{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T01:12:44Z","timestamp":1769821964249,"version":"3.49.0"},"reference-count":51,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T00:00:00Z","timestamp":1714176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Stress is an important risk factor for the onset of anxiety and depression. The ability to cope with stressful events varies among different subjects, probably depending on different genetic variants, sex and previous life experiences. The Val66Met variant of Brain-Derived Neurotrophic Factor (BDNF), which impairs the activity-dependent secretion of BDNF, has been associated with increased susceptibility to the development of various neuropsychiatric disorders. Adult male and female wild-type Val\/Val (BDNFV\/V) and heterozygous Val\/Met (BDNFV\/M) mice were exposed to two sessions of forced swimming stress (FSS) per day for two consecutive days. The mice were behaviorally tested 1 day (short-term effect) or 11 days (long-term effect) after the last stress session. Protein and mRNA levels were measured in the hippocampus 16 days after the end of stress exposure. Stressed mice showed a higher anxiety-like phenotype compared to non-stressed mice, regardless of the sex and genotype, when analyzed following the short period of stress. In the prolonged period, anxiety-like behavior persisted only in male BDNFV\/M mice (p &lt; 0.0001). Interestingly, recovery in male BDNFV\/V mice was accompanied by an increase in pCREB (p &lt; 0.001) and Bdnf4 (p &lt; 0.01) transcript and a decrease in HDAC1 (p &lt; 0.05) and Dnmt3a (p = 0.01) in the hippocampus. Overall, our results show that male and female BDNF Val66Met knock-in mice can recover from subchronic stress in different ways.<\/jats:p>","DOI":"10.3390\/biology13050303","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T10:33:36Z","timestamp":1714386816000},"page":"303","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Short- and Long-Term Effects of Subchronic Stress Exposure in Male and Female Brain-Derived Neurotrophic Factor Knock-In Val66Met Mice"],"prefix":"10.3390","volume":"13","author":[{"given":"Fernando Antonio Costa","family":"Xavier","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90619-900, Brazil"},{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7486-2637","authenticated-orcid":false,"given":"Silvia Stella","family":"Barbieri","sequence":"additional","affiliation":[{"name":"Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4670-8664","authenticated-orcid":false,"given":"Maurizio","family":"Popoli","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6737-7695","authenticated-orcid":false,"given":"Alessandro","family":"Ieraci","sequence":"additional","affiliation":[{"name":"Department of Theoretical and Applied Sciences, eCampus University, 22060 Novedrate, Italy"},{"name":"Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/sj.npp.1301569","article-title":"Anxiety as a developmental disorder","volume":"33","author":"Leonardo","year":"2008","journal-title":"Neuropsychopharmacology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1017\/S1121189X00001421","article-title":"The global burden of mental disorders: An update from the WHO World Mental Health (WMH) surveys","volume":"18","author":"Kessler","year":"2009","journal-title":"Epidemiol. Psichiatr. Soc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1038\/nn.4086","article-title":"Mechanisms of stress in the brain","volume":"18","author":"McEwen","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Daviu, N., Bruchas, M.R., Moghaddam, B., Sandi, C., and Beyeler, A. (2019). Neurobiological links between stress and anxiety. Neurobiol. Stress, 11.","DOI":"10.1016\/j.ynstr.2019.100191"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.neuropharm.2011.07.014","article-title":"Stress and anxiety: Structural plasticity and epigenetic regulation as a consequence of stress","volume":"62","author":"McEwen","year":"2012","journal-title":"Neuropharmacology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.jad.2023.07.107","article-title":"Sex differences in depression, anxiety and health-promoting lifestyles among community residents: A network approach","volume":"340","author":"Zheng","year":"2023","journal-title":"J. Affect. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1016\/j.jpsychires.2011.03.006","article-title":"Gender differences in anxiety disorders: Prevalence, course of illness, comorbidity and burden of illness","volume":"45","author":"McLean","year":"2011","journal-title":"J. Psychiatr. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.jad.2019.11.121","article-title":"Gender differences in depression, anxiety, and stress among college students: A longitudinal study from China","volume":"263","author":"Gao","year":"2020","journal-title":"J. Affect. Disord."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2921","DOI":"10.1007\/s00213-022-06176-8","article-title":"The role of MeCP2 and the BDNF\/TrkB signaling pathway in the stress resilience of mice subjected to CSDS","volume":"239","author":"Huang","year":"2022","journal-title":"Psychopharmacology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1038\/npp.2012.5","article-title":"Physical Exercise and Antidepressants Enhance BDNF Targeting in Hippocampal CA3 Dendrites: Further Evidence of a Spatial Code for BDNF Splice Variants","volume":"37","author":"Baj","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Bazzari, A.H., and Bazzari, F.H. (2022). BDNF Therapeutic Mechanisms in Neuropsychiatric Disorders. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158417"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1038\/s41380-019-0639-2","article-title":"Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders","volume":"25","author":"Notaras","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S0092-8674(03)00035-7","article-title":"The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function","volume":"112","author":"Egan","year":"2003","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1126\/science.1129663","article-title":"Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior","volume":"314","author":"Chen","year":"2006","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hosang, G.M., Shiles, C., Tansey, K.E., McGuffin, P., and Uher, R. (2014). Interaction between stress and the BDNF Val66Met polymorphism in depression: A systematic review and meta-analysis. BMC Med., 12.","DOI":"10.1186\/1741-7015-12-7"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/mp.2015.27","article-title":"The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: Progress and controversy","volume":"20","author":"Notaras","year":"2015","journal-title":"Mol. Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4092","DOI":"10.1523\/JNEUROSCI.5048-11.2012","article-title":"Variant Brain-Derived Neurotrophic Factor Val66Met Polymorphism Alters Vulnerability to Stress and Response to Antidepressants","volume":"32","author":"Yu","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Sandrini, L., Ieraci, A., Amadio, P., Veglia, F., Popoli, M., Lee, F.S., Tremoli, E., and Barbieri, S.S. (2018). Sub-chronic stress exacerbates the pro-thrombotic phenotype in BDNFVal\/Met mice: Gene-environment interaction in the modulation of arterial thrombosis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103235"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3834","DOI":"10.1002\/jcp.30833","article-title":"Acute stress induces an aberrant increase of presynaptic release of glutamate and cellular activation in the hippocampus of BDNFVal\/Met mice","volume":"237","author":"Musazzi","year":"2022","journal-title":"J. Cell. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/978-981-32-9705-0_6","article-title":"Gene-environment interactions and role of epigenetics in anxiety disorders","volume":"Volume 1191","author":"Lin","year":"2020","journal-title":"Advances in Experimental Medicine and Biology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.neuroscience.2012.12.034","article-title":"Epigenetic regulation in memory and cognitive disorders","volume":"264","author":"Rudenko","year":"2014","journal-title":"Neuroscience"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.ejphar.2018.08.021","article-title":"Epigenetic tools (The Writers, The Readers and The Erasers) and their implications in cancer therapy","volume":"837","author":"Biswas","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e324","DOI":"10.1038\/emm.2017.11","article-title":"Writing, erasing and reading histone lysine methylations","volume":"49","author":"Hyun","year":"2017","journal-title":"Exp. Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11451","DOI":"10.1523\/JNEUROSCI.1758-09.2009","article-title":"Antidepressant Actions of Histone Deacetylase Inhibitors","volume":"29","author":"Covington","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Persaud, N.S., and Cates, H.M. (2023). The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review. eNeuro, 10.","DOI":"10.1523\/ENEURO.0109-21.2021"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Barbieri, S.S., Sandrini, L., Musazzi, L., Popoli, M., and Ieraci, A. (2021). Apocynin Prevents Anxiety-Like Behavior and Histone Deacetylases Overexpression Induced by Sub-Chronic Stress in Mice. Biomolecules, 11.","DOI":"10.3390\/biom11060885"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1080\/15622975.2018.1500029","article-title":"Chronic social defeat stress differentially regulates the expression of BDNF transcripts and epigenetic modifying enzymes in susceptible and resilient mice","volume":"20","author":"Mallei","year":"2019","journal-title":"World J. Biol. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1080\/15592294.2016.1146850","article-title":"Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus","volume":"11","author":"Zheng","year":"2016","journal-title":"Epigenetics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"E3687","DOI":"10.1073\/pnas.1209990110","article-title":"Stress-induced epigenetic transcriptional memory of acetylcholinesterase by HDAC4","volume":"109","author":"Sailaja","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1093\/cercor\/bhaa337","article-title":"DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors","volume":"31","author":"Wei","year":"2021","journal-title":"Cereb. Cortex"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"16362","DOI":"10.1523\/JNEUROSCI.1392-15.2015","article-title":"Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress","volume":"35","author":"Hodes","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ravanelli, F., Musazzi, L., Barbieri, S.S., Rovati, G., Popoli, M., Barbon, A., and Ieraci, A. (2023). Differential Epigenetic Changes in the Dorsal Hippocampus of Male and Female SAMP8 Mice: A Preliminary Study. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241713084"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/978-1-61779-458-2_7","article-title":"Modeling Depression in Animal Models","volume":"Volume 829","author":"Overstreet","year":"2012","journal-title":"Methods in Molecular Biology (Clifton, N.J.)"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"113811","DOI":"10.1016\/j.bbr.2022.113811","article-title":"Sub-chronic stress induces similar behavioral effects in male and female mice despite sex-specific molecular adaptations in the nucleus accumbens","volume":"425","author":"Baugher","year":"2022","journal-title":"Behav. Brain Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9371","DOI":"10.1073\/pnas.0504011102","article-title":"Stress duration modulates the spatiotemporal patterns of spine formation in the basolateral amygdala","volume":"102","author":"Mitra","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5573","DOI":"10.1073\/pnas.0705615105","article-title":"Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy","volume":"105","author":"Mitra","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Caradonna, S.G., Paul, M.R., and Marrocco, J. (2022). An allostatic epigenetic memory on chromatin footprints after double-hit acute stress. Neurobiol. Stress, 20.","DOI":"10.1016\/j.ynstr.2022.100475"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/s41398-023-02366-w","article-title":"Changes at glutamate tripartite synapses in the prefrontal cortex of a new animal model of resilience\/vulnerability to acute stress","volume":"13","author":"Bonifacino","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Gupta, K., and Chattarji, S. (2021). Sex differences in the delayed impact of acute stress on the amygdala. Neurobiol. Stress, 14.","DOI":"10.1016\/j.ynstr.2020.100292"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Torrisi, S.A., Lavanco, G., Maurel, O.M., Gulisano, W., Laudani, S., Geraci, F., Grasso, M., Barbagallo, C., Caraci, F., and Bucolo, C. (2020). A novel arousal-based individual screening reveals susceptibility and resilience to PTSD-like phenotypes in mice. Neurobiol. Stress, 14.","DOI":"10.1016\/j.ynstr.2020.100286"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nn1659","article-title":"Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action","volume":"9","author":"Tsankova","year":"2006","journal-title":"Nat. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.alcohol.2017.01.001","article-title":"Epigenetic mechanisms of alcoholism and stress-related disorders","volume":"60","author":"Palmisano","year":"2017","journal-title":"Alcohol"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1038\/npp.2009.66","article-title":"Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogenesis in the hippocampus","volume":"34","author":"Li","year":"2009","journal-title":"Neuropsychopharmacology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.neulet.2015.12.038","article-title":"Early mood behavioral changes following exposure to monotonous environment during isolation stress is associated with altered hippocampal synaptic plasticity in male rats","volume":"612","author":"Das","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5022","DOI":"10.1523\/JNEUROSCI.5557-03.2004","article-title":"Partial deletion of the cAMP response element-binding protein gene promotes alcohol-drinking behaviors","volume":"24","author":"Pandey","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2378","DOI":"10.1038\/npp.2010.114","article-title":"Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models","volume":"35","author":"Schmidt","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1111\/jnc.15735","article-title":"Involvement of brain-derived neurotrophic factor methylation in the prefrontal cortex and hippocampus induced by chronic unpredictable mild stress in male mice","volume":"164","author":"Cheng","year":"2023","journal-title":"J. Neurochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.bbr.2018.01.022","article-title":"Antidepressant administration modulates stress-induced DNA methylation and DNA methyltransferase expression in rat prefrontal cortex and hippocampus","volume":"343","author":"Sales","year":"2018","journal-title":"Behav. Brain Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1007\/s12035-020-02145-4","article-title":"Modulation of DNA Methylation and Gene Expression in Rodent Cortical Neuroplasticity Pathways Exerts Rapid Antidepressant-Like Effects","volume":"58","author":"Sales","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/jnr.23863","article-title":"Sex differences in brain-derived neurotrophic factor signaling and functions","volume":"95","author":"Chan","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.biopsych.2012.03.032","article-title":"Variant brain-derived neurotrophic factor (Valine66Methionine) polymorphism contributes to developmental and estrous stage-specific expression of anxiety-like behavior in female mice","volume":"72","author":"Bath","year":"2012","journal-title":"Biol. Psychiatry"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/13\/5\/303\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:34:53Z","timestamp":1760106893000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/13\/5\/303"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,27]]},"references-count":51,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["biology13050303"],"URL":"https:\/\/doi.org\/10.3390\/biology13050303","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,27]]}}}