{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T01:18:00Z","timestamp":1789780680536,"version":"4.0.1"},"reference-count":91,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/100000049","name":"U.S. Department of Health & Human Services | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["AG083841"],"award-info":[{"award-number":["AG083841"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"U.S. Department of Health & Human Services | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["AG062166"],"award-info":[{"award-number":["AG062166"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"U.S. Department of Health & Human Services | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["AG064895"],"award-info":[{"award-number":["AG064895"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"U.S. Department of Health & Human Services | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["AG076235"],"award-info":[{"award-number":["AG076235"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Psychiatry"],"published-print":{"date-parts":[[2025,10]]},"DOI":"10.1038\/s41380-025-03067-0","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T17:48:49Z","timestamp":1749059329000},"page":"4720-4735","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Chronic social isolation-unpredictable stress induces early-onset cognitive deficits and exacerbates A\u03b2 accumulation in the 5xFAD mouse model of Alzheimer\u2019s disease"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4572-6078","authenticated-orcid":false,"given":"Yun","family":"Lei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8501-7116","authenticated-orcid":false,"given":"Jayvon","family":"Nougaisse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Malek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miskatul M.","family":"Mishu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8518-3712","authenticated-orcid":false,"given":"Kirstyn","family":"Denney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quansheng","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0612-2837","authenticated-orcid":false,"given":"Alexis M.","family":"Stranahan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob C.","family":"Garza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9103-4542","authenticated-orcid":false,"given":"Xin-Yun","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"3067_CR1","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association. 2024 Alzheimer\u2019s disease facts and figures. Alzheimers Dement 2024;20:3708\u2013821.","DOI":"10.1002\/alz.13809"},{"key":"3067_CR2","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1038\/353844a0","volume":"353","author":"MC Chartier-Harlin","year":"1991","unstructured":"Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, et al. Early-onset Alzheimer\u2019s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature. 1991;353:844\u20136.","journal-title":"Nature"},{"key":"3067_CR3","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/349704a0","volume":"349","author":"A Goate","year":"1991","unstructured":"Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer\u2019s disease. Nature. 1991;349:704\u20136.","journal-title":"Nature"},{"key":"3067_CR4","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/375754a0","volume":"375","author":"R Sherrington","year":"1995","unstructured":"Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer\u2019s disease. Nature. 1995;375:754\u201360.","journal-title":"Nature"},{"key":"3067_CR5","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1038\/376775a0","volume":"376","author":"EI Rogaev","year":"1995","unstructured":"Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, et al. Familial Alzheimer\u2019s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer\u2019s disease type 3 gene. Nature. 1995;376:775\u20138.","journal-title":"Nature"},{"key":"3067_CR6","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1093\/hmg\/5.7.985","volume":"5","author":"R Sherrington","year":"1996","unstructured":"Sherrington R, Froelich S, Sorbi S, Campion D, Chi H, Rogaeva EA, et al. Alzheimer\u2019s disease associated with mutations in presenilin 2 is rare and variably penetrant. Hum Mol Genet. 1996;5:985\u20138.","journal-title":"Hum Mol Genet"},{"key":"3067_CR7","doi-asserted-by":"crossref","first-page":"10129","DOI":"10.1523\/JNEUROSCI.1202-06.2006","volume":"26","author":"H Oakley","year":"2006","unstructured":"Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer\u2019s disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006;26:10129\u201340.","journal-title":"J Neurosci"},{"key":"3067_CR8","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S0042-6989(01)00146-8","volume":"42","author":"B Chang","year":"2002","unstructured":"Chang B, Hawes NL, Hurd RE, Davisson MT, Nusinowitz S, Heckenlively JR. Retinal degeneration mutants in the mouse. Vision Res. 2002;42:517\u201325.","journal-title":"Vision Res"},{"key":"3067_CR9","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/j.1460-9568.2005.04551.x","volume":"23","author":"M Ohno","year":"2006","unstructured":"Ohno M, Chang L, Tseng W, Oakley H, Citron M, Klein WL, et al. Temporal memory deficits in Alzheimer\u2019s mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci. 2006;23:251\u201360.","journal-title":"Eur J Neurosci"},{"key":"3067_CR10","first-page":"70","volume":"5","author":"MJ Duncan","year":"2019","unstructured":"Duncan MJ, Farlow H, Tirumalaraju C, Yun DH, Wang C, Howard JA, et al. Effects of the dual orexin receptor antagonist DORA-22 on sleep in 5XFAD mice. Alzheimers Dement. 2019;5:70\u201380.","journal-title":"Alzheimers Dement"},{"key":"3067_CR11","doi-asserted-by":"crossref","first-page":"e0263332","DOI":"10.1371\/journal.pone.0263332","volume":"17","author":"KR Sadleir","year":"2022","unstructured":"Sadleir KR, Popovic J, Khatri A, Vassar R. Oral nimodipine treatment has no effect on amyloid pathology or neuritic dystrophy in the 5XFAD mouse model of amyloidosis. PLoS ONE. 2022;17:e0263332.","journal-title":"PLoS ONE"},{"key":"3067_CR12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.15761\/JSIN.1000123","volume":"2","author":"H Qosa","year":"2016","unstructured":"Qosa H, Kaddoumi A. Effect of mouse strain as a background for Alzheimer\u2019s disease models on the clearance of amyloid-beta. J Syst Integr Neurosci. 2016;2:135\u201340.","journal-title":"J Syst Integr Neurosci"},{"key":"3067_CR13","doi-asserted-by":"crossref","first-page":"868473","DOI":"10.3389\/fnbeh.2022.868473","volume":"16","author":"M Ammassari-Teule","year":"2022","unstructured":"Ammassari-Teule M. Inbred mice again at stake: how the cognitive profile of the wild-type mouse background discloses pathogenic effects of APP mutations. Front Behav Neurosci. 2022;16:868473.","journal-title":"Front Behav Neurosci"},{"key":"3067_CR14","doi-asserted-by":"crossref","first-page":"113192","DOI":"10.1016\/j.bbr.2021.113192","volume":"404","author":"A Locci","year":"2021","unstructured":"Locci A, Orellana H, Rodriguez G, Gottliebson M, McClarty B, Dominguez S, et al. Comparison of memory, affective behavior, and neuropathology in APP(NLGF) knock-in mice to 5xFAD and APP\/PS1 mice. Behav Brain Res. 2021;404:113192.","journal-title":"Behav Brain Res"},{"key":"3067_CR15","doi-asserted-by":"crossref","first-page":"713726","DOI":"10.3389\/fnagi.2021.713726","volume":"13","author":"AL Oblak","year":"2021","unstructured":"Oblak AL, Lin PB, Kotredes KP, Pandey RS, Garceau D, Williams HM, et al. Comprehensive evaluation of the 5XFAD mouse model for preclinical testing applications: a MODEL-AD study. Front Aging Neurosci. 2021;13:713726.","journal-title":"Front Aging Neurosci"},{"key":"3067_CR16","doi-asserted-by":"crossref","DOI":"10.1038\/s41597-021-01054-y","volume":"8","author":"S Forner","year":"2021","unstructured":"Forner S, Kawauchi S, Balderrama-Gutierrez G, Kramar EA, Matheos DP, Phan J, et al. Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer\u2019s disease. Sci Data. 2021;8:270.","journal-title":"Sci Data"},{"key":"3067_CR17","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/S1474-4422(21)00066-1","volume":"20","author":"B Dubois","year":"2021","unstructured":"Dubois B, Villain N, Frisoni GB, Rabinovici GD, Sabbagh M, Cappa S, et al. Clinical diagnosis of Alzheimer\u2019s disease: recommendations of the international working group. Lancet Neurol. 2021;20:484\u201396.","journal-title":"Lancet Neurol"},{"key":"3067_CR18","doi-asserted-by":"crossref","first-page":"830 e831","DOI":"10.1016\/j.neurobiolaging.2011.07.005","volume":"33","author":"SM Rothman","year":"2012","unstructured":"Rothman SM, Herdener N, Camandola S, Texel SJ, Mughal MR, Cong WN, et al. 3xTgAD mice exhibit altered behavior and elevated Abeta after chronic mild social stress. Neurobiol Aging. 2012;33:830 e831\u2013812.","journal-title":"Neurobiol Aging"},{"key":"3067_CR19","doi-asserted-by":"crossref","first-page":"14436","DOI":"10.1523\/JNEUROSCI.3836-11.2011","volume":"31","author":"JC Carroll","year":"2011","unstructured":"Carroll JC, Iba M, Bangasser DA, Valentino RJ, James MJ, Brunden KR, et al. Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy. J Neurosci. 2011;31:14436\u201349.","journal-title":"J Neurosci"},{"key":"3067_CR20","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.neuroscience.2004.05.040","volume":"127","author":"H Dong","year":"2004","unstructured":"Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG. Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress. Neuroscience. 2004;127:601\u20139.","journal-title":"Neuroscience"},{"key":"3067_CR21","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1111\/jnc.13195","volume":"134","author":"D Baglietto-Vargas","year":"2015","unstructured":"Baglietto-Vargas D, Chen Y, Suh D, Ager RR, Rodriguez-Ortiz CJ, Medeiros R, et al. Short-term modern life-like stress exacerbates Abeta-pathology and synapse loss in 3xTg-AD mice. J Neurochem. 2015;134:915\u201326.","journal-title":"J Neurochem"},{"key":"3067_CR22","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/j.1471-4159.1993.tb03537.x","volume":"61","author":"EM Elliott","year":"1993","unstructured":"Elliott EM, Mattson MP, Vanderklish P, Lynch G, Chang I, Sapolsky RM. Corticosterone exacerbates kainate-induced alterations in hippocampal tau immunoreactivity and spectrin proteolysis in vivo. J Neurochem. 1993;61:57\u201367.","journal-title":"J Neurochem"},{"key":"3067_CR23","doi-asserted-by":"crossref","first-page":"9047","DOI":"10.1523\/JNEUROSCI.2797-06.2006","volume":"26","author":"KN Green","year":"2006","unstructured":"Green KN, Billings LM, Roozendaal B, McGaugh JL, LaFerla FM. Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer\u2019s disease. J Neurosci. 2006;26:9047\u201356.","journal-title":"J Neurosci"},{"key":"3067_CR24","doi-asserted-by":"crossref","first-page":"7840","DOI":"10.1523\/JNEUROSCI.0730-11.2011","volume":"31","author":"I Sotiropoulos","year":"2011","unstructured":"Sotiropoulos I, Catania C, Pinto LG, Silva R, Pollerberg GE, Takashima A, et al. Stress acts cumulatively to precipitate Alzheimer\u2019s disease-like tau pathology and cognitive deficits. J Neurosci. 2011;31:7840\u20137.","journal-title":"J Neurosci"},{"key":"3067_CR25","doi-asserted-by":"crossref","first-page":"2704","DOI":"10.1210\/en.2011-0145","volume":"152","author":"Y Wang","year":"2011","unstructured":"Wang Y, Li M, Tang J, Song M, Xu X, Xiong J, et al. Glucocorticoids facilitate astrocytic amyloid-beta peptide deposition by increasing the expression of APP and BACE1 and decreasing the expression of amyloid-beta-degrading proteases. Endocrinology. 2011;152:2704\u201315.","journal-title":"Endocrinology"},{"key":"3067_CR26","doi-asserted-by":"crossref","first-page":"167","DOI":"10.3233\/JAD-2012-120328","volume":"31","author":"YB Joshi","year":"2012","unstructured":"Joshi YB, Chu J, Pratico D. Stress hormone leads to memory deficits and altered tau phosphorylation in a model of Alzheimer\u2019s disease. J Alzheimers Dis. 2012;31:167\u201376.","journal-title":"J Alzheimers Dis"},{"key":"3067_CR27","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1038\/s41380-019-0352-1","volume":"25","author":"Y Lei","year":"2020","unstructured":"Lei Y, Wang J, Wang D, Li C, Liu B, Fang X, et al. SIRT1 in forebrain excitatory neurons produces sexually dimorphic effects on depression-related behaviors and modulates neuronal excitability and synaptic transmission in the medial prefrontal cortex. Mol Psychiatry. 2020;25:1094\u2013111.","journal-title":"Mol Psychiatry"},{"key":"3067_CR28","doi-asserted-by":"crossref","first-page":"4948","DOI":"10.1038\/s41380-022-01778-2","volume":"27","author":"Y Lei","year":"2022","unstructured":"Lei Y, Wang D, Bai Y, Nougaisse J, Weintraub NL, Guo M, et al. Leptin enhances social motivation and reverses chronic unpredictable stress-induced social anhedonia during adolescence. Mol Psychiatry. 2022;27:4948\u201358.","journal-title":"Mol Psychiatry"},{"key":"3067_CR29","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1038\/s41380-020-01004-x","volume":"26","author":"X Fang","year":"2021","unstructured":"Fang X, Jiang S, Wang J, Bai Y, Kim CS, Blake D, et al. Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity. Mol Psychiatry. 2021;26:2299\u2013315.","journal-title":"Mol Psychiatry"},{"key":"3067_CR30","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1038\/s41380-022-01872-5","volume":"28","author":"X Fang","year":"2023","unstructured":"Fang X, Chen Y, Wang J, Zhang Z, Bai Y, Denney K, et al. Increased intrinsic and synaptic excitability of hypothalamic POMC neurons underlies chronic stress-induced behavioral deficits. Mol Psychiatry. 2023;28:1365\u201382.","journal-title":"Mol Psychiatry"},{"key":"3067_CR31","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1126\/science.274.5284.99","volume":"274","author":"K Hsiao","year":"1996","unstructured":"Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996;274:99\u2013102.","journal-title":"Science"},{"key":"3067_CR32","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/0166-4328(88)90157-X","volume":"31","author":"A Ennaceur","year":"1988","unstructured":"Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data. Behav Brain Res. 1988;31:47\u201359.","journal-title":"Behav Brain Res"},{"key":"3067_CR33","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.bbr.2009.12.036","volume":"215","author":"A Ennaceur","year":"2010","unstructured":"Ennaceur A. One-trial object recognition in rats and mice: methodological and theoretical issues. Behav Brain Res. 2010;215:244\u201354.","journal-title":"Behav Brain Res"},{"key":"3067_CR34","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1038\/nprot.2013.155","volume":"8","author":"M Leger","year":"2013","unstructured":"Leger M, Quiedeville A, Bouet V, Haelewyn B, Boulouard M, Schumann-Bard P, et al. Object recognition test in mice. Nat Protoc. 2013;8:2531\u20137.","journal-title":"Nat Protoc"},{"key":"3067_CR35","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","volume":"9","author":"J Schindelin","year":"2012","unstructured":"Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676\u201382.","journal-title":"Nat Methods"},{"key":"3067_CR36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4137\/BCI.S13025","volume":"6","author":"CL Maarouf","year":"2013","unstructured":"Maarouf CL, Kokjohn TA, Whiteside CM, Macias MP, Kalback WM, Sabbagh MN, et al. Molecular differences and similarities between Alzheimer\u2019s disease and the 5XFAD transgenic mouse model of amyloidosis. Biochem Insights. 2013;6:1\u201310.","journal-title":"Biochem Insights"},{"key":"3067_CR37","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1016\/j.celrep.2016.06.060","volume":"16","author":"T Liebmann","year":"2016","unstructured":"Liebmann T, Renier N, Bettayeb K, Greengard P, Tessier-Lavigne M, Flajolet M. Three-dimensional study of Alzheimer\u2019s disease hallmarks using the iDISCO clearing method. Cell Rep. 2016;16:1138\u201352.","journal-title":"Cell Rep"},{"key":"3067_CR38","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.cell.2014.10.010","volume":"159","author":"N Renier","year":"2014","unstructured":"Renier N, Wu Z, Simon DJ, Yang J, Ariel P, Tessier-Lavigne M. iDISCO: a simple, rapid method to immunolabel large tissue samples for volume imaging. Cell. 2014;159:896\u2013910.","journal-title":"Cell"},{"key":"3067_CR39","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.bbi.2023.09.021","volume":"115","author":"AM Stranahan","year":"2024","unstructured":"Stranahan AM, Tabet A, Anikeeva P. Region-specific targeting of microglia in vivo using direct delivery of tamoxifen metabolites via microfluidic polymer fibers. Brain Behav Immun. 2024;115:131\u201342.","journal-title":"Brain Behav Immun"},{"key":"3067_CR40","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2105-13-316","volume":"13","author":"A Bria","year":"2012","unstructured":"Bria A, Iannello G. TeraStitcher - a tool for fast automatic 3D-stitching of teravoxel-sized microscopy images. BMC Bioinformatics. 2012;13:316.","journal-title":"BMC Bioinformatics"},{"key":"3067_CR41","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.cviu.2007.09.014","volume":"110","author":"H Bay","year":"2008","unstructured":"Bay H, Ess A, Tuytelaars T, Van Gool L. Speeded-Up robust features (SURF). Comput Vis Image Und. 2008;110:346\u201359.","journal-title":"Comput Vis Image Und"},{"key":"3067_CR42","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s10339-011-0430-z","volume":"13","author":"M Antunes","year":"2012","unstructured":"Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process. 2012;13:93\u2013110.","journal-title":"Cogn Process"},{"key":"3067_CR43","volume":"12","author":"YL Rao","year":"2022","unstructured":"Rao YL, Ganaraja B, Murlimanju BV, Joy T, Krishnamurthy A, Agrawal A. Hippocampus and its involvement in Alzheimer\u2019s disease: a review. 3 Biotech. 2022;12:55.","journal-title":"3 Biotech"},{"key":"3067_CR44","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.tins.2022.11.006","volume":"46","author":"KM Igarashi","year":"2023","unstructured":"Igarashi KM. Entorhinal cortex dysfunction in Alzheimer\u2019s disease. Trends Neurosci. 2023;46:124\u201336.","journal-title":"Trends Neurosci"},{"key":"3067_CR45","doi-asserted-by":"crossref","first-page":"fcab125","DOI":"10.1093\/braincomms\/fcab125","volume":"3","author":"DD Jobson","year":"2021","unstructured":"Jobson DD, Hase Y, Clarkson AN, Kalaria RN. The role of the medial prefrontal cortex in cognition, ageing and dementia. Brain Commun. 2021;3:fcab125.","journal-title":"Brain Commun"},{"key":"3067_CR46","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/s41586-022-05378-6","volume":"611","author":"C Grienberger","year":"2022","unstructured":"Grienberger C, Magee JC. Entorhinal cortex directs learning-related changes in CA1 representations. Nature. 2022;611:554\u201362.","journal-title":"Nature"},{"key":"3067_CR47","doi-asserted-by":"crossref","first-page":"e06426","DOI":"10.7554\/eLife.06426","volume":"4","author":"A Maass","year":"2015","unstructured":"Maass A, Berron D, Libby LA, Ranganath C, Duzel E. Functional subregions of the human entorhinal cortex. eLife. 2015;4:e06426.","journal-title":"eLife"},{"key":"3067_CR48","doi-asserted-by":"crossref","first-page":"20130369","DOI":"10.1098\/rstb.2013.0369","volume":"369","author":"JJ Knierim","year":"2014","unstructured":"Knierim JJ, Neunuebel JP, Deshmukh SS. Functional correlates of the lateral and medial entorhinal cortex: objects, path integration and local-global reference frames. Philos Trans R Soc Lond B Biol Sci. 2014;369:20130369.","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"3067_CR49","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.brainresbull.2022.02.001","volume":"181","author":"LA Oliveira","year":"2022","unstructured":"Oliveira LA, Carvalho II, Kurokawa RY, Duarte JO, Busnardo C, Crestani CC. Differential roles of prelimbic and infralimbic cholinergic neurotransmissions in control of cardiovascular responses to restraint stress in rats. Brain Res Bull. 2022;181:175\u201382.","journal-title":"Brain Res Bull"},{"key":"3067_CR50","doi-asserted-by":"crossref","first-page":"107117","DOI":"10.1016\/j.nlm.2019.107117","volume":"169","author":"JT Porter","year":"2020","unstructured":"Porter JT, Sepulveda-Orengo MT. Learning-induced intrinsic and synaptic plasticity in the rodent medial prefrontal cortex. Neurobiol Learn Mem. 2020;169:107117.","journal-title":"Neurobiol Learn Mem"},{"key":"3067_CR51","doi-asserted-by":"crossref","first-page":"109867","DOI":"10.1016\/j.neuropharm.2024.109867","volume":"248","author":"MA Laine","year":"2024","unstructured":"Laine MA, Greiner EM, Shansky RM. Sex differences in the rodent medial prefrontal cortex - what do and don\u2019t we know? Neuropharmacology. 2024;248:109867.","journal-title":"Neuropharmacology"},{"key":"3067_CR52","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/sj.mp.4001979","volume":"12","author":"MJ Kas","year":"2007","unstructured":"Kas MJ, Fernandes C, Schalkwyk LC, Collier DA. Genetics of behavioural domains across the neuropsychiatric spectrum; of mice and men. Mol Psychiatry. 2007;12:324\u201330.","journal-title":"Mol Psychiatry"},{"key":"3067_CR53","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1111\/j.1469-7610.2005.01557.x","volume":"47","author":"M Rutter","year":"2006","unstructured":"Rutter M, Moffitt TE, Caspi A. Gene-environment interplay and psychopathology: multiple varieties but real effects. J Child Psychol Psychiatry. 2006;47:226\u201361.","journal-title":"J Child Psychol Psychiatry"},{"key":"3067_CR54","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s13024-017-0231-7","volume":"12","author":"JL Jankowsky","year":"2017","unstructured":"Jankowsky JL, Zheng H. Practical considerations for choosing a mouse model of Alzheimer\u2019s disease. Mol Neurodegener. 2017;12:89.","journal-title":"Mol Neurodegener"},{"key":"3067_CR55","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13024-024-00712-0","volume":"19","author":"MZ Zhong","year":"2024","unstructured":"Zhong MZ, Peng T, Duarte ML, Wang M, Cai D. Updates on mouse models of Alzheimer\u2019s disease. Mol Neurodegener. 2024;19:23.","journal-title":"Mol Neurodegener"},{"key":"3067_CR56","doi-asserted-by":"crossref","first-page":"6766","DOI":"10.3390\/ijms25126766","volume":"25","author":"MS Padua","year":"2024","unstructured":"Padua MS, Guil-Guerrero JL, Lopes PA. Behaviour hallmarks in Alzheimer\u2019s disease 5xFAD mouse model. Int J Mol Sci. 2024;25:6766.","journal-title":"Int J Mol Sci"},{"key":"3067_CR57","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.nbd.2011.09.001","volume":"45","author":"L Devi","year":"2012","unstructured":"Devi L, Ohno M. Mitochondrial dysfunction and accumulation of the beta-secretase-cleaved C-terminal fragment of APP in Alzheimer\u2019s disease transgenic mice. Neurobiol Dis. 2012;45:417\u201324.","journal-title":"Neurobiol Dis"},{"key":"3067_CR58","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/s42003-019-0599-8","volume":"2","author":"R Gail Canter","year":"2019","unstructured":"Gail Canter R, Huang WC, Choi H, Wang J, Ashley Watson L, Yao CG, et al. 3D mapping reveals network-specific amyloid progression and subcortical susceptibility in mice. Commun Biol. 2019;2:360.","journal-title":"Commun Biol"},{"key":"3067_CR59","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1152\/physrev.00041.2006","volume":"87","author":"BS McEwen","year":"2007","unstructured":"McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev. 2007;87:873\u2013904.","journal-title":"Physiol Rev"},{"key":"3067_CR60","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.neubiorev.2020.05.010","volume":"115","author":"CE Lyons","year":"2020","unstructured":"Lyons CE, Bartolomucci A. Stress and Alzheimer\u2019s disease: a senescence link? Neurosci Biobehav Rev. 2020;115:285\u201398.","journal-title":"Neurosci Biobehav Rev"},{"key":"3067_CR61","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ynstr.2018.04.002","volume":"8","author":"NJ Justice","year":"2018","unstructured":"Justice NJ. The relationship between stress and Alzheimer\u2019s disease. Neurobiol Stress. 2018;8:127\u201333.","journal-title":"Neurobiol Stress"},{"key":"3067_CR62","doi-asserted-by":"crossref","DOI":"10.1186\/1756-6606-3-34","volume":"3","author":"L Devi","year":"2010","unstructured":"Devi L, Alldred MJ, Ginsberg SD, Ohno M. Sex- and brain region-specific acceleration of beta-amyloidogenesis following behavioral stress in a mouse model of Alzheimer\u2019s disease. Mol Brain. 2010;3:34.","journal-title":"Mol Brain"},{"key":"3067_CR63","doi-asserted-by":"crossref","first-page":"112366","DOI":"10.1016\/j.bbr.2019.112366","volume":"379","author":"JL Peterman","year":"2020","unstructured":"Peterman JL, White JD, Calcagno A, Hagen C, Quiring M, Paulhus K, et al. Prolonged isolation stress accelerates the onset of Alzheimer\u2019s disease-related pathology in 5xFAD mice despite running wheels and environmental enrichment. Behav Brain Res. 2020;379:112366.","journal-title":"Behav Brain Res"},{"key":"3067_CR64","doi-asserted-by":"crossref","DOI":"10.1186\/s12974-022-02515-w","volume":"19","author":"S Bachiller","year":"2022","unstructured":"Bachiller S, Hidalgo I, Garcia MG, Boza-Serrano A, Paulus A, Denis Q, et al. Early-life stress elicits peripheral and brain immune activation differently in wild type and 5xFAD mice in a sex-specific manner. J Neuroinflammation. 2022;19:151.","journal-title":"J Neuroinflammation"},{"key":"3067_CR65","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/npp.2015.171","volume":"41","author":"BS McEwen","year":"2016","unstructured":"McEwen BS, Nasca C, Gray JD. Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology. 2016;41:3\u201323.","journal-title":"Neuropsychopharmacology"},{"key":"3067_CR66","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.neuron.2023.12.021","volume":"112","author":"N Yadav","year":"2024","unstructured":"Yadav N, Toader A, Rajasethupathy P. Beyond hippocampus: thalamic and prefrontal contributions to an evolving memory. Neuron. 2024;112:1045\u201359.","journal-title":"Neuron"},{"key":"3067_CR67","first-page":"190","volume":"9","author":"T Sigurdsson","year":"2015","unstructured":"Sigurdsson T, Duvarci S. Hippocampal-prefrontal interactions in cognition, behavior and psychiatric disease. Front Syst Neurosci. 2015;9:190.","journal-title":"Front Syst Neurosci"},{"key":"3067_CR68","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1038\/nn.4661","volume":"20","author":"J Lisman","year":"2017","unstructured":"Lisman J, Buzsaki G, Eichenbaum H, Nadel L, Ranganath C, Redish AD. Viewpoints: how the hippocampus contributes to memory, navigation and cognition. Nat Neurosci. 2017;20:1434\u201347.","journal-title":"Nat Neurosci"},{"key":"3067_CR69","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.tins.2021.08.003","volume":"44","author":"KZ Gerlei","year":"2021","unstructured":"Gerlei KZ, Brown CM, Surmeli G, Nolan MF. Deep entorhinal cortex: from circuit organization to spatial cognition and memory. Trends Neurosci. 2021;44:876\u201387.","journal-title":"Trends Neurosci"},{"key":"3067_CR70","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.nlm.2008.05.008","volume":"90","author":"GM Dillon","year":"2008","unstructured":"Dillon GM, Qu X, Marcus JN, Dodart JC. Excitotoxic lesions restricted to the dorsal CA1 field of the hippocampus impair spatial memory and extinction learning in C57BL\/6 mice. Neurobiol Learn Mem. 2008;90:426\u201333.","journal-title":"Neurobiol Learn Mem"},{"key":"3067_CR71","doi-asserted-by":"crossref","first-page":"110659","DOI":"10.1016\/j.celrep.2022.110659","volume":"39","author":"P Vogel","year":"2022","unstructured":"Vogel P, Hahn J, Duvarci S, Sigurdsson T. Prefrontal pyramidal neurons are critical for all phases of working memory. Cell Rep. 2022;39:110659.","journal-title":"Cell Rep"},{"key":"3067_CR72","doi-asserted-by":"crossref","DOI":"10.1038\/s41398-019-0471-0","volume":"9","author":"AM Bygrave","year":"2019","unstructured":"Bygrave AM, Jahans-Price T, Wolff AR, Sprengel R, Kullmann DM, Bannerman DM, et al. Hippocampal-prefrontal coherence mediates working memory and selective attention at distinct frequency bands and provides a causal link between schizophrenia and its risk gene GRIA1. Transl Psychiatry. 2019;9:142.","journal-title":"Transl Psychiatry"},{"key":"3067_CR73","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1093\/cercor\/bhs033","volume":"23","author":"T Van Cauter","year":"2013","unstructured":"Van Cauter T, Camon J, Alvernhe A, Elduayen C, Sargolini F, Save E. Distinct roles of medial and lateral entorhinal cortex in spatial cognition. Cereb Cortex. 2013;23:451\u20139.","journal-title":"Cereb Cortex"},{"key":"3067_CR74","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1212\/WNL.0b013e318238eec1","volume":"77","author":"ED Vidoni","year":"2011","unstructured":"Vidoni ED, Townley RA, Honea RA, Burns JM, Alzheimer\u2019s Disease Neuroimaging I. Alzheimer disease biomarkers are associated with body mass index. Neurology. 2011;77:1913\u201320.","journal-title":"Neurology"},{"key":"3067_CR75","doi-asserted-by":"crossref","first-page":"349","DOI":"10.2174\/1567205010666131120110930","volume":"11","author":"Y Gu","year":"2014","unstructured":"Gu Y, Scarmeas N, Cosentino S, Brandt J, Albert M, Blacker D, et al. Change in body mass index before and after Alzheimer\u2019s disease onset. Curr Alzheimer Res. 2014;11:349\u201356.","journal-title":"Curr Alzheimer Res"},{"key":"3067_CR76","doi-asserted-by":"crossref","first-page":"e0151710","DOI":"10.1371\/journal.pone.0151710","volume":"11","author":"I Cova","year":"2016","unstructured":"Cova I, Clerici F, Rossi A, Cucumo V, Ghiretti R, Maggiore L, et al. Weight loss predicts progression of mild cognitive impairment to Alzheimer\u2019s disease. PLoS ONE. 2016;11:e0151710.","journal-title":"PLoS ONE"},{"key":"3067_CR77","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.cmet.2012.06.015","volume":"16","author":"HJ Grill","year":"2012","unstructured":"Grill HJ, Hayes MR. Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab. 2012;16:296\u2013309.","journal-title":"Cell Metab"},{"key":"3067_CR78","doi-asserted-by":"crossref","first-page":"115398","DOI":"10.1016\/j.bbr.2024.115398","volume":"480","author":"M Arcon","year":"2025","unstructured":"Arcon M. The interplay between hypothalamic and brainstem nuclei in homeostatic control of energy balance. Behav Brain Res. 2025;480:115398.","journal-title":"Behav Brain Res"},{"key":"3067_CR79","doi-asserted-by":"crossref","first-page":"E399","DOI":"10.1152\/ajpcell.1990.258.3.C399","volume":"258","author":"DC Simonson","year":"1990","unstructured":"Simonson DC, DeFronzo RA. Indirect calorimetry: methodological and interpretative problems. Am J Physiol. 1990;258:E399\u2013412.","journal-title":"Am J Physiol"},{"key":"3067_CR80","doi-asserted-by":"crossref","first-page":"eaba3884","DOI":"10.1126\/sciadv.aba3884","volume":"6","author":"J Huang","year":"2020","unstructured":"Huang J, van Zijl PCM, Han X, Dong CM, Cheng GWY, Tse KH, et al. Altered d-glucose in brain parenchyma and cerebrospinal fluid of early Alzheimer\u2019s disease detected by dynamic glucose-enhanced MRI. Sci Adv. 2020;6:eaba3884.","journal-title":"Sci Adv"},{"key":"3067_CR81","doi-asserted-by":"crossref","first-page":"9540","DOI":"10.3390\/ijms23179540","volume":"23","author":"V Kumar","year":"2022","unstructured":"Kumar V, Kim SH, Bishayee K. Dysfunctional glucose metabolism in Alzheimer\u2019s disease onset and potential pharmacological interventions. Int J Mol Sci. 2022;23:9540.","journal-title":"Int J Mol Sci"},{"key":"3067_CR82","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1176\/ajp.2006.163.12.2164","volume":"163","author":"JG Csernansky","year":"2006","unstructured":"Csernansky JG, Dong H, Fagan AM, Wang L, Xiong C, Holtzman DM, et al. Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia. Am J Psychiatry. 2006;163:2164\u20139.","journal-title":"Am J Psychiatry"},{"key":"3067_CR83","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.biopsych.2007.03.013","volume":"62","author":"GM Peavy","year":"2007","unstructured":"Peavy GM, Lange KL, Salmon DP, Patterson TL, Goldman S, Gamst AC, et al. The effects of prolonged stress and APOE genotype on memory and cortisol in older adults. Biol Psychiatry. 2007;62:472\u20138.","journal-title":"Biol Psychiatry"},{"key":"3067_CR84","first-page":"45","volume":"2","author":"RH Pietrzak","year":"2017","unstructured":"Pietrzak RH, Laws SM, Lim YY, Bender SJ, Porter T, Doecke J, et al. Plasma cortisol, brain amyloid-beta, and cognitive decline in preclinical Alzheimer\u2019s disease: a 6-year prospective cohort study. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017;2:45\u201352.","journal-title":"Biol Psychiatry Cogn Neurosci Neuroimaging"},{"key":"3067_CR85","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.neurobiolaging.2014.10.031","volume":"36","author":"J Popp","year":"2015","unstructured":"Popp J, Wolfsgruber S, Heuser I, Peters O, Hull M, Schroder J, et al. Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer\u2019s type. Neurobiol Aging. 2015;36:601\u20137.","journal-title":"Neurobiol Aging"},{"key":"3067_CR86","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3233\/JAD-2012-121438","volume":"33","author":"EK Hebda-Bauer","year":"2013","unstructured":"Hebda-Bauer EK, Simmons TA, Sugg A, Ural E, Stewart JA, Beals JL, et al. 3xTg-AD mice exhibit an activated central stress axis during early-stage pathology. J Alzheimers Dis. 2013;33:407\u201322.","journal-title":"J Alzheimers Dis"},{"key":"3067_CR87","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1002\/j.2040-4603.2016.tb00694.x","volume":"6","author":"JP Herman","year":"2016","unstructured":"Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol. 2016;6:603\u201321.","journal-title":"Compr Physiol"},{"key":"3067_CR88","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/S0166-2236(96)10069-2","volume":"20","author":"JP Herman","year":"1997","unstructured":"Herman JP, Cullinan WE. Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci. 1997;20:78\u201384.","journal-title":"Trends Neurosci"},{"key":"3067_CR89","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1210\/edrv-12-2-118","volume":"12","author":"L Jacobson","year":"1991","unstructured":"Jacobson L, Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev. 1991;12:118\u201334.","journal-title":"Endocr Rev"},{"key":"3067_CR90","doi-asserted-by":"crossref","first-page":"7863","DOI":"10.1523\/JNEUROSCI.23-21-07863.2003","volume":"23","author":"XY Lu","year":"2003","unstructured":"Lu XY, Barsh GS, Akil H, Watson SJ. Interaction between alpha-melanocyte-stimulating hormone and corticotropin-releasing hormone in the regulation of feeding and hypothalamo-pituitary-adrenal responses. J Neurosci. 2003;23:7863\u201372.","journal-title":"J Neurosci"},{"key":"3067_CR91","volume-title":"The mouse brain in stereotaxic coordinates","author":"KB Franklin","year":"2001","unstructured":"Franklin KB. The mouse brain in stereotaxic coordinates. San Diego: Academic Press; 2001."}],"container-title":["Molecular Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03067-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03067-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03067-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T15:43:15Z","timestamp":1757950995000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03067-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,4]]},"references-count":91,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["3067"],"URL":"https:\/\/doi.org\/10.1038\/s41380-025-03067-0","relation":{},"ISSN":["1359-4184","1476-5578"],"issn-type":[{"value":"1359-4184","type":"print"},{"value":"1476-5578","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,4]]},"assertion":[{"value":"3 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 May 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 June 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All animal procedures were approved by the Institutional Animal Care and Use Committee of Augusta University (Animal Use Protocol #2017-0868) and conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}]}}