{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T00:04:27Z","timestamp":1793232267208,"version":"4.5.0"},"reference-count":90,"publisher":"National Academy of Sciences","issue":"49","license":[{"start":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T00:00:00Z","timestamp":1669939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jim and Betty Anne Rodgers Chair Fund","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,12,6]]},"abstract":"<jats:p>\n                    We report the effects of aspartame on anxiety-like behavior, neurotransmitter signaling and gene expression in the amygdala, a brain region associated with the regulation of anxiety and fear responses. C57BL\/6 mice consumed drinking water containing 0.015% or 0.03% aspartame, a dose equivalent of 8 to 15% of the FDA recommended maximum human daily intake, or plain drinking water. Robust anxiety-like behavior (evaluated using open field test and elevated zero maze) was observed in male and female mice consuming the aspartame-containing water. Diazepam, an allosteric modulator of the GABA-A receptor, alleviated the anxiety-like behavior. RNA sequencing of the amygdala followed by KEGG biological pathway analysis of differentially expressed genes showed glutamatergic and GABAergic synapse pathways as significantly enriched. Quantitative PCR showed upregulation of mRNA for the glutamate NMDA receptor subunit 2D (\n                    <jats:italic>Grin2d<\/jats:italic>\n                    ) and metabotropic receptor 4 (\n                    <jats:italic>Grm4<\/jats:italic>\n                    ) and downregulation of the GABA-A receptor associated protein (\n                    <jats:italic>Gabarap<\/jats:italic>\n                    ) mRNA. Thus, taken together, our diazepam and gene expression data show that aspartame consumption shifted the excitation-inhibition equilibrium in the amygdala toward excitation. Even more strikingly, the anxiety-like behavior, its response to diazepam, and changes in amygdala gene expression were transmitted to male and female offspring in two generations descending from the aspartame-exposed males. Extrapolation of the findings to humans suggests that aspartame consumption at doses below the FDA recommended maximum daily intake may produce neurobehavioral changes in aspartame-consuming individuals and their descendants. Thus, human population at risk of aspartame\u2019s potential mental health effects may be larger than current expectations, which only include aspartame-consuming individuals.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2213120119","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T15:23:13Z","timestamp":1669994593000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":78,"title":["Transgenerational transmission of aspartame-induced anxiety and changes in glutamate-GABA signaling and gene expression in the amygdala"],"prefix":"10.1073","volume":"119","author":[{"given":"Sara K.","family":"Jones","sequence":"first","affiliation":[{"name":"Biomedical Sciences, Florida State University, Tallahassee, FL 32306"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deirdre M.","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Biomedical Sciences, Florida State University, Tallahassee, FL 32306"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3941-3614","authenticated-orcid":false,"given":"Cynthia","family":"Vied","sequence":"additional","affiliation":[{"name":"Translational Science Laboratory, Florida State University, Tallahassee, FL 32306"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregg D.","family":"Stanwood","sequence":"additional","affiliation":[{"name":"Biomedical Sciences, Florida State University, Tallahassee, FL 32306"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Schatschneider","sequence":"additional","affiliation":[{"name":"Psychology, Florida State University, Tallahassee, FL 32306"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4236-9415","authenticated-orcid":false,"given":"Pradeep G.","family":"Bhide","sequence":"additional","affiliation":[{"name":"Biomedical Sciences, Florida State University, Tallahassee, FL 32306"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,12,2]]},"reference":[{"key":"e_1_3_4_1_2","unstructured":"FDA Aspartame commissioner\u2019s final decision. ed D. o. H. a. H. Services (Federal Register Washington D.C. 1981) 46 pp. 3824\u201338308."},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-813280-7.00048-7"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/40.1.1"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0031-9384(86)90366-5"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/116.3.356"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(86)90324-8"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejcn.1602866"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1080\/10408440701516184"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(98)00282-3"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(90)91729-Z"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01677429"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/0278-6915(87)90015-9"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfda.2017.11.001"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/nur.21595"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.116.016027"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-3223(93)90251-8"},{"key":"e_1_3_4_17_2","first-page":"2092","article-title":"Studies on the effects of aspartame on memory and oxidative stress in brain of mice","volume":"16","author":"Abdel-Salam O. M.","year":"2012","unstructured":"O. M. Abdel-Salam , Studies on the effects of aspartame on memory and oxidative stress in brain of mice. Eur. Rev. Med. Pharmacol. Sci. 16, 2092\u20132101 (2012).","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ntt.2014.02.001"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nlm.2016.12.021"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.acthis.2017.11.004"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0892-0362(91)90024-Q"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0194416"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0031570"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12940-021-00725-y"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12940-021-00789-w"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-317505"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11894-017-0602-9"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajim.22296"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-06-0203"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13690-019-0355-z"},{"key":"e_1_3_4_31_2","unstructured":"National Toxicology Program NTP report on the toxicology studies of aspartame (CAS No. 22839\u201347-0) in genetically modified (FVB Tg.AC hemizygous) and B6.129-Cdkn2atm1Rdp (N2) deficient mice and carcinogenicity studies of aspartame in genetically modified [B6.129-Trp53tm1Brd (N5) haploinsufficient] mice (feed studies). Natl. Toxicol. Program Genet. Modif. Model Rep. 1 1\u2013222 (2005)."},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2013.07.040"},{"key":"e_1_3_4_33_2","volume-title":"Additional Information about High-Intensity Sweeteners Permitted for Use in Food in the United States","author":"FDA","year":"2018","unstructured":"FDA, Additional Information about High-Intensity Sweeteners Permitted for Use in Food in the United States (U.S. Food and Drug Administration, Washington, D.C., 2018)."},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-018-0063-8"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ne.15.030192.002033"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2010.04.027"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3945"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2004.02.017"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/chemse\/26.7.905"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2016.04.047"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1556\/APhysiol.97.2010.4.9"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2013.05.005"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.4103\/0976-0105.177703"},{"key":"e_1_3_4_44_2","doi-asserted-by":"crossref","unstructured":"C. Fitch K. S. Keim; Academy of Nutrition and Dietetics Position of the academy of nutrition and dietetics: Use of nutritive and nonnutritive sweeteners. J. Acad. Nutr. Diet 112 739\u2013758 (2012).","DOI":"10.1016\/j.jand.2012.03.009"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.31887\/DCNS.2017.19.2\/wcarlezon"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2017.00013"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1021\/cn5000056"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14519"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0091-3057(01)00629-3"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.31887\/DCNS.2017.19.2\/bbandelow"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-018-0123-8"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2017.08.029"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2009.109"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.09.002"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1093\/eep\/dvaa009"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-68883-6"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.14060"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-ecolsys-110218-024613"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2015.02.010"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1508347112"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3964"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3818"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioab116"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrrev.2017.04.001"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.alcohol.2016.11.001"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01622-7"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.2006497"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2022.173355"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(83)90873-1"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-021-00818-0"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-02267-2"},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-420170-5.00011-8"},{"key":"e_1_3_4_73_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2012.11.040"},{"key":"e_1_3_4_74_2","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2016.87"},{"key":"e_1_3_4_75_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1678"},{"key":"e_1_3_4_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tree.2019.09.003"},{"key":"e_1_3_4_77_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0003745"},{"key":"e_1_3_4_78_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_3_4_79_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4197"},{"key":"e_1_3_4_80_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_4_81_2","doi-asserted-by":"publisher","DOI":"10.1088\/1742-6596\/705\/1\/012003"},{"key":"e_1_3_4_82_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki475"},{"key":"e_1_3_4_83_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt439"},{"key":"e_1_3_4_84_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0139103"},{"key":"e_1_3_4_85_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.23989"},{"key":"e_1_3_4_86_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2014.00257"},{"key":"e_1_3_4_87_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2015.4322"},{"key":"e_1_3_4_88_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0019398"},{"key":"e_1_3_4_89_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aai7459"},{"key":"e_1_3_4_90_2","doi-asserted-by":"crossref","unstructured":"L. Varela Hunger-promoting AgRP neurons trigger an astrocyte-mediated feed-forward autoactivation loop in mice. J. Clin. Invest. 131 e144239 (2021). e144239","DOI":"10.1172\/JCI144239"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2213120119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T08:45:09Z","timestamp":1695285909000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2213120119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,2]]},"references-count":90,"journal-issue":{"issue":"49","published-print":{"date-parts":[[2022,12,6]]}},"alternative-id":["10.1073\/pnas.2213120119"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2213120119","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,2]]},"assertion":[{"value":"2022-08-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2213120119"}}