TY - JOUR T1 - Effects of different social interactions on hippocampal neurogenesis and neuron numbers in juvenile rats: a histological and behavioral study TT - Juvenil sıçanlarda farklı sosyal etkileşimlerin hipokampal nörogenez ve nöron sayıları üzerindeki etkileri: histolojik ve davranışsal bir çalışma AU - Ersoy, Semiha AU - Yavaş, Senem Esin PY - 2025 DA - October Y2 - 2025 DO - 10.31362/patd.1657975 JF - Pamukkale Medical Journal JO - Pam Tıp Derg PB - Pamukkale Üniversitesi WT - DergiPark SN - 1308-0865 SP - 783 EP - 793 VL - 18 IS - 4 LA - en AB - Purpose: Adolescence is a period of development affected by numerous hormonal and neurochemical changes. During this period, time spent with peers and experiences are known to have neurodevelopmental benefits. The hippocampus is a brain region where the production of new neurons after birth continues throughout life and is sensitive to changing social interactions. In this study, we aimed to investigate the effects of changing social interactions on behavioral parameters, doublecortin (DCX) expression, and total neuron numbers in the hippocampus of rat pups.Materials and methods: 21-day-old male and female Wistar albino rats were divided into three groups: control, social isolation, and environmental enrichment. Social isolation and environmental enrichment were applied for 4 weeks. Behavioral parameters were analyzed using ball burying, social interaction, and open-field tests. Following the behavioral tests, the rats were euthanized, and their hippocampal tissues were extracted. Cresyl violet staining was performed on paraffin sections, and DCX immunohistochemistry was performed on floating sections.Results: Increased social interactions had positive effects on exploratory behavior in adolescent rats. Decreased social interactions caused anxiety, depression behaviors, and increased locomotor activity. Histological analysis revealed a significant increase in the total number of neurons and DCX-positive neuroblasts in the dentate gyrus in the environmental enrichment group. In the social isolation group, a significant decrease in the total number of neurons and DCX-positive neuroblasts was observed.Conclusion: These results implied that changing social interactions during the weaning period have an effect on neurogenesis and the number of mature neurons in the DG, and this effect is regulated by different survival mechanisms. KW - Hippocampus KW - neurogenesis KW - doublecortin protein KW - social isolation KW - social interaction N2 - Amaç: Ergenlik, çok sayıda hormonal ve nörokimyasal değişimden etkilenen bir gelişim dönemidir. Bu dönemde akranlarla geçirilen zamanın ve deneyimlerin nörogelişimsel faydaları olduğu bilinmektedir. Hipokampus, doğumdan sonra yeni nöron üretiminin yaşam boyunca devam ettiği ve değişen sosyal etkileşimlere duyarlı bir beyin bölgesidir. Bu çalışmada, değişen sosyal etkileşimlerin sıçan yavrularının hipokampusundaki davranışsal parametreler, doublecortin (DCX) ekspresyonu ve toplam nöron sayıları üzerindeki etkilerini araştırmayı amaçladık.Gereç ve yöntem: 21 günlük erkek ve dişi Wistar albino sıçanlar kontrol, sosyal izolasyon ve çevresel zenginleştirme olmak üzere üç gruba ayrıldı. Sosyal izolasyon ve çevresel zenginleştirme 4 hafta boyunca uygulandı. Davranışsal parametreler bilye gömme, sosyal etkileşim ve açık alan testleri kullanılarak analiz edildi. Davranış testlerinin ardından sakrifiye edilen sıçanların hipokampüsleri çıkarıldı. Parafin kesitlerde Crezil violet boyaması ve yüzen kesitlerde DCX immünohistokimyası yapıldı.Bulgular: Artan sosyal etkileşimlerin ergen sıçanlarda keşif davranışı üzerinde olumlu etkileri olmuştur. Azalan sosyal etkileşimler anksiyete, depresyon davranışları ve lokomotor aktivitede artışa neden olmuştur. Histolojik analiz, çevresel zenginleştirme grubunda dentat girustaki toplam nöron ve DCX-pozitif nöroblast sayısında önemli bir artış olduğunu ortaya koymuştur. Sosyal izolasyon grubunda ise toplam nöron ve DCX-pozitif nöroblast sayısında anlamlı bir azalma gözlenmiştir.Sonuç: Bu sonuçlar, sütten kesme döneminde değişen sosyal etkileşimlerin nörogenez ve DG'daki olgun nöron sayısı üzerinde etkisi olduğunu ve bu etkinin farklı hayatta kalma mekanizmaları tarafından düzenlendiğini göstermiştir. CR - Harlow HF, Zımmermann RR. Affectional responses in the infant monkey; orphaned baby monkeys develop a strong and persistent attachment to inanimate surrogate mothers. Science. 1959;130(3373):421-432. doi:10.1126/science.130.3373.421 CR - House JS, Landis KR, Umberson D. Social relationships and health. Science. 1988;29;241(4865):540-545. doi:10.1126/science.3399889 CR - Holt Lunstad J. Why Social Relationships Are Important for Physical Health: A Systems Approach to Understanding and Modifying Risk and Protection. Annu Rev Psychol. 2018;69:437-458. doi:10.1146/annurev-psych-122216-011902 CR - Koo JW, Duman RS. IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress. PNAS. 2008;105(2):751-756. doi:10.1073/pnas.0708092105 CR - Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Bio Psych. 2006;59(12):1116-1127. doi:10.1016/j.biopsych.2006.02.013 CR - Jacobsen JPR, Mork A. Chronic corticosterone decreases brain-derived neurotrophic factor (BDNF) mRNA and protein in the hippocampus, but not in the frontal cortex, of the rat. J Brain Res. 2006;11(10):221-225. doi:10.1016/j.brainres.2006.06.077 CR - Wong EY, Herbert J. Roles of mineralocorticoid and glucocorticoid receptors in the regulation of progenitor proliferation in the adult hippocampus. Eur J Neurosci. 2005;22:785-792. doi:10.1111/j.1460-9568.2005.04277 CR - Rosenzweig MR, Bennett EL. Psychobiology of plasticity: effects of training and experience on brain and behavior. Behav Brain Res. 1996;78(1):57-65. doi:10.1016/0166-4328(95)00216-2 CR - Zaias J, Queeney TJ, Kelley JB, Zakharova ES, Izenwasser S. Social and physical environmental enrichment differentially affect growth and activity of preadolescent and adolescent male rats. J Am Assoc Lab Anim Sci. 2008;47(2):30-34. CR - Johansson BB, Ohlsson AL. Environment, social interaction, and physical activity as determinants of functional outcome after cerebral infarction in the rat. Exp Neurol. 1996;139(2):322-327. doi:10.1006/exnr.1996.0106 CR - Branchi I, Francia N, Alleva E. Epigenetic control of neurobehavioural plasticity: the role of neurotrophins. Behav Pharmacol. 2004;15(5):353-362. doi:10.1097/00008877-200409000-00006 CR - Kang H, Schuman EM. Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science. 1995;267:1658-1662. doi:10.1126/science.7886457 CR - Pham TM, Ickes B, Albeck D, et al. Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year. Neuroscience. 1999;94(1):279-286. doi:10.1016/s0306-4522(99)00316-4 CR - Jacobs BL, van Praag H, Gage FH. Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry. 2000;5:262-269. doi:10.1038/sj.mp.4000712 CR - Liu JYW, Matarin M, Reeves C, et al. Doublecortin-expressing cell types in temporal lobe epilepsy. Acta Neuropathol Commun. 2018;6:60. doi:10.1186/s40478-018-0566-5 CR - Banerjee D, Rai M. Social isolation in Covid-19: The impact of loneliness. Int J Social Psychiatry. 2020;66(6):525-527. doi:10.1177/0020764020922269 CR - Mumtaz F, Khan MI, Zubair M, Dehpour AR. Neurobiology and consequences of social isolation stress in animal model—A comprehensive review. Biomed Pharmacother. 2018;105:1205-1222. doi:10.1016/j.biopha.2018.05.086 CR - Hisey EE, Fritsch EL, Newman EL, Ressler KJ, Kangas BD, Carlezon WA. Early life stress in male mice blunts responsiveness in a translationally-relevant reward task. Neuropsychopharmacol. 2023;48(12):1752-1759. doi:10.1038/s41386-023-01610-7 CR - Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 6th edition. San Diego: Academic Press; 2009. CR - Holt Lunstad J, Smith TB, Layton JB. Social relationships and mortality risk: a meta-analytic review. PLoS Med. 2010;7(7):e1000316. doi:10.1371/journal.pmed.1000316 CR - Lee FS, Heimer H, Giedd JN, et al. Adolescent mental health—Opportunity and obligation. Science. 2014;346(6209):547-549. doi:10.1126/science.1260497 CR - Aoki C, Romeo RD, Smith SS. Adolescence as a critical period for developmental plasticity. Brain Res. 2017;1654:85-86. doi:10.1016/j.brainres.2016.11.026 CR - Crews F, He J, Hodge C. Adolescent cortical development: A critical period of vulnerability for addiction. Pharmacol Biochemis Behav. 2007;86(2):189-199. doi:10.1016/j.pbb.2006.12.001 CR - Fuhrmann D, Knoll LJ, Blakemore SJ. Adolescence as a Sensitive Period of Brain Development. Trends Cogn Sci. 2015;19(10):558-566. doi:10.1016/j.tics.2015.07.008 CR - Foulkes L, Leung JT, Fuhrmann D, Knoll LJ, Blakemore SJ. Age differences in the prosocial influence effect. Dev Sci. 2018;21(6):e126666. doi:10.1111/desc.12666 CR - Paez Martinez N, Flores Serrano Z, Ortiz Lopez L, Ramirez Rodriguez G. Environmental enrichment increases doublecortin-associated new neurons and decreases neuronal death without modifying anxiety-like behavior in mice chronically exposed to toluene. Behav Brain Res. 2013;256(1):432-440. doi:10.1016/j.bbr.2013.09.007 CR - Chumley MJ, Catchpole T, Silvany RE, Kernie SG, Henkemeyer M. EphB receptors regulate stem/progenitor cell proliferation, migration, and polarity during hippocampal neurogenesis. J Neurosci. 2007;27(49):13481-13490. doi:10.1523/jneurosci.4158-07.2007 CR - Vrankova S, Galandakova Z, Benko J, Cebova M, Riecansky I, Pechanova, O. Duration of social isolation affects production of nitric oxide in the rat brain. Int J Mol Sci. 2021;22(19):10340. doi:10.3390/ijms221910340 CR - Ieraci A, Mallei A, Popoli M. Social isolation stress induces anxious-depressive-like behavior and alterations of neuroplasticity-related genes in adult male mice. Neural Plast. 2016:1-13. doi:10.1155/2016/6212983 CR - Begni V, Sanson A, Pfeiffer N, et al. Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity. PLOS One. 2020;15(10):e0240439. doi:10.1371/journal.pone.0240439 CR - Sapkale B, Sawal A. Attention deficit hyperactivity disorder (ADHD) causes and diagnosis in adults: A review. Cureus. 2023;15(11):e49144. doi:10.7759/cureus.49144 CR - Hodges TE, Baumbach JL, McCormick CM. Predictors of social instability stress effects on social interaction and anxiety in adolescent male rats. Dev Psychobiol. 2018;60(6):651-663. doi:10.1002/dev.21626 CR - Herrera Isaza L, Zárate Guerrero S, Corredor K, Gómez Fonseca Á, Escobar Cornejo G, Cardenas FP. Role of environmental enrichment on social interaction, anxiety, locomotion, and memory in Wistar rats under chronic methylphenidate intake. Front Behav Neurosci. 2023;17:1251144. doi:10.3389/fnbeh.2023.1251144 CR - Brinton RD, Wang JM. Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer’s disease: allopregnanolone as a proof of concept neurogenic agent. Current Alzheimer Res. 2006;3(3):185-190. doi:10.2174/156720506777632817 CR - Petrik D, Lagace DC, Eisch AJ. The neurogenesis hypothesis of affective and anxiety disorders: Are we mistaking the scaffolding for the building? Neuropharmacol. 2012;62(1):21-34. doi:10.1016/j.neuropharm.2011.09.003 CR - Kempermann G, Jessberger S, Steiner B, Kronenberg G. Milestones of neuronal development in the adult hippocampus. Trends Neurosci. 2004;27(8):447-452. doi:10.1016/j.tins.2004.06.013 CR - Encinas JM, Enikolopov G. Identifying and quantitating neural stem and progenitor cells in the adult brain. Methods Cell Biol. 2008;85:243-272. doi:10.1016/S0091-679X(08)85011-4 CR - Revest JM, Dupret D, Koehl M, et al. Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol Psychiatry. 2009;14(10):959-967. doi:10.1038/mp.2009.15 CR - du Preez A, Onorato D, Eiben I, et al. Chronic stress followed by social isolation promotes depressive-like behavior, alters microglial and astrocyte biology, and reduces hippocampal neurogenesis in male mice. Brain Behav Immun. 2021;91:24-47. doi:10.1016/j.bbi.2020.07.015 CR - Cinini SM, Barnabe GF, Galvão Coelho N, et al. Social isolation disrupts hippocampal neurogenesis in young non-human primates. Front Neurosci. 2014;27(8):45. doi:10.3389/fnins.2014.00045 CR - Ausas MS, Mazzitelli Fuentes L, et al. Social isolation impairs active avoidance performance and decreases neurogenesis in the dorsomedial telencephalon of rainbow trout. Physiol Behav. 2019;198(1):1-10. doi:10.1016/j.physbeh.2018.10.006 CR - Chan JN, Lee JC, Lee SS, et al. Interaction effect of social isolation and high dose corticosteroid on neurogenesis and emotional behavior. Front Behav Neurosci. 2017;11:18. doi:10.3389/fnbeh.2017.00018 CR - Dioli C, Patrício P, Sousa N, et al. Chronic stress triggers divergent dendritic alterations in immature neurons of the adult hippocampus, depending on their ultimate terminal fields. Transl Psychiatry. 2019;9(1):143. doi:10.1038/s41398-019-0477-7 CR - Vyas A, Mitra R, Shankaranarayana Rao BS, Chattarji S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci. 2002;22(15):6810-6818. doi:10.1523/jneurosci.22-15-06810.2002 CR - Radley JJ, Sisti HM, Hao J, et al. Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience. 2004;125(1):1-6. doi:10.1016/j.neuroscience.2004.01.006 CR - Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci. 1998;18(16):7330-7338. doi:10.1523/JNEUROSCI.18-16-07330.1998 CR - Mirescu C, Peters JD, Gould E. Early life experience alters response of adult neurogenesis to stress. Nat Neurosci. 2004;7(8):841-846. doi:10.1038/nn1283 CR - Conrad CD, Ortiz JB, Judd JM. Chronic stress and hippocampal dendritic complexity: Methodological and functional considerations. Physiol Behav. 2017;178(1):66-81. doi:10.1016/j.physbeh.2016.11.017 CR - Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature. 1997;386(6624):493-495. doi:10.1038/386493a0 CR - Garthe A, Roeder I, Kempermann G. Mice in an enriched environment learn more flexibly because of adult hippocampal neurogenesis. Hippocampus. 2016;26(2):261-271. doi:10.1002/hipo.22520 CR - van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 1999;2(3):266-270. doi:10.1038/6368 CR - Branchi I, D’Andrea I, Fiore M, Di Giovanni G, Alleva E. Early social enrichment shapes social behavior and brain development in rats. Dev Psychobiol. 2013;55(7):623-635. doi:10.1002/dev.21069 UR - https://doi.org/10.31362/patd.1657975 L1 - https://dergipark.org.tr/tr/download/article-file/4691170 ER -