{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T14:10:37Z","timestamp":1762179037007,"version":"build-2065373602"},"reference-count":220,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AquaSynapse EU framework"},{"name":"European Union\u2019s HORIZON 2020 research and innovation program under the Marie Sk\u0142odowska-Curie","award":["101086453"],"award-info":[{"award-number":["101086453"]}]},{"name":"NIIOPP state task Ministry of Education and Research","award":["RF FGFU-2025-0012"],"award-info":[{"award-number":["RF FGFU-2025-0012"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The study of molecular mechanisms underlying late-life depression (LLD) is increasingly important in light of population aging. To date, LLD-related molecular brain changes remain poorly understood. Furthermore, environmental factors such as climate change and geography contribute to LDD risks. One overlooked factor might be deuterium\u2014a stable hydrogen isotope\u2014whose concentration in drinking water can vary geographically (~90\u2013155 ppm) and alter the incidence of mood disorders. Conversely, potential effects of natural variations in deuterium content in drinking water on LLD symptoms and brain gene expression remain unknown. We conducted Illumina gene expression profiling in the hippocampi and prefrontal cortexes of 18-month-old C57BL\/6J mice, a model of LLD-like behaviors, compared to 3-month-old controls. Separately, aged mice were allowed to consume deuterium-depleted (DDW, ~90 ppm) or control (~140 ppm) water for 21 days and were studied for LLD-like behaviors and Illumina gene expression of the brain. Na\u00efve old mice displayed \u22652-fold significant changes of 35 genes. Housing on DDW increased their hedonic sensitivity and novelty exploration, reduced helplessness, improved memory, and significantly altered brain expression of Egr1, Per2, Homer1, Gadd45a, and Prdx4, among others. These genes revealed significant alterations in several GO-BP and KEGG pathways implicated in inflammation, cellular stress, synaptic plasticity, emotionality, and regeneration. Additionally, we found that incubation of primary neuronal cultures in DDW-containing buffer ameliorated Ca2+ influx and mitochondrial potential in a toxicity model, suggesting the involvement of mitochondrial mechanisms in the effects of decreased deuterium levels. Thus, aging induced profound brain molecular changes that may at least in part contribute to LLD pathophysiology. Reduced deuterium intake exerted modest but significant effects on LLD-related behaviors in aged mice, which can be attributed to, but not limited by ameliorated mitochondrial function and changes in brain gene expression.<\/jats:p>","DOI":"10.3390\/ijms262110626","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:15:14Z","timestamp":1762175714000},"page":"10626","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptomic Insights into Late-Life Depression and the Role of Environmental Drinking Water Composition: A Study on 18-Month-Old Mice"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0127-5420","authenticated-orcid":false,"given":"Jo\u00e3o Pedro","family":"Costa-Nunes","sequence":"first","affiliation":[{"name":"Faculdade de Medicina, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal"},{"name":"Department of Psychiatry and Neuropsychology, Maastricht University, 6229 ER Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8870-7403","authenticated-orcid":false,"given":"Kseniia","family":"Sitdikova","sequence":"additional","affiliation":[{"name":"Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3501-574X","authenticated-orcid":false,"given":"Evgeniy","family":"Svirin","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuropsychology, Maastricht University, 6229 ER Maastricht, The Netherlands"},{"name":"Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia"},{"name":"Neuroplast B.V., 6222 NK Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7583-1464","authenticated-orcid":false,"given":"Johannes","family":"de Munter","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuropsychology, Maastricht University, 6229 ER Maastricht, The Netherlands"},{"name":"Neuroplast B.V., 6222 NK Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9116-6417","authenticated-orcid":false,"given":"Gabor","family":"Somlyai","sequence":"additional","affiliation":[{"name":"HYD LLC for Cancer Research and Drug Development, 1118 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Gorlova","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuropsychology, Maastricht University, 6229 ER Maastricht, The Netherlands"},{"name":"Research and Education Resource Center, Peoples Friendship University of Russia (RUDN University), 117198 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0460-4992","authenticated-orcid":false,"given":"Alexandr","family":"Litavrin","sequence":"additional","affiliation":[{"name":"Department of Normal Physiology, Sechenov University, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7638-4162","authenticated-orcid":false,"given":"Gohar M.","family":"Arajyan","sequence":"additional","affiliation":[{"name":"Pharmacology and Pathohistology Laboratory, Scientific Technological Center of the Organic and Pharmaceutical Chemistry Institute of Armenia, Yerevan 0019, Armenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zlata","family":"Nefedova","sequence":"additional","affiliation":[{"name":"Department of Normal Physiology, Sechenov University, 119991 Moscow, 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Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anton","family":"Chernopiatko","sequence":"additional","affiliation":[{"name":"Timantti AB, 174 07 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatyana","family":"Strekalova","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuropsychology, Maastricht University, 6229 ER Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1001\/archpsyc.62.12.1313","article-title":"Cost-Effectiveness of Improving Primary Care Treatment of Late-Life Depression","volume":"62","author":"Katon","year":"2005","journal-title":"Arch. 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