bioRxiv"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"S5","DOI":"10.1016\/j.eplepsyres.2005.07.015","article-title":"The neurobiology of aging","volume":"68","author":"Kelly","year":"2006","journal-title":"Epilepsy Res."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.psyneuen.2017.08.013","article-title":"Distinct effects of estrogen receptor antagonism on object recognition and spatial memory consolidation in ovariectomized mice","volume":"85","author":"Kim","year":"2017","journal-title":"Psychoneuroendocrinology"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"5795","DOI":"10.1210\/en.2010-0581","article-title":"Semicomprehensive analysis of the postnatal age-related changes in the mRNA expression of sex steroidogenic enzymes and sex steroid receptors in the male rat hippocampus","volume":"151","author":"Kimoto","year":"2010","journal-title":"Endocrinology"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"3578","DOI":"10.1210\/endo.142.8.8327","article-title":"Neurosteroid synthesis by cytochrome p450-containing systems localized in the rat brain hippocampal neurons: N-methyl-D-aspartate and calcium-dependent synthesis","volume":"142","author":"Kimoto","year":"2001","journal-title":"Endocrinology"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1210\/en.2010-0607","article-title":"Developmental time course of estradiol, testosterone, and dihydrotestosterone levels in discrete regions of male and female rat brain","volume":"152","author":"Konkle","year":"2011","journal-title":"Endocrinology"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.yhbeh.2019.01.002","article-title":"Activation of androgen receptors protects intact male mice from memory impairments caused by aromatase inhibition","volume":"111","author":"Koss","year":"2019","journal-title":"Horm. Behav."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"5913","DOI":"10.1523\/JNEUROSCI.5186-03.2004","article-title":"Hippocampal synapses depend on hippocampal estrogen synthesis","volume":"24","author":"Kretz","year":"2004","journal-title":"J. Neurosci."},{"key":"ref68","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1089\/andro.2021.0022","article-title":"Androgen effects on neural plasticity","volume":"2","author":"Kuwahara","year":"2021","journal-title":"Androg. Clin. Res. Ther."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1016\/0197-4580(95)02014-4","article-title":"Executive system dysfunction in the aged monkey: spatial and object reversal learning","volume":"16","author":"Lai","year":"1995","journal-title":"Neurobiol. Aging"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"1588","DOI":"10.1523\/JNEUROSCI.23-05-01588.2003","article-title":"Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats","volume":"23","author":"Leranth","year":"2003","journal-title":"J. Neurosci."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/S0306-4522(00)00369-9","article-title":"Hormonal regulation of hippocampal spine synapse density involves subcortical mediation","volume":"101","author":"Leranth","year":"2000","journal-title":"Neuroscience"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1002\/cne.10230","article-title":"Gonadal hormones are responsible for maintaining the integrity of spine synapses in the CA1 hippocampal subfield of female nonhuman primates","volume":"447","author":"Leranth","year":"2002","journal-title":"J. Comp. Neurol."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1038\/nrm.2016.122","article-title":"Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors","volume":"17","author":"Levin","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref74","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.psyneuen.2018.11.037","article-title":"Detection of estradiol in rat brain tissues: contribution of local versus systemic production","volume":"102","author":"Li","year":"2019","journal-title":"Psychoneuroendocrinology"},{"key":"ref75","doi-asserted-by":"publisher","first-page":"76","DOI":"10.3390\/geriatrics5040076","article-title":"Age-related male hypogonadism and cognitive impairment in the elderly: focus on the effects of testosterone replacement therapy on cognition","volume":"5","author":"Lisco","year":"2020","journal-title":"Geriatr. (Basel)"},{"key":"ref76","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1038\/nn2057","article-title":"Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory","volume":"11","author":"Liu","year":"2008","journal-title":"Nat. Neurosci."},{"key":"ref77","doi-asserted-by":"publisher","first-page":"2792","DOI":"10.1523\/JNEUROSCI.1970-18.2019","article-title":"Neuron-derived estrogen regulates synaptic plasticity and memory","volume":"39","author":"Lu","year":"2019","journal-title":"J. Neurosci."},{"key":"ref78","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/j.yfrne.2012.07.004","article-title":"Estrogens facilitate memory processing through membrane mediated mechanisms and alterations in spine density","volume":"33","author":"Luine","year":"2012","journal-title":"Front. Neuroendocrinol."},{"key":"ref79","doi-asserted-by":"publisher","first-page":"104711","DOI":"10.1016\/j.yhbeh.2020.104711","article-title":"Estrogenic regulation of memory: the first 50 years","volume":"121","author":"Luine","year":"2020","journal-title":"Horm. Behav."},{"key":"ref80","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1016\/j.neuroscience.2022.06.002","article-title":"Androgens enhance recognition memory and dendritic spine density in the hippocampus and prefrontal cortex of ovariectomized female rats","volume":"568","author":"Luine","year":"2022","journal-title":"Neuroscience"},{"key":"ref81","doi-asserted-by":"publisher","first-page":"316386","DOI":"10.1155\/2011\/316386","article-title":"Age-related deficits in spatial memory and hippocampal spines in virgin, female Fischer 344 rats","volume":"2011","author":"Luine","year":"2011","journal-title":"Curr. Gerontol. Geriatr. Res."},{"key":"ref82","doi-asserted-by":"publisher","first-page":"143","DOI":"10.3109\/13685538.2013.853731","article-title":"Recommendations on the diagnosis, treatment and monitoring of late-onset hypogonadism in men - a suggested update","volume":"16","author":"Lunenfeld","year":"2013","journal-title":"Aging Male"},{"key":"ref83","doi-asserted-by":"publisher","first-page":"4154","DOI":"10.1210\/en.2004-0477","article-title":"Effects of dehydroepiandrosterone and flutamide on hippocampal CA1 spine synapse density in male and female rats: implications for the role of androgens in maintenance of hippocampal structure","volume":"145","author":"MacLusky","year":"2004","journal-title":"Endocrinology"},{"key":"ref84","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1210\/en.2004-0730","article-title":"The 17alpha and 17beta isomers of estradiol both induce rapid spine synapse formation in the CA1 hippocampal subfield of ovariectomized female rats","volume":"146","author":"MacLusky","year":"2005","journal-title":"Endocrinology"},{"key":"ref85","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1002\/hipo.20034","article-title":"Sexually dimorphic aging of dendritic morphology in CA1 of hippocampus","volume":"15","author":"Markham","year":"2005","journal-title":"Hippocampus"},{"key":"ref86","doi-asserted-by":"publisher","first-page":"10985","DOI":"10.1523\/JNEUROSCI.22-24-10985.2002","article-title":"Effectiveness of estrogen replacement in restoration of cognitive function after long-term estrogen withdrawal in aging rats","volume":"22","author":"Markowska","year":"2002","journal-title":"J. Neurosci."},{"key":"ref87","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/S0197-4580(89)80008-9","article-title":"Individual differences in aging: behavioral and neurobiological correlates","volume":"10","author":"Markowska","year":"1989","journal-title":"Neurobiol. Aging"},{"key":"ref88","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1210\/endrev\/bnab041","article-title":"Membrane-initiated estrogen, androgen, and progesterone receptor signaling in health and disease","volume":"43","author":"Mauvais-Jarvis","year":"2022","journal-title":"Endocr. Rev."},{"key":"ref89","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1016\/S0092-8674(00)81828-0","article-title":"Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice","volume":"87","author":"McHugh","year":"1996","journal-title":"Cell"},{"key":"ref90","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.steroids.2017.09.012","article-title":"The expression of select genes necessary for membrane-associated estrogen receptor signaling differ by sex in adult rat hippocampus","volume":"142","author":"Meitzen","year":"2019","journal-title":"Steroids"},{"key":"ref91","doi-asserted-by":"publisher","first-page":"4293","DOI":"10.1210\/en.2013-1172","article-title":"Palmitoylation of estrogen receptors is essential for neuronal membrane signaling","volume":"154","author":"Meitzen","year":"2013","journal-title":"Endocrinology"},{"key":"ref92","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1002\/cne.20724","article-title":"Ultrastructural localization of estrogen receptor beta immunoreactivity in the rat hippocampal formation","volume":"491","author":"Milner","year":"2005","journal-title":"J. Comp. Neurol."},{"key":"ref93","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1002\/hipo.450030106","article-title":"Hippocampal plasticity induced by primed burst, but not long-term potentiation, stimulation is impaired in area CA1 of aged Fischer 344 rats","volume":"3","author":"Moore","year":"1993","journal-title":"Hippocampus"},{"key":"ref94","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/S0026-0495(97)90057-3","article-title":"Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men","volume":"46","author":"Morley","year":"1997","journal-title":"Metabolism"},{"key":"ref95","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1038\/nrn3200","article-title":"The ageing cortical synapse: hallmarks and implications for cognitive decline","volume":"13","author":"Morrison","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref96","doi-asserted-by":"publisher","first-page":"10332","DOI":"10.1523\/JNEUROSCI.3369-06.2006","article-title":"Estrogen, menopause, and the aging brain: how basic neuroscience can inform hormone therapy in women","volume":"26","author":"Morrison","year":"2006","journal-title":"J. Neurosci."},{"key":"ref97","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1126\/science.278.5337.412","article-title":"Life and death of neurons in the aging brain","volume":"278","author":"Morrison","year":"1997","journal-title":"Science"},{"key":"ref98","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1016\/s0079-6123(02)36039-4","article-title":"Selective vulnerability of corticocortical and hippocampal circuits in aging and Alzheimer's disease","volume":"136","author":"Morrison","year":"2002","journal-title":"Prog. Brain Res."},{"key":"ref99","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1016\/j.bbagen.2009.11.002","article-title":"Modulation of synaptic plasticity by brain estrogen in the hippocampus","volume":"1800","author":"Mukai","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref100","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1111\/j.1471-4159.2006.04264.x","article-title":"Rapid modulation of long-term depression and spinogenesis via synaptic estrogen receptors in hippocampal principal neurons","volume":"100","author":"Mukai","year":"2007","journal-title":"J. Neurochem."},{"key":"ref101","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1016\/j.bbrc.2008.12.076","article-title":"Social isolation stimulates hippocampal estradiol synthesis","volume":"379","author":"Munetsuna","year":"","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref102","doi-asserted-by":"publisher","first-page":"4260","DOI":"10.1210\/en.2008-1644","article-title":"Retinoic acid stimulates 17beta-estradiol and testosterone synthesis in rat hippocampal slice cultures","volume":"150","author":"Munetsuna","year":"","journal-title":"Endocrinology"},{"key":"ref103","doi-asserted-by":"publisher","DOI":"10.1111\/jne.12561","article-title":"Rapid nongenomic modulation by neurosteroids of dendritic spines in the hippocampus: androgen, oestrogen and corticosteroid","volume":"30","author":"Murakami","year":"2018","journal-title":"J. Neuroendocrinol."},{"key":"ref104","doi-asserted-by":"publisher","first-page":"4059","DOI":"10.1523\/JNEUROSCI.16-13-04059.1996","article-title":"Regulation of dendritic spine density in cultured rat hippocampal neurons by steroid hormones","volume":"16","author":"Murphy","year":"1996","journal-title":"J. Neurosci."},{"key":"ref105","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1159\/000126951","article-title":"Aromatase immunoreactivity in axon terminals of the vertebrate brain. An immunocytochemical study on quail, rat, monkey and human tissues","volume":"63","author":"Naftolin","year":"1996","journal-title":"Neuroendocrinology"},{"key":"ref106","doi-asserted-by":"publisher","first-page":"13100","DOI":"10.1073\/pnas.1210023109","article-title":"Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis","volume":"109","author":"Okamoto","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref107","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.jsbmb.2011.10.004","article-title":"Modulation of synaptic plasticity in the hippocampus by hippocampus-derived estrogen and androgen","volume":"131","author":"Ooishi","year":"2012","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref108","doi-asserted-by":"publisher","first-page":"e29598","DOI":"10.1371\/journal.pone.0029598","article-title":"Testosterone deficiency accelerates neuronal and vascular aging of SAMP8 mice: protective role of eNOS and SIRT1","volume":"7","author":"Ota","year":"2012","journal-title":"PLoS One"},{"key":"ref109","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.yhbeh.2018.05.019","article-title":"Rapid effects of estrogens on short-term memory: possible mechanisms","volume":"104","author":"Paletta","year":"2018","journal-title":"Horm. Behav."},{"key":"ref110","doi-asserted-by":"publisher","first-page":"100215","DOI":"10.1016\/j.ynstr.2020.100215","article-title":"Allopregnanolone: from molecular pathophysiology to therapeutics. A historical perspective","volume":"12","author":"Paul","year":"2020","journal-title":"Neurobiol. Stress"},{"key":"ref111","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.devcel.2014.04.016","article-title":"Membrane-localized estrogen receptor \u03b1 is required for normal organ development and function","volume":"29","author":"Pedram","year":"2014","journal-title":"Dev. Cell"},{"key":"ref112","doi-asserted-by":"publisher","first-page":"2057","DOI":"10.1007\/s11357-012-9495-6","article-title":"BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat","volume":"35","author":"Perovic","year":"2013","journal-title":"Age (Dordr.)"},{"key":"ref113","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1210\/en.2010-1273","article-title":"Rapid effects of estrogen receptor alpha and beta selective agonists on learning and dendritic spines in female mice","volume":"152","author":"Phan","year":"2011","journal-title":"Endocrinology"},{"key":"ref114","doi-asserted-by":"publisher","first-page":"16018","DOI":"10.1073\/pnas.1522150112","article-title":"Rapid increases in immature synapses parallel estrogen-induced hippocampal learning enhancements","volume":"112","author":"Phan","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref115","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.yfrne.2009.04.015","article-title":"Protective actions of sex steroid hormones in Alzheimer's disease","volume":"30","author":"Pike","year":"2009","journal-title":"Front. Neuroendocrinol."},{"key":"ref116","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1152\/jn.1999.81.3.1404","article-title":"Estradiol increases spine density and NMDA-dependent Ca2+ transients in spines of CA1 pyramidal neurons from hippocampal slices","volume":"81","author":"Pozzo-Miller","year":"1999","journal-title":"J. Neurophysiol."},{"key":"ref117","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1002\/hipo.10075","article-title":"Para\/autocrine regulation of estrogen receptors in hippocampal neurons","volume":"13","author":"Prange-Kiel","year":"2003","journal-title":"Hippocampus"},{"key":"ref118","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.18.9926","article-title":"Preserved neuron number in the hippocampus of aged rats with spatial learning deficits","volume":"93","author":"Rapp","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref119","doi-asserted-by":"publisher","first-page":"1923","DOI":"10.1097\/00001756-199705260-00026","article-title":"Impaired spatial information processing in aged monkeys with preserved recognition memory","volume":"8","author":"Rapp","year":"1997","journal-title":"Neuroreport"},{"key":"ref120","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/0197-4580(95)02032-2","article-title":"Memory impaired aged rats: no loss of principal hippocampal and subicular neurons","volume":"17","author":"Rasmussen","year":"1996","journal-title":"Neurobiol. Aging"},{"key":"ref121","doi-asserted-by":"publisher","first-page":"1621","DOI":"10.1152\/jn.00749.2011","article-title":"Sex-specific, rapid neuroestrogen fluctuations and neurophysiological actions in the songbird auditory forebrain","volume":"107","author":"Remage-Healey","year":"2012","journal-title":"J. Neurophysiol."},{"key":"ref122","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.brainres.2010.08.068","article-title":"Testosterone regulation of Alzheimer-like neuropathology in male 3xTg-AD mice involves both estrogen and androgen pathways","volume":"1359","author":"Rosario","year":"2010","journal-title":"Brain Res."},{"key":"ref123","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.1001\/jama.292.12.1431-b","article-title":"Age-related testosterone depletion and the development of Alzheimer disease","volume":"292","author":"Rosario","year":"2004","journal-title":"JAMA"},{"key":"ref124","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/S0301-0082(02)00126-0","article-title":"Impact of aging on hippocampal function: plasticity, network dynamics, and cognition","volume":"69","author":"Rosenzweig","year":"2003","journal-title":"Prog. Neurobiol."},{"key":"ref125","first-page":"23","article-title":"Dendritic changes in the aging human rhinencephalon","volume":"101","author":"Scheibel","year":"1976","journal-title":"Trans. Am. Neurol. Assoc."},{"key":"ref126","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3109\/10253899709014738","article-title":"Neurosteroids in the Hippocampus: neuronal plasticity and memory","volume":"2","author":"Schumacher","year":"1997","journal-title":"Stress (Amsterdam, Netherlands)"},{"key":"ref127","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/s12264-010-0913-4","article-title":"Effects of synaptic plasticity regulated by 17beta-estradiol on learning and memory in rats with Alzheimer's disease","volume":"26","author":"Shang","year":"2010","journal-title":"Neurosci. Bull."},{"key":"ref128","doi-asserted-by":"publisher","first-page":"e2300191120","DOI":"10.1073\/pnas.2300191120","article-title":"Social memory in female mice is rapidly modulated by 17\u03b2-estradiol through ERK and Akt modulation of synapse formation","volume":"120","author":"Sheppard","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref129","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/s0304-4165(02)00489-0","article-title":"Hippocampal cytochrome P450s synthesize brain neurosteroids which are paracrine neuromodulators of synaptic signal transduction","volume":"1619","author":"Shibuya","year":"2003","journal-title":"Biochim. Biophys. Acta"},{"key":"ref130","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1210\/endo-96-1-219","article-title":"The control of progesterone secretion during the estrous cycle and early pseudopregnancy in the rat: prolactin, gonadotropin and steroid levels associated with rescue of the corpus luteum of pseudopregnancy","volume":"96","author":"Smith","year":"1975","journal-title":"Endocrinology"},{"key":"ref131","doi-asserted-by":"publisher","first-page":"8517","DOI":"10.1523\/JNEUROSCI.5279-05.2006","article-title":"Estradiol-induced increase in the magnitude of long-term potentiation is prevented by blocking NR2B-containing receptors","volume":"26","author":"Smith","year":"2006","journal-title":"J. Neurosci."},{"key":"ref132","doi-asserted-by":"publisher","first-page":"282","DOI":"10.3389\/fnins.2018.00282","article-title":"Src kinase dependent rapid non-genomic modulation of hippocampal spinogenesis induced by androgen and estrogen","volume":"12","author":"Soma","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref133","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.neuroscience.2004.08.048","article-title":"Ultrastructural evidence that androgen receptors are located at extranuclear sites in the rat hippocampal formation","volume":"130","author":"Tabori","year":"2005","journal-title":"Neuroscience"},{"key":"ref134","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1038\/s41583-020-0362-7","article-title":"Oestradiol as a neuromodulator of learning and memory","volume":"21","author":"Taxier","year":"2020","journal-title":"Nat. Rev. Neurosci."},{"key":"ref135","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1126\/science.272.5264.1017","article-title":"Increase in single L-type calcium channels in hippocampal neurons during aging","volume":"272","author":"Thibault","year":"1996","journal-title":"Science"},{"key":"ref136","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1101\/SQB.1996.061.01.025","article-title":"Hippocampal CA1-region-restricted knockout of NMDAR1 gene disrupts synaptic plasticity, place fields, and spatial learning","volume":"61","author":"Tonegawa","year":"1996","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"ref137","doi-asserted-by":"publisher","first-page":"534","DOI":"10.3389\/fncel.2019.00534","article-title":"Bidirectional synaptic plasticity is driven by sex neurosteroids targeting estrogen and androgen receptors in hippocampal CA1 pyramidal neurons","volume":"13","author":"Tozzi","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref138","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1210\/jc.2006-1375","article-title":"A population-level decline in serum testosterone levels in American men","volume":"92","author":"Travison","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref139","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1523\/JNEUROSCI.3135-15.2016","article-title":"Estradiol-mediated spine changes in the dorsal Hippocampus and medial prefrontal cortex of Ovariectomized female mice depend on ERK and mTOR activation in the dorsal Hippocampus","volume":"36","author":"Tuscher","year":"","journal-title":"J. Neurosci."},{"key":"ref140","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.yhbeh.2016.05.001","article-title":"Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice","volume":"83","author":"Tuscher","year":"","journal-title":"Horm. Behav."},{"key":"ref141","doi-asserted-by":"publisher","first-page":"8116","DOI":"10.1523\/JNEUROSCI.5319-11.2012","article-title":"Aromatase inhibition abolishes LTP generation in female but not in male mice","volume":"32","author":"Vierk","year":"2012","journal-title":"J. Neurosci."},{"key":"ref142","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/S0361-9230(00)00377-4","article-title":"17beta-estradiol suppresses expression of long-term depression in aged rats","volume":"53","author":"Vouimba","year":"2000","journal-title":"Brain Res. Bull."},{"key":"ref143","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.psyneuen.2017.12.025","article-title":"Effects of testosterone dose on spatial memory among castrated adult male rats","volume":"89","author":"Wagner","year":"2018","journal-title":"Psychoneuroendocrinology"},{"key":"ref144","doi-asserted-by":"publisher","first-page":"7935","DOI":"10.1523\/JNEUROSCI.0801-18.2018","article-title":"Memory-related synaptic plasticity is sexually dimorphic in rodent hippocampus","volume":"38","author":"Wang","year":"2018","journal-title":"J. Neurosci."},{"key":"ref145","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1016\/S0140-6736(94)92338-8","article-title":"Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease","volume":"344","author":"West","year":"1994","journal-title":"Lancet (London, England)"},{"key":"ref146","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1016\/j.neurobiolaging.2003.12.005","article-title":"Hippocampal neurons in pre-clinical Alzheimer's disease","volume":"25","author":"West","year":"2004","journal-title":"Neurobiol. Aging"},{"key":"ref147","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1037\/\/0882-7974.12.2.372","article-title":"Age-related differences in an ecologically based study of route learning","volume":"12","author":"Wilkniss","year":"1997","journal-title":"Psychol. Aging"},{"key":"ref148","doi-asserted-by":"publisher","first-page":"4035","DOI":"10.1523\/jneurosci.10-12-04035.1990","article-title":"Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons","volume":"10","author":"Woolley","year":"1990","journal-title":"J. Neurosci."},{"key":"ref149","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.1523\/JNEUROSCI.17-05-01848.1997","article-title":"Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA receptor-mediated synaptic input: correlation with dendritic spine density","volume":"17","author":"Woolley","year":"1997","journal-title":"J. Neurosci."},{"key":"ref150","doi-asserted-by":"publisher","first-page":"e55559","DOI":"10.1371\/journal.pone.0055559","article-title":"De novo synthesized estradiol protects against methylmercury-induced neurotoxicity in cultured rat hippocampal slices","volume":"8","author":"Yamazaki","year":"2013","journal-title":"PLoS One"}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2025.1695565\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T15:26:59Z","timestamp":1769614019000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2025.1695565\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,28]]},"references-count":150,"alternative-id":["10.3389\/fncel.2025.1695565"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2025.1695565","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,28]]},"article-number":"1695565"}}