{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T01:51:26Z","timestamp":1777341086927,"version":"3.51.4"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,8,11]],"date-time":"2016-08-11T00:00:00Z","timestamp":1470873600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,8,11]],"date-time":"2016-08-11T00:00:00Z","timestamp":1470873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A<jats:sub>2A<\/jats:sub> receptor (A<jats:sub>2A<\/jats:sub>R), which is upregulated in the human forebrain of aged and Alzheimer\u2019s disease (AD) patients. We have previously shown that an anti-A<jats:sub>2A<\/jats:sub>R therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A<jats:sub>2A<\/jats:sub>R over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A<jats:sub>2A<\/jats:sub>R overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A<jats:sub>2A<\/jats:sub>R over-activation and were rescued by anti-A<jats:sub>2A<\/jats:sub>R therapy; finally, we demonstrate that A<jats:sub>2A<\/jats:sub>R act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A<jats:sub>2A<\/jats:sub>R is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A<jats:sub>2A<\/jats:sub>R antagonists, namely caffeine, on Alzheimer\u2019s and age-related cognitive impairments may rely on its ability to modulate GR actions.<\/jats:p>","DOI":"10.1038\/srep31493","type":"journal-article","created":{"date-parts":[[2016,8,11]],"date-time":"2016-08-11T09:15:05Z","timestamp":1470906905000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function"],"prefix":"10.1038","volume":"6","author":[{"given":"V\u00e2nia L.","family":"Batalha","sequence":"first","affiliation":[]},{"given":"Diana G.","family":"Ferreira","sequence":"additional","affiliation":[]},{"given":"Joana E.","family":"Coelho","sequence":"additional","affiliation":[]},{"given":"Jorge S.","family":"Valadas","sequence":"additional","affiliation":[]},{"given":"Rui","family":"Gomes","sequence":"additional","affiliation":[]},{"given":"Mariana","family":"Temido-Ferreira","sequence":"additional","affiliation":[]},{"given":"Tatiana","family":"Shmidt","sequence":"additional","affiliation":[]},{"given":"Younis","family":"Baqi","sequence":"additional","affiliation":[]},{"given":"Luc","family":"Bu\u00e9e","sequence":"additional","affiliation":[]},{"given":"Christa E.","family":"M\u00fcller","sequence":"additional","affiliation":[]},{"given":"Malika","family":"Hamdane","sequence":"additional","affiliation":[]},{"given":"Tiago F.","family":"Outeiro","sequence":"additional","affiliation":[]},{"given":"Michael","family":"Bader","sequence":"additional","affiliation":[]},{"given":"Sebastiaan H.","family":"Meijsing","sequence":"additional","affiliation":[]},{"given":"Ghazaleh","family":"Sadri-Vakili","sequence":"additional","affiliation":[]},{"given":"David","family":"Blum","sequence":"additional","affiliation":[]},{"given":"Lu\u00edsa V.","family":"Lopes","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2016,8,11]]},"reference":[{"key":"BFsrep31493_CR1","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1038\/mp.2012.8","volume":"18","author":"VL Batalha","year":"2013","unstructured":"Batalha, V. L. et al. Adenosine A(2A) receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation. Mol Psychiatry 18, 320\u2013331, 10.1038\/mp.2012.8 (2013).","journal-title":"Mol Psychiatry"},{"key":"BFsrep31493_CR2","doi-asserted-by":"publisher","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 12, 118\u2013134, 10.1210\/edrv-12-2-118 (1991).","journal-title":"Endocr Rev"},{"key":"BFsrep31493_CR3","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/271","volume":"1","author":"SJ Lupien","year":"1998","unstructured":"Lupien, S. J. et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci 1, 69\u201373, 10.1038\/271 (1998).","journal-title":"Nat Neurosci"},{"key":"BFsrep31493_CR4","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1001\/archpsyc.64.7.810","volume":"64","author":"BK Lee","year":"2007","unstructured":"Lee, B. K. et al. Associations of salivary cortisol with cognitive function in the Baltimore memory study. Arch Gen Psychiatry 64, 810\u2013818, 64\/7\/810 (2007).","journal-title":"Arch Gen Psychiatry"},{"key":"BFsrep31493_CR5","doi-asserted-by":"publisher","first-page":"2164","DOI":"10.1176\/ajp.2006.163.12.2164","volume":"163","author":"JG Csernansky","year":"2006","unstructured":"Csernansky, J. G. et al. Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia. Am J Psychiatry 163, 2164\u20132169, 163\/12\/2164 (2006).","journal-title":"Am J Psychiatry"},{"key":"BFsrep31493_CR6","doi-asserted-by":"publisher","first-page":"9047","DOI":"10.1523\/JNEUROSCI.2797-06.2006","volume":"26","author":"KN Green","year":"2006","unstructured":"Green, K. N., Billings, L. M., Roozendaal, B., McGaugh, J. L. & LaFerla, F. M. Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer\u2019s disease. J Neurosci 26, 9047\u20139056, 26\/35\/9047 (2006).","journal-title":"J Neurosci"},{"key":"BFsrep31493_CR7","doi-asserted-by":"publisher","first-page":"2688","DOI":"10.1002\/dvdy.22780","volume":"240","author":"D Caroll","year":"2011","unstructured":"Caroll, D. & Zhang, B. Primer and interviews: advances in targeted gene modification. Interview by Julie C. Kiefer. Dev Dyn 240, 2688\u20132696, 10.1002\/dvdy.22780 (2011).","journal-title":"Dev Dyn"},{"key":"BFsrep31493_CR8","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1179\/016164110\u00d712816242542698","volume":"33","author":"YY Yao","year":"2011","unstructured":"Yao, Y. Y., Wu, Q. S., Li, W. Z. & Li, W. P. Dexamethasone potentiated Abeta-induced learning and memory impairment in rats. Neurol Res 33, 371\u2013380, 10.1179\/016164110\u00d712816242542698 (2011).","journal-title":"Neurol Res"},{"key":"BFsrep31493_CR9","doi-asserted-by":"publisher","first-page":"2815","DOI":"10.1016\/j.biocel.2008.05.016","volume":"40","author":"YC Chen","year":"2008","unstructured":"Chen, Y. C., Huang, S. H. & Wang, S. M. Adenosine-stimulated adrenal steroidogenesis involves the adenosine A2A and A2B receptors and the Janus kinase 2-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase signaling pathway. Int J Biochem Cell Biol 40, 2815\u20132825, 10.1016\/j.biocel.2008.05.016 (2008).","journal-title":"Int J Biochem Cell Biol"},{"key":"BFsrep31493_CR10","doi-asserted-by":"publisher","first-page":"64","DOI":"10.3171\/spi.2006.4.1.64","volume":"4","author":"DO Okonkwo","year":"2006","unstructured":"Okonkwo, D. O. et al. A comparison of adenosine A2A agonism and methylprednisolone in attenuating neuronal damage and improving functional outcome after experimental traumatic spinal cord injury in rabbits. J Neurosurg Spine 4, 64\u201370, 10.3171\/spi.2006.4.1.64 (2006).","journal-title":"J Neurosurg Spine"},{"key":"BFsrep31493_CR11","doi-asserted-by":"publisher","first-page":"1733","DOI":"10.1046\/j.1471-4159.1999.731733.x","volume":"73","author":"LV Lopes","year":"1999","unstructured":"Lopes, L. V., Cunha, R. A. & Ribeiro, J. A. Increase in the number, G protein coupling, and efficiency of facilitatory adenosine A2A receptors in the limbic cortex, but not striatum, of aged rats. J Neurochem 73, 1733\u20131738 (1999).","journal-title":"J Neurochem"},{"key":"BFsrep31493_CR12","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1111\/j.1750-3639.2007.00112.x","volume":"18","author":"JL Albasanz","year":"2008","unstructured":"Albasanz, J. L., Perez, S., Barrachina, M., Ferrer, I. & Martin, M. Up-regulation of adenosine receptors in the frontal cortex in Alzheimer\u2019s disease. Brain Pathol 18, 211\u2013219, 10.1111\/j.1750-3639.2007.00112.x (2008).","journal-title":"Brain Pathol"},{"key":"BFsrep31493_CR13","first-page":"153","volume":"125","author":"VL Batalha","year":"2013","unstructured":"Batalha, V. L., Valadas, J. S., Baqi, Y., Radjainia, H. & Lopes, L. V. Adenosine A2A receptor activation-trigger to aging-like modifications on adenosine modulation in the hippocampus. Journal of Neurochemistry 125, 153 (2013).","journal-title":"Journal of Neurochemistry"},{"key":"BFsrep31493_CR14","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1016\/j.neuroscience.2006.07.021","volume":"142","author":"GW Arendash","year":"2006","unstructured":"Arendash, G. W. et al. Caffeine protects Alzheimer\u2019s mice against cognitive impairment and reduces brain beta-amyloid production. Neuroscience 142, 941\u2013952, S0306-4522(06)00937-7 (2006).","journal-title":"Neuroscience"},{"key":"BFsrep31493_CR15","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.biopsych.2012.12.003","volume":"74","author":"D Baglietto-Vargas","year":"2013","unstructured":"Baglietto-Vargas, D., Medeiros, R., Martinez-Coria, H., LaFerla, F. M. & Green, K. N. Mifepristone alters amyloid precursor protein processing to preclude amyloid beta and also reduces tau pathology. Biol Psychiatry 74, 357\u2013366, 10.1016\/j.biopsych.2012.12.003 (2013).","journal-title":"Biol Psychiatry"},{"key":"BFsrep31493_CR16","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1038\/npp.2015.25","volume":"40","author":"F Lante","year":"2015","unstructured":"Lante, F. et al. Subchronic glucocorticoid receptor inhibition rescues early episodic memory and synaptic plasticity deficits in a mouse model of Alzheimer\u2019s disease. Neuropsychopharmacology 40, 1772\u20131781, 10.1038\/npp.2015.25 (2015).","journal-title":"Neuropsychopharmacology"},{"key":"BFsrep31493_CR17","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1038\/mp.2015.115","volume":"21","author":"C Laurent","year":"2016","unstructured":"Laurent, C. et al. A2A adenosine receptor deletion is protective in a mouse model of Tauopathy. Mol Psychiatry 21, 149, 10.1038\/mp.2015.115 (2016).","journal-title":"Mol Psychiatry"},{"key":"BFsrep31493_CR18","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1046\/j.0953-816x.2001.01781.x","volume":"14","author":"JL Bizon","year":"2001","unstructured":"Bizon, J. L. et al. Hypothalamic-pituitary-adrenal axis function and corticosterone receptor expression in behaviourally characterized young and aged Long-Evans rats. Eur J Neurosci 14, 1739\u20131751 (2001).","journal-title":"Eur J Neurosci"},{"key":"BFsrep31493_CR19","first-page":"107","volume":"33","author":"EA Popova","year":"2002","unstructured":"Popova, E. A., Krivokharchenko, A. S. & Vil\u2019ianovich, L. I. [In vitro development of murine embryos using different types of microinjections]. Ontogenez 33, 107\u2013110 (2002).","journal-title":"Ontogenez"},{"key":"BFsrep31493_CR20","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1101\/SQB.1996.061.01.024","volume":"61","author":"M Mayford","year":"1996","unstructured":"Mayford, M., Bach, M. E. & Kandel, E. CaMKII function in the nervous system explored from a genetic perspective. Cold Spring Harb Symp Quant Biol 61, 219\u2013224 (1996).","journal-title":"Cold Spring Harb Symp Quant Biol"},{"key":"BFsrep31493_CR21","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1038\/nprot.2008.73","volume":"3","author":"TD Schmittgen","year":"2008","unstructured":"Schmittgen, T. D. & Livak, K. J. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3, 1101\u20131108 (2008).","journal-title":"Nat Protoc"},{"key":"BFsrep31493_CR22","doi-asserted-by":"publisher","first-page":"4662","DOI":"10.1128\/IAI.72.8.4662-4667.2004","volume":"72","author":"SD Palacios","year":"2004","unstructured":"Palacios, S. D. et al. Role of p38 mitogen-activated protein kinase in middle ear mucosa hyperplasia during bacterial otitis media. Infect Immun 72, 4662\u20134667, 10.1128\/IAI.72.8.4662-4667.2004 (2004).","journal-title":"Infect Immun"},{"key":"BFsrep31493_CR23","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","volume":"193","author":"OH Lowry","year":"1951","unstructured":"Lowry, O. H., Rosebrough, N. J., Farr, A. L. & Randall, R. J. Protein measurement with the Folin phenol reagent. J Biol Chem 193, 265\u2013275 (1951).","journal-title":"J Biol Chem"},{"key":"BFsrep31493_CR24","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1111\/jnc.12050","volume":"123","author":"JS Valadas","year":"2012","unstructured":"Valadas, J. S. et al. Neuroprotection afforded by adenosine A2A receptor blockade is modulated by corticotrophin-releasing factor (CRF) in glutamate injured cortical neurons. J Neurochem 123, 1030\u20131040, 10.1111\/jnc.12050 (2012).","journal-title":"J Neurochem"},{"key":"BFsrep31493_CR25","doi-asserted-by":"publisher","first-page":"3308","DOI":"10.1021\/jo0358574","volume":"69","author":"J Hockemeyer","year":"2004","unstructured":"Hockemeyer, J., Burbiel, J. C. & Muller, C. E. Multigram-scale syntheses, stability, and photoreactions of A2A adenosine receptor antagonists with 8-styrylxanthine structure: potential drugs for Parkinson\u2019s disease. J Org Chem 69, 3308\u20133318, 10.1021\/jo0358574 (2004).","journal-title":"J Org Chem"},{"key":"#cr-split#-BFsrep31493_CR26.1","unstructured":"Batalha, V. F., Coelho, D. G., Valadas, J. E, Bader, J. S., Gomes, M., R. A. Blum, D. & Lopes, L. V. Adenosine neuromodulation of hippocampal synaptic transmission in chronic stress: aging-like effect. Paper presented at FENS Forum 2014"},{"key":"#cr-split#-BFsrep31493_CR26.2","unstructured":"Barcelona. Publisher: http:\/\/fens2014.meetingxpert.net\/FENS_427\/poster_100713\/program.aspx\/anchor100713 (2014)."},{"key":"BFsrep31493_CR27","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1002\/hipo.20294","volume":"17","author":"MJ Diogenes","year":"2007","unstructured":"Diogenes, M. J., Assaife-Lopes, N., Pinto-Duarte, A., Ribeiro, J. A. & Sebastiao, A. M. Influence of age on BDNF modulation of hippocampal synaptic transmission: interplay with adenosine A2A receptors. Hippocampus 17, 577\u2013585, 10.1002\/hipo.20294 (2007).","journal-title":"Hippocampus"},{"key":"BFsrep31493_CR28","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1002\/syn.1060","volume":"41","author":"SA Masino","year":"2001","unstructured":"Masino, S. A., Latini, S., Bordoni, F., Pedata, F. & Dunwiddie, T. V. Changes in hippocampal adenosine efflux, ATP levels, and synaptic transmission induced by increased temperature. Synapse 41, 58\u201364, 10.1002\/syn.1060 (2001).","journal-title":"Synapse"},{"key":"BFsrep31493_CR29","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1038\/npp.2011.64","volume":"36","author":"MJ Diogenes","year":"2011","unstructured":"Diogenes, M. J. et al. Enhancement of LTP in aged rats is dependent on endogenous BDNF. Neuropsychopharmacology 36, 1823\u20131836, 10.1038\/npp.2011.64 (2011).","journal-title":"Neuropsychopharmacology"},{"key":"BFsrep31493_CR30","doi-asserted-by":"publisher","first-page":"3196","DOI":"10.1152\/jn.1999.82.6.3196","volume":"82","author":"LV Lopes","year":"1999","unstructured":"Lopes, L. V., Cunha, R. A. & Ribeiro, J. A. Cross talk between A(1) and A(2A) adenosine receptors in the hippocampus and cortex of young adult and old rats. J Neurophysiol 82, 3196\u20133203 (1999).","journal-title":"J Neurophysiol"},{"key":"BFsrep31493_CR31","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1016\/S1074-7613(00)80398-2","volume":"7","author":"F D\u2019Adamio","year":"1997","unstructured":"D\u2019Adamio, F. et al. A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR\/CD3-activated cell death. Immunity 7, 803\u2013812, S1074-7613(00)80398-2 (1997).","journal-title":"Immunity"},{"key":"BFsrep31493_CR32","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.brainres.2014.09.073","volume":"1589C","author":"Y Feng","year":"2014","unstructured":"Feng, Y. et al. Dexamethasone-induced neuroprotection in hypoxic-ischemic brain injury in newborn rats is partly mediated via Akt activation. Brain Res 1589C, 68\u201377, S0006-8993(14)01347-X (2014).","journal-title":"Brain Res"},{"key":"BFsrep31493_CR33","doi-asserted-by":"publisher","first-page":"3756","DOI":"10.1128\/MCB.00062-12","volume":"32","author":"TE Reddy","year":"2012","unstructured":"Reddy, T. E., Gertz, J., Crawford, G. E., Garabedian, M. J. & Myers, R. M. The hypersensitive glucocorticoid response specifically regulates period 1 and expression of circadian genes. Mol Cell Biol 32, 3756\u20133767, 10.1128\/MCB.00062-12 (2012).","journal-title":"Mol Cell Biol"},{"key":"BFsrep31493_CR34","doi-asserted-by":"publisher","first-page":"2515","DOI":"10.1111\/j.1471-4159.2008.05575.x","volume":"106","author":"S van der Laan","year":"2008","unstructured":"van der Laan, S. et al. Chromatin immunoprecipitation scanning identifies glucocorticoid receptor binding regions in the proximal promoter of a ubiquitously expressed glucocorticoid target gene in brain. J Neurochem 106, 2515\u20132523, 10.1111\/j.1471-4159.2008.05575.x (2008).","journal-title":"J Neurochem"},{"key":"BFsrep31493_CR35","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1186\/1471-2202-13-118","volume":"13","author":"JA Polman","year":"2012","unstructured":"Polman, J. A. et al. A genome-wide signature of glucocorticoid receptor binding in neuronal PC12 cells. BMC neuroscience 13, 118, 10.1186\/1471-2202-13-118 (2012).","journal-title":"BMC neuroscience"},{"key":"BFsrep31493_CR36","doi-asserted-by":"publisher","first-page":"6194","DOI":"10.1038\/sj.onc.1210438","volume":"26","author":"Q Li","year":"2007","unstructured":"Li, Q., Dashwood, W. M., Zhong, X., Nakagama, H. & Dashwood, R. H. Bcl-2 overexpression in PhIP-induced colon tumors: cloning of the rat Bcl-2 promoter and characterization of a pathway involving beta-catenin, c-Myc and E2F1. Oncogene 26, 6194\u20136202, 10.1038\/sj.onc.1210438 (2007).","journal-title":"Oncogene"},{"key":"BFsrep31493_CR37","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/196","volume":"1","author":"NM Porter","year":"1998","unstructured":"Porter, N. M. & Landfield, P. W. Stress hormones and brain aging: adding injury to insult? Nat Neurosci 1, 3\u20134, 10.1038\/196 (1998).","journal-title":"Nat Neurosci"},{"key":"BFsrep31493_CR38","doi-asserted-by":"publisher","first-page":"1615","DOI":"10.1016\/j.neurobiolaging.2009.09.007","volume":"32","author":"L Gerritsen","year":"2011","unstructured":"Gerritsen, L., Comijs, H. C., Deeg, D. J., Penninx, B. W. & Geerlings, M. I. Salivary cortisol, APOE-epsilon4 allele and cognitive decline in a prospective study of older persons. Neurobiol Aging 32, 1615\u20131625, 10.1016\/j.neurobiolaging.2009.09.007 (2011).","journal-title":"Neurobiol Aging"},{"key":"BFsrep31493_CR39","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.neuron.2009.11.031","volume":"65","author":"MS Fanselow","year":"2010","unstructured":"Fanselow, M. S. & Dong, H. W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65, 7\u201319, 10.1016\/j.neuron.2009.11.031 (2010).","journal-title":"Neuron"},{"key":"BFsrep31493_CR40","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/0165-0173(86)90010-X","volume":"396","author":"RM Sapolsky","year":"1986","unstructured":"Sapolsky, R. M. & Meaney, M. J. Maturation of the adrenocortical stress response: neuroendocrine control mechanisms and the stress hyporesponsive period. Brain Res 396, 64\u201376 (1986).","journal-title":"Brain Res"},{"key":"BFsrep31493_CR41","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s12020-009-9291-y","volume":"37","author":"AJ Knoops","year":"2010","unstructured":"Knoops, A. J., van der Graaf, Y., Mali, W. P. & Geerlings, M. I. Age-related changes in hypothalamic-pituitary-adrenal axis activity in patients with manifest arterial disease. Endocrine 37, 231\u2013238, 10.1007\/s12020-009-9291-y (2010).","journal-title":"Endocrine"},{"key":"BFsrep31493_CR42","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1007\/s12017-009-8107-9","volume":"12","author":"SM Rothman","year":"2010","unstructured":"Rothman, S. M. & Mattson, M. P. Adverse stress, hippocampal networks, and Alzheimer\u2019s disease. Neuromolecular Med 12, 56\u201370, 10.1007\/s12017-009-8107-9 (2010).","journal-title":"Neuromolecular Med"},{"key":"BFsrep31493_CR43","doi-asserted-by":"publisher","first-page":"167","DOI":"10.3233\/JAD-2012-120328","volume":"31","author":"YB Joshi","year":"2012","unstructured":"Joshi, Y. B., Chu, J. & Pratico, D. Stress hormone leads to memory deficits and altered tau phosphorylation in a model of Alzheimer\u2019s disease. J Alzheimers Dis 31, 167\u2013176, 10.3233\/JAD-2012-120328 (2012).","journal-title":"J Alzheimers Dis"},{"key":"BFsrep31493_CR44","doi-asserted-by":"publisher","first-page":"e21660","DOI":"10.1371\/journal.pone.0021660","volume":"6","author":"W Chadwick","year":"2011","unstructured":"Chadwick, W. et al. Amitriptyline-mediated cognitive enhancement in aged 3xTg Alzheimer\u2019s disease mice is associated with neurogenesis and neurotrophic activity. PLoS One 6, e21660, 10.1371\/journal.pone.0021660 (2011).","journal-title":"PLoS One"},{"key":"BFsrep31493_CR45","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1177\/0748730415598608","volume":"30","author":"LE Chun","year":"2015","unstructured":"Chun, L. E., Woodruff, E. R., Morton, S., Hinds, L. R. & Spencer, R. L. Variations in Phase and Amplitude of Rhythmic Clock Gene Expression across Prefrontal Cortex, Hippocampus, Amygdala, and Hypothalamic Paraventricular and Suprachiasmatic Nuclei of Male and Female Rats. Journal of biological rhythms 30, 417\u2013436, 10.1177\/0748730415598608 (2015).","journal-title":"Journal of biological rhythms"},{"key":"BFsrep31493_CR46","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1007\/s11373-004-8176-6","volume":"12","author":"KR Shieh","year":"2005","unstructured":"Shieh, K. R., Yang, S. C., Lu, X. Y., Akil, H. & Watson, S. J. Diurnal rhythmic expression of the rhythm-related genes, rPeriod1, rPeriod2, and rClock, in the rat brain. Journal of biomedical science 12, 209\u2013217, 10.1007\/s11373-004-8176-6 (2005).","journal-title":"Journal of biomedical science"},{"key":"BFsrep31493_CR47","doi-asserted-by":"publisher","first-page":"305ra146","DOI":"10.1126\/scitranslmed.aac5125","volume":"7","author":"TM Burke","year":"2015","unstructured":"Burke, T. M. et al. Effects of caffeine on the human circadian clock in vivo and in vitro . Sci Transl Med 7, 305ra146, 10.1126\/scitranslmed.aac5125 (2015).","journal-title":"Sci Transl Med"},{"key":"BFsrep31493_CR48","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/nrd3955","volume":"12","author":"JF Chen","year":"2013","unstructured":"Chen, J. F., Eltzschig, H. K. & Fredholm, B. B. Adenosine receptors as drug targets\u2013what are the challenges? Nat Rev Drug Discov 12, 265\u2013286, 10.1038\/nrd3955 (2013).","journal-title":"Nat Rev Drug Discov"},{"key":"BFsrep31493_CR49","doi-asserted-by":"publisher","first-page":"S95","DOI":"10.3233\/JAD-2010-1408","volume":"20","author":"RA Cunha","year":"2010","unstructured":"Cunha, R. A. & Agostinho, P. M. Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline. J Alzheimers Dis 20 Suppl 1, S95\u2013116, 10.3233\/JAD-2010-1408 (2010).","journal-title":"J Alzheimers Dis"},{"key":"BFsrep31493_CR50","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/nn.3623","volume":"17","author":"D Borota","year":"2014","unstructured":"Borota, D. et al. Post-study caffeine administration enhances memory consolidation in humans. Nat Neurosci 17, 201\u2013203, 10.1038\/nn.3623 (2014).","journal-title":"Nat Neurosci"},{"key":"BFsrep31493_CR51","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.2174\/138161208784480090","volume":"14","author":"RA Cunha","year":"2008","unstructured":"Cunha, R. A., Ferre, S., Vaugeois, J. M. & Chen, J. F. Potential therapeutic interest of adenosine A2A receptors in psychiatric disorders. Curr Pharm Des 14, 1512\u20131524 (2008).","journal-title":"Curr Pharm Des"},{"key":"BFsrep31493_CR52","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.1001\/archinternmed.2011.393","volume":"171","author":"M Lucas","year":"2011","unstructured":"Lucas, M. et al. Coffee, caffeine, and risk of depression among women. Arch Intern Med 171, 1571\u20131578, 10.1001\/archinternmed.2011.393 (2011).","journal-title":"Arch Intern Med"},{"key":"BFsrep31493_CR53","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.brainres.2014.11.033","volume":"1621","author":"M Baudry","year":"2015","unstructured":"Baudry, M. et al. Multiple cellular cascades participate in long-term potentiation and in hippocampus-dependent learning. Brain Res 1621, 73\u201381, 10.1016\/j.brainres.2014.11.033 (2015).","journal-title":"Brain Res"},{"key":"BFsrep31493_CR54","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/S0006-8993(99)02194-0","volume":"851","author":"AR Costenla","year":"1999","unstructured":"Costenla, A. R., de Mendonca, A. & Ribeiro, J. A. Adenosine modulates synaptic plasticity in hippocampal slices from aged rats. Brain Res 851, 228\u2013234, S0006-8993(99)02194-0 (1999).","journal-title":"Brain Res"},{"key":"BFsrep31493_CR55","doi-asserted-by":"publisher","first-page":"1680","DOI":"10.1016\/j.neurobiolaging.2014.01.024","volume":"35","author":"VC Sousa","year":"2014","unstructured":"Sousa, V. C. et al. Maternal separation impairs long term-potentiation in CA1-CA3 synapses and hippocampal-dependent memory in old rats. Neurobiol Aging 35, 1680\u20131685, 10.1016\/j.neurobiolaging.2014.01.024 (2014).","journal-title":"Neurobiol Aging"},{"key":"BFsrep31493_CR56","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1111\/j.1365-2826.2003.01116.x","volume":"15","author":"S Jegou","year":"2003","unstructured":"Jegou, S. et al. Adenosine A2A receptor gene disruption provokes marked changes in melanocortin content and pro-opiomelan-ocortin gene expression. Journal of neuroendocrinology 15, 1171\u20131177 (2003).","journal-title":"Journal of neuroendocrinology"},{"key":"BFsrep31493_CR57","doi-asserted-by":"publisher","first-page":"1788","DOI":"10.1523\/JNEUROSCI.10-06-01788.1990","volume":"10","author":"KE Burgin","year":"1990","unstructured":"Burgin, K. E. et al. In situ hybridization histochemistry of Ca2+\/calmodulin-dependent protein kinase in developing rat brain. J Neurosci 10, 1788\u20131798 (1990).","journal-title":"J Neurosci"},{"key":"BFsrep31493_CR58","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.pneurobio.2007.07.005","volume":"83","author":"BB Fredholm","year":"2007","unstructured":"Fredholm, B. B., Chern, Y., Franco, R. & Sitkovsky, M. Aspects of the general biology of adenosine A2A signaling. Progress in neurobiology 83, 263\u2013276, 10.1016\/j.pneurobio.2007.07.005 (2007).","journal-title":"Progress in neurobiology"},{"key":"BFsrep31493_CR59","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1016\/j.bbamem.2010.05.009","volume":"1808","author":"S Keuerleber","year":"2011","unstructured":"Keuerleber, S., Gsandtner, I. & Freissmuth, M. From cradle to twilight: the carboxyl terminus directs the fate of the A(2A)-adenosine receptor. Biochimica et biophysica acta 1808, 1350\u20131357, 10.1016\/j.bbamem.2010.05.009 (2011).","journal-title":"Biochimica et biophysica acta"},{"key":"BFsrep31493_CR60","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1111\/j.1748-1716.2010.02115.x","volume":"199","author":"JA Ribeiro","year":"2010","unstructured":"Ribeiro, J. A. & Sebastiao, A. M. Modulation and metamodulation of synapses by adenosine. Acta physiologica 199, 161\u2013169, 10.1111\/j.1748-1716.2010.02115.x (2010).","journal-title":"Acta physiologica"},{"key":"BFsrep31493_CR61","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.1128\/MCB.00325-07","volume":"28","author":"SJ Kim","year":"2008","unstructured":"Kim, S. J., Nian, C., Widenmaier, S. & McIntosh, C. H. Glucose-dependent insulinotropic polypeptide-mediated up-regulation of beta-cell antiapoptotic Bcl-2 gene expression is coordinated by cyclic AMP (cAMP) response element binding protein (CREB) and cAMP-responsive CREB coactivator 2. Mol Cell Biol 28, 1644\u20131656, 10.1128\/MCB.00325-07 (2008).","journal-title":"Mol Cell Biol"},{"key":"BFsrep31493_CR62","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1074\/jbc.M209241200","volume":"278","author":"SA Tischkau","year":"2003","unstructured":"Tischkau, S. A., Mitchell, J. W., Tyan, S. H., Buchanan, G. F. & Gillette, M. U. Ca2+\/cAMP response element-binding protein (CREB)-dependent activation of Per1 is required for light-induced signaling in the suprachiasmatic nucleus circadian clock. J Biol Chem 278, 718\u2013723, 10.1074\/jbc.M209241200 (2003).","journal-title":"J Biol Chem"},{"key":"BFsrep31493_CR63","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1210\/mend.6.9.1435789","volume":"6","author":"PN Rangarajan","year":"1992","unstructured":"Rangarajan, P. N., Umesono, K. & Evans, R. M. Modulation of glucocorticoid receptor function by protein kinase A. Molecular endocrinology 6, 1451\u20131457, 10.1210\/mend.6.9.1435789 (1992).","journal-title":"Molecular endocrinology"},{"key":"BFsrep31493_CR64","doi-asserted-by":"publisher","first-page":"11893","DOI":"10.1073\/pnas.220413297","volume":"97","author":"V Doucas","year":"2000","unstructured":"Doucas, V. et al. Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-kappa B and the glucocorticoid receptor. Proceedings of the National Academy of Sciences of the United States of America 97, 11893\u201311898, 10.1073\/pnas.220413297 (2000).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"BFsrep31493_CR65","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.cell.2011.03.027","volume":"145","author":"M Surjit","year":"2011","unstructured":"Surjit, M. et al. Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor. Cell 145, 224\u2013241, 10.1016\/j.cell.2011.03.027 (2011).","journal-title":"Cell"},{"key":"BFsrep31493_CR66","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.1128\/MCB.01151-12","volume":"33","author":"S Ramamoorthy","year":"2013","unstructured":"Ramamoorthy, S. & Cidlowski, J. A. Ligand-induced repression of the glucocorticoid receptor gene is mediated by an NCoR1 repression complex formed by long-range chromatin interactions with intragenic glucocorticoid response elements. Mol Cell Biol 33, 1711\u20131722, 10.1128\/MCB.01151-12 (2013).","journal-title":"Mol Cell Biol"},{"key":"BFsrep31493_CR67","first-page":"63","volume":"3","author":"RH Oakley","year":"1993","unstructured":"Oakley, R. H. & Cidlowski, J. A. Homologous down regulation of the glucocorticoid receptor: the molecular machinery. Crit Rev Eukaryot Gene Expr 3, 63\u201388 (1993).","journal-title":"Crit Rev Eukaryot Gene Expr"},{"key":"BFsrep31493_CR68","doi-asserted-by":"publisher","first-page":"7462","DOI":"10.1523\/JNEUROSCI.18-18-07462.1998","volume":"18","author":"JP Herman","year":"1998","unstructured":"Herman, J. P. & Spencer, R. Regulation of hippocampal glucocorticoid receptor gene transcription and protein expression in vivo . J Neurosci 18, 7462\u20137473 (1998).","journal-title":"J Neurosci"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep31493.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep31493","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep31493.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T05:13:24Z","timestamp":1672895604000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep31493"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,11]]},"references-count":69,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,8,30]]}},"alternative-id":["BFsrep31493"],"URL":"https:\/\/doi.org\/10.1038\/srep31493","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,11]]},"assertion":[{"value":"7 April 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 July 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"31493"}}