{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:48:36Z","timestamp":1790765316317,"version":"4.1.0"},"reference-count":82,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T00:00:00Z","timestamp":1698019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation (ISF)","doi-asserted-by":"publisher","award":["993\/20"],"award-info":[{"award-number":["993\/20"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aging is associated with changes in cognitive and emotional function. Cannabidiol (CBD) has been reported to attenuate stress and anxiety in human and animal studies. In this study, we aimed to assess the therapeutic potential of CBD among middle-aged female rats exposed to social isolation (SI) and the potential involvement of brain-derived neurotrophic factor (BDNF) in these effects. Thirteen-month-old female rats were group-housed (GH) or exposed to social isolation (SI) and treated with vehicle or CBD (10 mg\/kg). CBD restored the SI-induced immobility in the forced swim test and the SI-induced decrease in the expression of BDNF protein levels in the nucleus accumbens (NAc). CBD also increased the time that rats spent in the center in an open field, improved spatial training, and increased BDNF expression in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). BDNF expression was found to be correlated with an antidepressant (in the NAc) and an anxiolytic (in the mPFC, BLA, NAc) phenotype, and with learning improvement in the PFC. Together, our results suggest that CBD may serve as a beneficial agent for wellbeing in old age and may help with age-related cognitive decline.<\/jats:p>","DOI":"10.3390\/ijms242015492","type":"journal-article","created":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T10:32:24Z","timestamp":1698057144000},"page":"15492","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Cannabidiol Modulates Emotional Function and Brain-Derived Neurotrophic Factor Expression in Middle-Aged Female Rats Exposed to Social Isolation"],"prefix":"10.3390","volume":"24","author":[{"given":"Nadya","family":"Saad","sequence":"first","affiliation":[{"name":"Department of Psychology, School of Psychological Sciences, University of Haifa, Haifa 3498838, Israel"},{"name":"The Integrated Brain and Behavior Research Center (IBBRC), University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Raviv","sequence":"additional","affiliation":[{"name":"Department of Psychology, School of Psychological Sciences, University of Haifa, Haifa 3498838, Israel"},{"name":"The Integrated Brain and Behavior Research Center (IBBRC), University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomer","family":"Mizrachi Zer-Aviv","sequence":"additional","affiliation":[{"name":"Department of Psychology, School of Psychological Sciences, University of Haifa, Haifa 3498838, Israel"},{"name":"The Integrated Brain and Behavior Research Center (IBBRC), University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7633-5953","authenticated-orcid":false,"given":"Irit","family":"Akirav","sequence":"additional","affiliation":[{"name":"Department of Psychology, School of Psychological Sciences, University of Haifa, Haifa 3498838, Israel"},{"name":"The Integrated Brain and Behavior Research Center (IBBRC), University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.exger.2017.12.015","article-title":"Aging, Inflammation and the Environment","volume":"105","author":"Bektas","year":"2018","journal-title":"Exp. Gerontol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1037\/0735-7044.117.3.485","article-title":"Age-related deficits in mice performing working memory tasks in a water maze","volume":"117","author":"Magnusson","year":"2003","journal-title":"Behav. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"891842","DOI":"10.3389\/fphar.2022.891842","article-title":"Dose-dependent antidepressant-like effects of cannabidiol in aged rats","volume":"13","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.jagp.2013.01.053","article-title":"The age-by-disease interaction hypothesis of late-life depression","volume":"21","author":"McKinney","year":"2013","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1016\/j.neurobiolaging.2003.12.006","article-title":"Within-subject memory decline in middle-aged rats: Effects of intraseptal tacrine","volume":"25","author":"Sabolek","year":"2004","journal-title":"Neurobiol. Aging"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/0197-4580(92)90003-G","article-title":"Progressive decline in spatial learning and integrity of forebrain cholinergic neurons in rats during aging","volume":"13","author":"Fischer","year":"1992","journal-title":"Neurobiol. Aging"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/S0197-4580(99)00098-6","article-title":"Decline in visual attention and spatial memory in aged rats","volume":"20","author":"Muir","year":"1999","journal-title":"Neurobiol. Aging"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.physbeh.2010.09.019","article-title":"Emotional behavior in middle-aged rats: Implications for geriatric psychopathologies","volume":"102","author":"Moretti","year":"2011","journal-title":"Physiol. Behav."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S0166-4328(02)00018-9","article-title":"Emotional changes related to age in rats\u2014A behavioral analysis","volume":"133","author":"Boguszewski","year":"2002","journal-title":"Behav. Brain Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.tics.2009.06.005","article-title":"Perceived social isolation and cognition","volume":"13","author":"Cacioppo","year":"2009","journal-title":"Trends Cogn. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1001\/archpsyc.64.2.234","article-title":"Loneliness and risk of Alzheimer disease","volume":"64","author":"Wilson","year":"2007","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/ijop.12772","article-title":"When loneliness dimensions drift apart: Emotional, social and physical loneliness during the COVID-19 lockdown and its associations with age, personality, stress and well-being","volume":"57","author":"Landmann","year":"2021","journal-title":"Int. J. Psychol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s11136-010-9717-2","article-title":"The impact of social isolation on the health status and health-related quality of life of older people","volume":"20","author":"Hawton","year":"2011","journal-title":"Qual. Life Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1017\/S0962728600024908","article-title":"Rats demand social contact","volume":"11","author":"Hunt","year":"2002","journal-title":"Anim. Welf."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.bbr.2017.12.022","article-title":"Ethological approach to social isolation effects in behavioral studies of laboratory rodents","volume":"341","author":"Arakawa","year":"2018","journal-title":"Behav. Brain Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/j.1749-6632.2011.06028.x","article-title":"Social isolation","volume":"1231","author":"Cacioppo","year":"2011","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.bbr.2009.10.006","article-title":"The lonely mouse: Verification of a separation-induced model of depression in female mice","volume":"207","author":"Martin","year":"2010","journal-title":"Behav. Brain Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s12031-014-0475-4","article-title":"Citalopram attenuates tau hyperphosphorylation and spatial memory deficit induced by social isolation rearing in middle-aged rats","volume":"56","author":"Ren","year":"2015","journal-title":"J. Mol. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1007\/s12035-016-9781-x","article-title":"Citalopram ameliorates synaptic plasticity deficits in different cognition-associated brain regions induced by social isolation in middle-aged rats","volume":"54","author":"Gong","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.neurobiolaging.2019.02.011","article-title":"Systemic administration of a fibroblast growth factor receptor 1 agonist rescues the cognitive deficit in aged socially isolated rats","volume":"78","author":"Valencia","year":"2019","journal-title":"Neurobiol. Aging"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"234","DOI":"10.12965\/jer.2040366.183","article-title":"Effects of swimming exercise on social isolation-induced memory impairment and apoptosis in old rats","volume":"16","author":"Park","year":"2020","journal-title":"J. Exerc. Rehabil."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.neuroscience.2016.02.009","article-title":"Sex differences in the outcome of juvenile social isolation on HPA axis function in rats","volume":"320","author":"Pisu","year":"2016","journal-title":"Neuroscience"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"R273","DOI":"10.1152\/ajpregu.00368.2005","article-title":"Social isolation and the inflammatory response: Sex differences in the enduring effects of a prior stressor","volume":"290","author":"Hermes","year":"2006","journal-title":"Am. J. Physiol.-Regul. Integr. Comp. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.brainres.2010.04.068","article-title":"Enduring and sex-specific effects of adolescent social isolation in rats on adult stress reactivity","volume":"1343","author":"Weintraub","year":"2010","journal-title":"Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Colucci-D\u2019Amato, L., Speranza, L., and Volpicelli, F. (2020). Neurotrophic factor BDNF, physiological functions and therapeutic potential in depression, neurodegeneration and brain cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21207777"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1515\/revneuro-2016-0072","article-title":"Hippocampal BDNF in physiological conditions and social isolation","volume":"28","author":"Zaletel","year":"2017","journal-title":"Rev. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.jagp.2012.10.026","article-title":"Involvement of brain-derived neurotrophic factor in late-life depression","volume":"21","author":"Dwivedi","year":"2013","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.bbr.2015.05.062","article-title":"TNF-alpha inhibition prevents cognitive decline and maintains hippocampal BDNF levels in the unpredictable chronic mild stress rat model of depression","volume":"292","author":"Karson","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.brainres.2010.09.095","article-title":"Chronic antidepressant administration alleviates frontal and hippocampal BDNF deficits in CUMS rat","volume":"1366","author":"Zhang","year":"2010","journal-title":"Brain Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.3389\/fphar.2019.01544","article-title":"Quercetin alleviates LPS-induced depression-like behavior in rats via regulating BDNF-related imbalance of Copine 6 and TREM1\/2 in the hippocampus and PFC","volume":"10","author":"Fang","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4796","DOI":"10.1523\/JNEUROSCI.5654-03.2004","article-title":"Brain-derived neurotrophic factor and tyrosine kinase receptor B involvement in amygdala-dependent fear conditioning","volume":"24","author":"Rattiner","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1017\/S1461145707007560","article-title":"Long-term down-regulation of BDNF mRNA in rat hippocampal CA1 subregion correlates with PTSD-like behavioural stress response","volume":"10","author":"Kozlovsky","year":"2007","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"114303","DOI":"10.1016\/j.bbr.2023.114303","article-title":"Behavior, BDNF and epigenetic mechanisms in response to social isolation and social support in middle aged rats exposed to chronic stress","volume":"441","author":"Borges","year":"2023","journal-title":"Behav. Brain Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"111965","DOI":"10.1016\/j.bbr.2019.111965","article-title":"Long-term environmental modifications affect BDNF concentrations in rat hippocampus, but not in serum","volume":"372","author":"Giacobbo","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.neuroscience.2013.01.074","article-title":"Stress effects on BDNF expression: Effects of age, sex, and form of stress","volume":"239","author":"Bath","year":"2013","journal-title":"Neuroscience"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/cercor\/bhn225","article-title":"Sex differences in the effects of acute and chronic stress and recovery after long-term stress on stress-related brain regions of rats","volume":"19","author":"Lin","year":"2009","journal-title":"Cereb. Cortex"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1080\/10253890.2019.1617692","article-title":"Decreased BDNF in female but not male rats after exposure to stress: A sex-sensitive rat model of stress?","volume":"22","author":"Weisbrod","year":"2019","journal-title":"Stress"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.jad.2014.11.044","article-title":"BDNF as a biomarker for successful treatment of mood disorders: A systematic & quantitative meta-analysis","volume":"174","author":"Polyakova","year":"2015","journal-title":"J. Affect. Disord."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3389\/fnbeh.2017.00101","article-title":"The evidence for altered BDNF expression in the brain of rats reared or housed in social isolation: A systematic review","volume":"11","year":"2017","journal-title":"Front. Behav. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.3389\/fimmu.2018.02009","article-title":"Translational investigation of the therapeutic potential of cannabidiol (CBD): Toward a new age","volume":"9","author":"Crippa","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1089\/can.2017.0009","article-title":"A conversion of oral cannabidiol to delta9-tetrahydrocannabinol seems not to occur in humans","volume":"2","author":"Nahler","year":"2017","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.jpsychires.2020.07.030","article-title":"Efficacy and acceptability of cannabinoids for anxiety disorders in adults: A systematic review & meta-analysis","volume":"129","author":"Bahji","year":"2020","journal-title":"J. Psychiatr. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"237","DOI":"10.2174\/157488611798280924","article-title":"Safety and side effects of cannabidiol, a Cannabis sativa constituent","volume":"6","author":"Crippa","year":"2011","journal-title":"Curr. Drug Saf."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1038\/cdd.2015.11","article-title":"The CB1 cannabinoid receptor signals striatal neuroprotection via a PI3K\/Akt\/mTORC1\/BDNF pathway","volume":"22","author":"Chiarlone","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.neulet.2009.10.011","article-title":"BDNF regulates neuronal sensitivity to endocannabinoids","volume":"467","author":"Maison","year":"2009","journal-title":"Neurosci. Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1007\/s12035-018-1143-4","article-title":"Cannabidiol induces rapid and sustained antidepressant-like effects through increased BDNF signaling and synaptogenesis in the prefrontal cortex","volume":"56","author":"Sales","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Bright, U., and Akirav, I. (2023). Cannabidiol Modulates Alterations in PFC microRNAs in a Rat Model of Depression. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032052"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/j.1601-5215.2011.00579.x","article-title":"Administration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala","volume":"23","author":"Stringari","year":"2011","journal-title":"Acta Neuropsychiatr."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Matheson, J., Bourgault, Z., and Le Foll, B. (2022). Sex differences in the neuropsychiatric effects and pharmacokinetics of cannabidiol: A scoping review. Biomolecules, 12.","DOI":"10.3390\/biom12101462"},{"key":"ref_50","first-page":"e52587","article-title":"The forced swim test as a model of depressive-like behavior","volume":"97","author":"Franko","year":"2015","journal-title":"JoVE J. Vis. Exp."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S0149-7634(01)00010-0","article-title":"Animal models of anxiety and depression: How are females different?","volume":"25","author":"Palanza","year":"2001","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"S101","DOI":"10.1590\/1516-4446-2013-1139","article-title":"Animal models of anxiety disorders and stress","volume":"35","author":"Campos","year":"2013","journal-title":"Braz. J. Psychiatry"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"439","DOI":"10.55782\/ane-2004-1526","article-title":"Experimental modeling of anxiety and depression","volume":"64","author":"Kalueff","year":"2004","journal-title":"Acta Neurobiol. Exp."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.ddmod.2006.11.003","article-title":"Animal models of depression","volume":"3","author":"Deussing","year":"2006","journal-title":"Drug Discov. Today Dis. Models"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.physbeh.2018.12.019","article-title":"Effects of cannabidiol in males and females in two different rat models of depression","volume":"201","author":"Shbiro","year":"2019","journal-title":"Physiol. Behav."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"G\u00e1ll, Z., Farkas, S., Albert, \u00c1., Ferencz, E., Vancea, S., Urkon, M., and Kolcs\u00e1r, M. (2020). Effects of chronic cannabidiol treatment in the rat chronic unpredictable mild stress model of depression. Biomolecules, 10.","DOI":"10.3390\/biom10050801"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1016\/j.pnpbp.2006.06.004","article-title":"Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test","volume":"30","author":"Moreira","year":"2006","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1159\/000443890","article-title":"Prohedonic effect of cannabidiol in a rat model of depression","volume":"73","author":"Shoval","year":"2016","journal-title":"Neuropsychobiology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1177\/0269881110389095","article-title":"Cannabidiol injected into the bed nucleus of the stria terminalis reduces the expression of contextual fear conditioning via 5-HT1A receptors","volume":"26","author":"Gomes","year":"2012","journal-title":"J. Psychopharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"109316","DOI":"10.1016\/j.neuropharm.2022.109316","article-title":"Cannabidiol attenuates fear memory expression in female rats via hippocampal 5-HT1A but not CB1 or CB2 receptors","volume":"223","author":"Franzen","year":"2023","journal-title":"Neuropharmacology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"113812","DOI":"10.1016\/j.bbr.2022.113812","article-title":"Cannabidiol (CBD) treatment improves spatial memory in 14-month-old female TAU58\/2 transgenic mice","volume":"425","author":"Kreilaus","year":"2022","journal-title":"Behav. Brain Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.euroneuro.2022.08.002","article-title":"Cannabidiol impairs fear memory reconsolidation in female rats through dorsal hippocampus CB1 but not CB2 receptor interaction","volume":"64","author":"Franzen","year":"2022","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Mottarlini, F., Fumagalli, M., Castillo-D\u00edaz, F., Piazza, S., Targa, G., Sangiovanni, E., Pacchetti, B., Sodergren, M.H., Dell\u2019Agli, M., and Fumagalli, F. (2022). Single and repeated exposure to cannabidiol differently modulate BDNF expression and signaling in the Cortico-Striatal Brain Network. Biomedicines, 10.","DOI":"10.3390\/biomedicines10081853"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1523\/JNEUROSCI.23-04-01517.2003","article-title":"Time-dependent relationship between the dorsal hippocampus and the prefrontal cortex in spatial memory","volume":"23","author":"Lee","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.nlm.2009.12.008","article-title":"Prefrontal and hippocampal contributions to encoding and retrieval of spatial memory","volume":"93","author":"Churchwell","year":"2010","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/aps.2010.184","article-title":"The role of BDNF in depression on the basis of its location in the neural circuitry","volume":"32","author":"Yu","year":"2011","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1038\/sj.mp.4002075","article-title":"Is it time to reassess the BDNF hypothesis of depression?","volume":"12","author":"Groves","year":"2007","journal-title":"Mol. Psychiatry"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1126\/science.1120972","article-title":"Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress","volume":"311","author":"Berton","year":"2006","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/npp.2015.171","article-title":"Stress effects on neuronal structure: Hippocampus, amygdala, and prefrontal cortex","volume":"41","author":"McEwen","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.neuroscience.2012.08.034","article-title":"Dynamic plasticity: The role of glucocorticoids, brain-derived neurotrophic factor and other trophic factors","volume":"239","author":"Gray","year":"2013","journal-title":"Neuroscience"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.pneurobio.2013.10.005","article-title":"Stress and trauma: BDNF control of dendritic-spine formation and regression","volume":"112","author":"Bennett","year":"2014","journal-title":"Prog. Neurobiol."},{"key":"ref_72","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":"2018","journal-title":"World J. Biol. Psychiatry"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.brainresbull.2011.07.008","article-title":"Brief social isolation in early adolescence affects reversal learning and forebrain BDNF expression in adult rats","volume":"86","author":"Han","year":"2011","journal-title":"Brain Res. Bull."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.brainres.2004.06.085","article-title":"Acute social defeat reduces neurotrophin expression in brain cortical and subcortical areas in mice","volume":"1025","author":"Pizarro","year":"2004","journal-title":"Brain Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.neuroscience.2010.02.064","article-title":"Short- and long-term effects of intermittent social defeat stress on brain-derived neurotrophic factor expression in mesocorticolimbic brain regions","volume":"167","author":"Fanous","year":"2010","journal-title":"Neuroscience"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1016\/j.neuropharm.2012.08.012","article-title":"Allopregnanolone regulates neurogenesis and depressive\/anxiety-like behaviour in a social isolation rodent model of chronic stress","volume":"63","author":"Evans","year":"2012","journal-title":"Neuropharmacology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nbd.2006.07.017","article-title":"Olfactory bulbectomy in mice leads to increased BDNF levels and decreased serotonin turnover in depression-related brain areas","volume":"25","author":"Hellweg","year":"2007","journal-title":"Neurobiol. Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.pnpbp.2018.06.002","article-title":"Antidepressant-like effect induced by Cannabidiol is dependent on brain serotonin levels","volume":"86","author":"Sales","year":"2018","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"112627","DOI":"10.1016\/j.bbr.2020.112627","article-title":"CBD modulates DNA methylation in the prefrontal cortex and hippocampus of mice exposed to forced swim","volume":"388","author":"Sales","year":"2020","journal-title":"Behav. Brain Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jneuroim.2014.09.011","article-title":"A higher anxiety state in old rats after social isolation is associated to an impairment of the immune response","volume":"277","author":"Cruces","year":"2014","journal-title":"J. Neuroimmunol."},{"key":"ref_81","unstructured":"Paxinos, G., and Watson, C. (2006). The Rat Brain in Stereotaxic Coordinates, Hard Cover Edition, Elsevier."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Portugalov, A., Zaidan, H., Gaisler-Salomon, I., Hillard, C.J., and Akirav, I. (2022). FAAH Inhibition Restores Early Life Stress-Induced Alterations in PFC microRNAs Associated with Depressive-Like Behavior in Male and Female Rats. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232416101"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15492\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:10:30Z","timestamp":1760130630000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15492"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,23]]},"references-count":82,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms242015492"],"URL":"https:\/\/doi.org\/10.3390\/ijms242015492","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,23]]}}}