Abstract
This review describes the role of social isolation in the development of anxiety and depression-like behavior in rodents. The duration of social isolation, age from onset of social isolation, sex, species, and strain of animals, the nature of the model used, and other factors have been shown to have influences. The molecular-cellular mechanisms of development of anxiety and depression-like behavior under the influence of social isolation and the roles of the HHAS, oxidative and nitrosative stress, neuroinflammation, BDNF, neurogenesis, synaptic plasticity, as well as monoamines in these mechanisms are discussed. This review presents data on sex differences in the effects of social isolation, along with the effects of interactions with other types of stress, and the roles of an enriched environment and other factors in ameliorating the negative sequelae of social isolation.
Keywords: social isolation, anxiety and depression-like behavior, stress, open field, elevated plus maze, sucrose preference test, forced swimming
Footnotes
Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 71, No. 6, pp. 760–784, November–December, 2021.
References
- Agrawal P, Kao D, Chung P, Looger LL. The neuropeptide drosulfakinin regulates social isolation-induced aggression in Drosophila. J. Exp. Biol. 2020;223(2):jeb207407. doi: 10.1242/jeb.207407. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Alshammari TK, Alghamdi H, Alkhader LF, et al. Analysis of the molecular and behavioral effects of acute social isolation on rats. Behav. Brain Res. 2020;377:112–191. doi: 10.1016/j.bbr.2019.112191. [DOI] [PubMed] [Google Scholar]
- Alshammari TK, Alghamdi H, Green TA, et al. Assessing the role of toll-like receptor in isolated, standard and enriched housing conditions. PLoS One. 2019;14(10):e0222818. doi: 10.1371/journal.pone.0222818. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Amiri S, Haj-Mirzaian A, Rahimi-Balaei M, et al. Co-occurrence of anxiety and depressive-like behaviors following adolescent social isolation in male mice; possible role of nitrergic system. Physiol. Behav. 2015;145:38–44. doi: 10.1016/j.physbeh.2015.03.032. [DOI] [PubMed] [Google Scholar]
- Arimoto T, Bing G. Up-regulation of inducible nitric oxide synthase in the substantia nigra by lipopolysaccharide causes microglial activation and neurodegeneration. Neurobiol. Dis. 2003;12:35–45. doi: 10.1016/S0969-9961(02)00017-7. [DOI] [PubMed] [Google Scholar]
- Arranz L, Giménez-Llort L, De Castro NM, et al. Social isolation during old age worsens cognitive, behavioral and immune impairment. Rev. Esp. Geriatr. Gerontol. 2009;44(3):137–142. doi: 10.1016/j.regg.2008.12.001. [DOI] [PubMed] [Google Scholar]
- Arzate-Mejía RG, Lottenbach Z, Schindler V, et al. Long-term impact of social isolation and molecular underpinnings. Front. Genet. 2020;11:589–621. doi: 10.3389/fgene.2020.589621. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Barrientos RM, Brunton PJ, Lenz KM, et al. Neuroimmunology of the female brain across the lifespan: Plasticity to psychopathology. Brain Behav. Immun. 2019;79:39–55. doi: 10.1016/j.bbi.2019.03.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bastos CP, Pereira LM, Ferreira-Vieira TH, et al. Object recognition memory deficit and depressive-like behavior caused by chronic ovariectomy can be transitorialy recovered by the acute activation of hippocampal estrogen receptors. Psychoneuroendocrinology. 2015;57:14–25. doi: 10.1016/j.psyneuen.2015.03.020. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Berry A, Bellisario V, Capoccia S, et al. Social deprivation stress is a triggering factor for the emergence of anxiety- and depression-like behaviours and leads to reduced brain BDNF levels in C57BL/6J mice. Psychoneuroendocrinology. 2012;37:762–772. doi: 10.1016/j.psyneuen.2011.09.007. [DOI] [PubMed] [Google Scholar]
- Bibancos T, Jardim DL, Aneas I, Chiavegatto S. Social isolation and expression of serotonergic neurotransmission-related genes in several brain areas of male mice. Genes Brain Behav. 2007;6(6):529. doi: 10.1111/j.1601-183X.2006.00280.x. [DOI] [PubMed] [Google Scholar]
- Boero G, Pisu MG, Biggio F, et al. Impaired glucocorticoid-mediated HPA axis negative feedback induced by juvenile social isolation in male rats. Neuropharmacology. 2018;133:242–253. doi: 10.1016/j.neuropharm.2018.01.045. [DOI] [PubMed] [Google Scholar]
- Bourke CH, Neigh GN. Behavioral effects of chronic adolescent stress are sustained and sexually dimorphic. Horm. Behav. 2011;60(1):112–20. doi: 10.1016/j.yhbeh.2011.03.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bowie A, O’Neill LA. Oxidative stress and nuclear factor kappaB activation: a reassessment of the evidence in the light of recent discoveries. Biochem. Pharmacol. 2000;59:13–23. doi: 10.1016/S0006-2952(99)00296-8. [DOI] [PubMed] [Google Scholar]
- Brenes JC, Fornaguera J. The effect of chronic fluoxetine on social isolation-induced changes on sucrose consumption, immobility behavior, and on serotonin and dopamine function in hippocampus and ventral striatum. Behav. Brain Res. 2009;198:199–205. doi: 10.1016/j.bbr.2008.10.036. [DOI] [PubMed] [Google Scholar]
- Brenes JC, Fornaguera J, Sequeira-Cordero A. Environmental enrichment and physical exercise attenuate the depressive-like effects induced by social isolation stress in rats. Front. Pharmacol. 2020;11:804. doi: 10.3389/fphar.2020.00804. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brenes JC, Villagra OR, Fornaguera J. Factor analysis of forced swimming test, sucrose preference test and open field test on enriched, social and isolated reared rats. Behav. Brain Res. 2006;169(1):57–65. doi: 10.1016/j.bbr.2005.12.001. [DOI] [PubMed] [Google Scholar]
- Butler TR, Carter E, Weiner JL. Adolescent social isolation does not lead to persistent increases in anxiety-like behavior or ethanol intake in female Long–Evans rats. Alcohol Clin. Exp. Res. 2014;38:2199–2207. doi: 10.1111/acer.12476. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carrier N, Kabbaj M. Testosterone and imipramine have antidepressant effects in socially isolated male but not female rats. Horm. Behav. 2012;61:678–685. doi: 10.1016/j.yhbeh.2012.03.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Caruso MJ, Kamens HM, Cavigelli SA. Exposure to chronic variable social stress during adolescence alters affect-related behaviors and adrenocortical activity in adult male and female inbred mice. Dev. Psychobiol. 2017;59(6):679–687. doi: 10.1002/dev.21541. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cassina P, Peluffo H, Pehar M, et al. Peroxynitrite triggers a phenotypic transformation in spinal cord astrocytes that induces motor neuron apoptosis. J. Neurosci. Res. 2002;67:21–29. doi: 10.1002/jnr.10107. [DOI] [PubMed] [Google Scholar]
- Chang LY, Slot JW, Geuze HJ, Crapo JD. Molecular immunocytochemistry of the CuZn superoxide dismutase in rat hepatocytes. J. Cell Biol. 1988;107:2169–2179. doi: 10.1083/jcb.107.6.2169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chappell AM, Carter E, McCool BA, Weiner JL. Adolescent rearing conditions influence the relationship between initial anxiety-like behavior and ethanol drinking in male Long Evans rats. Alcohol Clin. Exp. Res. 2013;37(Suppl. 1):E394–403. doi: 10.1111/j.1530-0277.2012.01926.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chelikani P, Fita I, Loewen PC. Diversity of structures and properties among catalases. Cell. Mol. Life Sci. 2004;61:192–208. doi: 10.1007/s00018-003-3206-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chen YW, Akad A, Aderogba R, et al. Dendrites of the dorsal and ventral hippocampal CA1 pyramidal neurons of singly housed female rats exhibit lamina-specific growths and retractions during adolescence that are responsive to pair housing. Synapse. 2018;72(7):e22034. doi: 10.1002/syn.22034. [DOI] [PubMed] [Google Scholar]
- Chmelova, M., Balagova, L., Marko, M., et al., “Behavioral alterations induced by post-weaning isolation rearing of rats are accompanied by reduced VGF/BDNF/TrkB signaling in the hippocampus,” Neurochem. Int., 104473 (2019). [DOI] [PubMed]
- Cirulli F, Berry A, Bonsignore LT, et al. Early life influences on emotional reactivity: evidence that social enrichment has greater effects than handling on anxiety-like behaviors, neuroendocrine responses to stress and central BDNF levels. Neurosci. Biobehav. Rev. 2010;34(6):808–820. doi: 10.1016/j.neubiorev.2010.02.008. [DOI] [PubMed] [Google Scholar]
- Colaianna M, Schiavone S, Zotti M, et al. Neuroendocrine profile in a rat model of psychosocial stress: relation to oxidative stress. Antioxid. Redox. Signal. 2013;18:1385–1399. doi: 10.1089/ars.2012.4569. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Connelly L, Palacios-Callender M, Ameixa C, et al. Biphasic regulation of NF-kappa B activity underlies the pro- and antiinflammatory actions of nitric oxide. J. Immunol. 2001;166:3873–3881. doi: 10.4049/jimmunol.166.6.3873. [DOI] [PubMed] [Google Scholar]
- Djordjevic J, Djordjevic A, Adzic M, Radojcic MB. Effects of chronic social isolation on Wistar rat behavior and brain plasticity markers. Neuropsychobiology. 2012;66(2):112–119. doi: 10.1159/000338605. [DOI] [PubMed] [Google Scholar]
- Donovan M, Mackey CS, Platt GN, et al. Social isolation alters behavior, the gut-immune-brain axis, and neurochemical circuits in male and female prairie voles. Neurobiol. Stress. 2020;13:100278. doi: 10.1016/j.ynstr.2020.100278. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Du Preez A, Law T, Onorato D, et al. The type of stress matters: repeated injection and permanent social isolation stress in male mice have a differential effect on anxiety- and depressive-like behaviours, and associated biological alterations. Transl. Psychiatry. 2020;10(1):325. doi: 10.1038/s41398-020-01000-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Du Preez A, Onorato D, Eiben I, et al. Chronic stress followed by social isolation promotes depressive-like behaviour, alters microglial and astrocyte biology and reduces hippocampal neurogenesis in male mice. Brain Behav. Immun. 2020;S0889-1591(20):30126–4. doi: 10.1016/j.bbi.2020.07.015. [DOI] [PubMed] [Google Scholar]
- Dunphy-Doherty, F., O’Mahony, S. M., Peterson, V. L., et al., “Postweaning social isolation of rats leads to long-term disruption of the gut microbiota-immune-brain axis,” Brain Behav. Immun., 261–273 (2018). [DOI] [PubMed]
- Einon DF, Morgan MJ. A critical period for social isolation in the rat. Dev. Psychobiol. 1977;10:123–132. doi: 10.1002/dev.420100205. [DOI] [PubMed] [Google Scholar]
- Evans J, Sun Y, McGregor A, Connor B. Allopregnanolone regulates neurogenesis and depressive/anxiety-like behaviour in a social isolation rodent model of chronic stress. Neuropharmacology. 2012;63(8):1315–1326. doi: 10.1016/j.neuropharm.2012.08.012. [DOI] [PubMed] [Google Scholar]
- Ferland CL, Schrader LA. Cage mate separation in pair-housed male rats evokes an acute stress corticosterone response. Neurosci. Lett. 2011;489:154–158. doi: 10.1016/j.neulet.2010.12.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Filipović D, Pajović SB. Differential regulation of CuZnSOD expression in rat brain by acute and/or chronic stress. Cell. Mol. Neurobiol. 2009;29:673–681. doi: 10.1007/s10571-009-9375-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Filipović D, Todorović N, Bernardi RE, Gass P. Oxidative and nitrosative stress pathways in the brain of socially isolated adult male rats demonstrating depressive- and anxiety-like symptoms. Brain Struct. Funct. 2017;222(1):1–20. doi: 10.1007/s00429-016-1218-9. [DOI] [PubMed] [Google Scholar]
- Fonken LK, Frank MG, Gaudet AD, et al. Neuroinflammatory priming to stress is differentially regulated in male and female rats. Brain Behav. Immun. 2018;70:257–267. doi: 10.1016/j.bbi.2018.03.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Frank MG, Baratta MV, Sprunger DB, et al. Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav. Immun. 2007;21(1):47–59. doi: 10.1016/j.bbi.2006.03.005. [DOI] [PubMed] [Google Scholar]
- Gandhi R, Hayley S, Gibb J, et al. Influence of poly I:C on sickness behaviors, plasma cytokines, corticosterone and central monoamine activity: moderation by social stressors. Brain Behav. Immun. 2007;21(4):477–89. doi: 10.1016/j.bbi.2006.12.005. [DOI] [PubMed] [Google Scholar]
- Ge F, Yang H, Lu W, et al. Ovariectomy induces microglial cell activation and inflammatory response in rat prefrontal cortices to accelerate the chronic unpredictable stress-mediated anxiety and depression. Biomed. Res. Int. 2020;2020:3609758. doi: 10.1155/2020/3609758. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gibb J, Hayley S, Gandhi R, et al. Synergistic and additive actions of a psychosocial stressor and endotoxin challenge: Circulating and brain cytokines, plasma corticosterone and behavioral changes in mice. Brain Behav. Immun. 2008;22(4):573–589. doi: 10.1016/j.bbi.2007.12.001. [DOI] [PubMed] [Google Scholar]
- Giustarini D, Rossi R, Milzani A, et al. S-glutathionylation: from redox regulation of protein functions to human diseases. J. Cell. Mol. Med. 2004;8:201–212. doi: 10.1111/j.1582-4934.2004.tb00275.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goh JY, O’Sullivan SE, Shortall SE, et al. Gestational poly(I:C) attenuates, not exacerbates, the behavioral, cytokine and mTOR changes caused by isolation rearing in a rat ‘dual-hit’ model for neurodevelopmental disorders. Brain Behav. Immun. 2020;89:100–117. doi: 10.1016/j.bbi.2020.05.076. [DOI] [PubMed] [Google Scholar]
- Gong Y, Tong L, Yang R, et al. Dynamic changes in hippocampal microglia contribute to depressive-like behavior induced by early social isolation. Neuropharmacology. 2018;135:223–233. doi: 10.1016/j.neuropharm.2018.03.023. [DOI] [PubMed] [Google Scholar]
- Gorlova AV, Pavlov DA, Zubkov EA, et al. Three-week isolation does not lead to depressive-like disorders in rats. Bull. Exp. Biol. Med. 2018;165(2):181–183. doi: 10.1007/s10517-018-4125-7. [DOI] [PubMed] [Google Scholar]
- Grigoryan GA, Gulyaeva NV. Modeling of depression in animals: behavior as a methodological basis, assessment criteria, and classification. Zh. Vyssh. Nerv. Deyat. 2015;65(6):643–660. [PubMed] [Google Scholar]
- Grigoryan GA. Memory and depression. Zh. Vyssh. Nerv. Deyat. 2005;56(4):556–570. [PubMed] [Google Scholar]
- Grigoryan GA, Dygalo NN, Gekht AB, et al. Molecular and cellular mechanisms of depression. The role of glucocorticoids, cytokines, and neurotrophic factors in the genesis of depressive disorders. Usp. Fiz. Nauk. 2014;44(2):3–20. [PubMed] [Google Scholar]
- Grippo AJ, Ihm E, Wardwell J, et al. The effects of environmental enrichment on depressive and anxiety-relevant behaviors in socially isolated prairie voles. Psychosom. Med. 2014;76(4):277–284. doi: 10.1097/PSY.0000000000000052. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Guarnieri LO, Pereira-Caxeta AR, Medeiros DC, et al. Proneurogenic effect of fluoxetine in the olfactory bulb is concomitant to improvements in social memory and depressive-like behavior of socially isolated mice. Transl. Psychiatry. 2020;10(1):33. doi: 10.1038/s41398-020-0701-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Guo M, Wu CF, Liu W, et al. Sex difference in psychological behavior changes induced by long-term social isolation in mice. Prog. Neuropsychopharm. Biol. Psychiatry. 2004;28(1):115–121. doi: 10.1016/j.pnpbp.2003.09.027. [DOI] [PubMed] [Google Scholar]
- Haj-Mirzaian A, Amiri S, Amini-Khoei H, et al. Attenuation of oxidative and nitrosative stress in cortical area associates with antidepressant-like effects of tropisetron in male mice following social isolation stress. Brain Res. Bull. 2016;124:150–63. doi: 10.1016/j.brainresbull.2016.04.018. [DOI] [PubMed] [Google Scholar]
- Hall, F. S., “Social deprivation of neonatal, adolescent, and adult rats has distinct neurochemical and behavioral consequences,” Crit. Rev. Neurobiol., 12, No. 1–2, 129–162 (1998). [DOI] [PubMed]
- Hall FS, Huang S, Fong GF, Pert AJ. The effects of social isolation on the forced swim test in Fawn hooded and Wistar rats. Neurosci. Methods. 1998;79(1):47–51. doi: 10.1016/S0165-0270(97)00155-6. [DOI] [PubMed] [Google Scholar]
- Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. 2. Oxford: Oxford University Press; 1989. [Google Scholar]
- Han X, Wang W, Xue X, et al. Brief social isolation in early adolescence affects reversal learning and forebrain BDNF expression in adult rats. Brain Res. Bull. 2011;86(3–4):173–178. doi: 10.1016/j.brainresbull.2011.07.008. [DOI] [PubMed] [Google Scholar]
- Heck AL, Handa RJ. Sex differences in the hypothalamic-pituitary-adrenal axis’ response to stress: an important role for gonadal hormones. Neuropsychopharmacology. 2019;44(1):45–58. doi: 10.1038/s41386-018-0167-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heck AL, Sheng JA, Miller AM, et al. Social isolation alters hypothalamic pituitary adrenal axis activity after chronic variable stress in male C57BL/6 mice. Stress. 2020;23(4):457–465. doi: 10.1080/10253890.2020.1733962. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heidbreder CA, Weiss IC, Domeney AM, et al. Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome. Neuroscience. 2000;100:749–768. doi: 10.1016/S0306-4522(00)00336-5. [DOI] [PubMed] [Google Scholar]
- Holgate JY, Garcia H, Chatterjee S, Bartlett SE. Social and environmental enrichment has different effects on ethanol and sucrose consumption in mice. Brain Behav. 2017;7(8):e00767. doi: 10.1002/brb3.767. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Holson RR, Scallet AC, Ali SF, et al. Adrenocortical, beta-endorphin and behavioral responses to graded stressors in differentially reared rats. Physiol. Behav. 1988;42:125–130. doi: 10.1016/0031-9384(88)90286-7. [DOI] [PubMed] [Google Scholar]
- Hong S, Flashner B, Chiu M, et al. Social isolation in adolescence alters behaviors in the forced swim and sucrose preference tests in female but not in male rats. Physiol. Behav. 2012;105(2):269–275. doi: 10.1016/j.physbeh.2011.08.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Howes SR, Dalley JW, Morrison CH, et al. Leftward shift in the acquisition of cocaine self-administration in isolation-reared rats: relationship to extracellular levels of dopamine, serotonin and glutamate in the nucleus accumbens and amygdala-striatal FOS expression. Psychopharmacology. 2000;151:55–63. doi: 10.1007/s002130000451. [DOI] [PubMed] [Google Scholar]
- Huang H, Wang L, Cao M, et al. Isolation housing exacerbates Alzheimer’s disease-like pathophysiology in aged APP/PS1 mice. Int. J. Neuropsychopharmacol. 2015;18(7):pyu116. doi: 10.1093/ijnp/pyu116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huang Q, Zhou Y, Liu LY. Effect of post-weaning isolation on anxiety- and depressive-like behaviors of C57BL/6J mice. Exp. Brain Res. 2017;235(9):2893–2899. doi: 10.1007/s00221-017-5021-5. [DOI] [PubMed] [Google Scholar]
- Ibi D, Takuma K, Koike H, et al. Social isolation rearing-induced impairment of the hippocampal neurogenesis is associated with deficits in spatial memory and emotion-related behaviors in juvenile mice. J. Neurochem. 2008;105(3):921–932. doi: 10.1111/j.1471-4159.2007.05207.x. [DOI] [PubMed] [Google Scholar]
- Ieraci, A., Mallei, A., and Popoli, M., “Social isolation stress induces anxious-depressive-like behavior and alterations of neuroplasticity-related genes in adult male mice,” Neural Plast., 6212983 (2016). [DOI] [PMC free article] [PubMed]
- Jahng JW, Yoo SB, Ryu V, Lee JH. Hyperphagia and depression-like behavior by adolescence social isolation in female rats. Int. J. Dev. Neurosci. 2012;30:47–53. doi: 10.1016/j.ijdevneu.2011.10.001. [DOI] [PubMed] [Google Scholar]
- Karkhanis AN, Alexander NJ, McCool BA, et al. Chronic social isolation during adolescence augments catecholamine response to acute ethanol in the basolateral amygdala. Synapse. 2015;69(8):385–395. doi: 10.1002/syn.21826. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Karkhanis AN, Locke JL, McCool BA, et al. Social isolation rearing increases nucleus accumbens dopamine and norepinephrine responses to acute ethanol in adulthood. Alcohol Clin. Exp. Res. 2014;38:2770–2779. doi: 10.1111/acer.12555. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Khayum MA, Moraga-Amaro R, Buwalda B, et al. Ovariectomyinduced depressive-like behavior and brain glucose metabolism changes in female rats are not affected by chronic mild stress. Psychoneuroendocrinology. 2020;115:104610. doi: 10.1016/j.psyneuen.2020.104610. [DOI] [PubMed] [Google Scholar]
- Krupina NA, Khlebnikova NN, Narkevich VB, et al. Levels of monoamines and their metabolites in brain structures in rats in social isolation for two and three months. Bull. Exp. Biol. Med. 2019;168(11):540–545. doi: 10.1007/s10517-020-04761-5. [DOI] [PubMed] [Google Scholar]
- Krupina NA, Shirenova SD, Khlebnikova NN. Prolonged social isolation, started early in life, impairs cognitive abilities in rats depending on sex. Brain Sci. 2020;10(11):799. doi: 10.3390/brainsci10110799. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kulesskaya N, Rauvala H, Voikar V. Evaluation of social and physical enrichment in modulation of behavioural phenotype in C57BL/6J female mice. PLoS One. 2011;6(9):e24755. doi: 10.1371/journal.pone.0024755. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kumari A, Singh P, Baghel MS, Thakur MK. Social isolation mediated anxiety like behavior is associated with enhanced expression and regulation of BDNF in the female mouse brain. Physiol. Behav. 2016;158:34–42. doi: 10.1016/j.physbeh.2016.02.032. [DOI] [PubMed] [Google Scholar]
- Li, H. and Xia, N., “The role of oxidative stress in cardiovascular disease caused by social isolation and loneliness,” Redox Biol., 101585 (2020). [DOI] [PMC free article] [PubMed]
- Lieberwirth C, Liu Y, Jia X, Wang Z. Social isolation impairs adult neurogenesis in the limbic system and alters behaviors in female prairie voles. Horm. Behav. 2012;62(4):357–366. doi: 10.1016/j.yhbeh.2012.03.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu N, Wang Y, An AY, et al. Single housing-induced effects on cognitive impairment and depression-like behavior in male and female mice involve neuroplasticity-related signaling. Eur. J. Neurosci. 2020;52(1):2694–2704. doi: 10.1111/ejn.14565. [DOI] [PubMed] [Google Scholar]
- Lu L, Bao G, Chen H, et al. Modification of hippocampal neurogenesis and neuroplasticity by social environments. Exp. Neurol. 2003;183:600–609. doi: 10.1016/S0014-4886(03)00248-6. [DOI] [PubMed] [Google Scholar]
- Lukkes JL, Engelman GH, Zelin NS, et al. Post-weaning social isolation of female rats, anxiety-related behavior, and serotonergic systems. Brain Res. 2012;1443:1–17. doi: 10.1016/j.brainres.2012.01.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lukkes JL, Summers CH, Scholl JL, et al. Early life social isolation alters corticotropin-releasing factor responses in adult rats. Neuroscience. 2009;158:845–855. doi: 10.1016/j.neuroscience.2008.10.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Madrigal JLM, García-Bueno B, Caso JR, et al. Stress-induced oxidative changes in brain. CNS Neurol. Disord. Drug Targets. 2006;5:561–568. doi: 10.2174/187152706778559327. [DOI] [PubMed] [Google Scholar]
- Maes M, Mihaylova I, Bosmans E. Not in the mind of neurasthenic lazybones but in the cell nucleus: patients with chronic fatigue syndrome have increased production of nuclear factor kappa beta. Neuro Endocrinol. Lett. 2007;28:456–462. [PubMed] [Google Scholar]
- Medendorp WE, Petersen ED, Pal A, et al. Altered behavior in mice socially isolated during adolescence corresponds with immature dendritic spine morphology and impaired plasticity in the prefrontal cortex. Front. Behav. Neurosci. 2018;12:87. doi: 10.3389/fnbeh.2018.00087. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meng Q, Li N, Han X, et al. Effects of adolescent social isolation on the expression of brain-derived neurotrophic factors in the forebrain. Eur. J. Pharmacol. 2011;650(1):229–232. doi: 10.1016/j.ejphar.2010.09.061. [DOI] [PubMed] [Google Scholar]
- Meyer M, Schreck R, Baeuerle P. AH2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J. 1993;12:2005–2015. doi: 10.1002/j.1460-2075.1993.tb05850.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mileva GR, Bielajew C. Environmental manipulation affects depressive-like behaviours in female Wistar–Kyoto rats. Behav. Brain Res. 2015;293:208–216. doi: 10.1016/j.bbr.2015.07.035. [DOI] [PubMed] [Google Scholar]
- Mileva GR, Rooke J, Ismail N, Bielajew C. Corticosterone and immune cytokine characterization following environmental manipulation in female WKY rats. Behav. Brain Res. 2017;316:197–204. doi: 10.1016/j.bbr.2016.09.004. [DOI] [PubMed] [Google Scholar]
- Miura H, Qiao H, Ohta T. Attenuating effects of the isolated rearing condition on increased brain serotonin and dopamine turnover elicited by novelty stress. Brain Res. 2002;926(1–2):10–17. doi: 10.1016/S0006-8993(01)03201-2. [DOI] [PubMed] [Google Scholar]
- Miura H, Shirokawa T, Isobe K, Ozaki N. Shifting the balance of brain tryptophan metabolism elicited by isolation housing and systemic administration of lipopolysaccharide in mice. Stress. 2009;12(3):206–14. doi: 10.1080/10253890802252442. [DOI] [PubMed] [Google Scholar]
- Mohale DS, Chandewar AV. Effect of social isolation on oxidative stress and transaminase level. Asian J. Biomed. Pharmaceut. Sci. 2012;2(15):41–44. [Google Scholar]
- Mora-Gallegos A, Fornaguera J. The effects of environmental enrichment and social isolation and their reversion on anxiety and fear conditioning. Behav. Proc. 2019;158:59–69. doi: 10.1016/j.beproc.2018.10.022. [DOI] [PubMed] [Google Scholar]
- Nishinaka T, Kinoshita M, Nakamoto K, Tokuyama S. Sex differences in depression-like behavior after nerve injury are associated with differential changes in brain-derived neurotrophic factor levels in mice subjected to early life stress. Neurosci. Lett. 2015;592:32–36. doi: 10.1016/j.neulet.2015.02.053. [DOI] [PubMed] [Google Scholar]
- O’Keefe LM, Doran SJ, Mwilambwe-Tshilobo L, et al. Social isolation after stroke leads to depressive-like behavior and decreased BDNF levels in mice. Behav. Brain Res. 2014;260:162–70. doi: 10.1016/j.bbr.2013.10.047. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Okudan N, Belviranlı M. Long-term voluntary exercise prevents post-weaning social isolation-induced cognitive impairment in rats. Neuroscience. 2017;60:1–8. doi: 10.1016/j.neuroscience.2017.07.045. [DOI] [PubMed] [Google Scholar]
- Painsipp E, Köfer MJ, Sinner F, Holzer P. Prolonged depression-like behavior caused by immune challenge: influence of mouse strain and social environment. PLoS One. 2011;6(6):e20719. doi: 10.1371/journal.pone.0020719. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Panksepp J. The ontogeny of play in rats. Dev. Psychobiol. 1981;14:327–332. doi: 10.1002/dev.420140405. [DOI] [PubMed] [Google Scholar]
- Park HS, Kim TW, Park SS, Lee SJJ. Swimming exercise ameliorates mood disorder and memory impairment by enhancing neurogenesis, serotonin expression, and inhibiting apoptosis in social isolation rats during adolescence. J. Exerc. Rehabil. 2020;16(2):132–140. doi: 10.12965/jer.2040216.108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Parker VMA. The socially isolated rat as a model of anxiety. Neuropharmacology. 1986;25:663–664. doi: 10.1016/0028-3908(86)90224-8. [DOI] [Google Scholar]
- Pavlova IV, Broshevitskaya ND, Zaichenko MI, Grigoryan GA. The effects of social isolation and an enriched environment on anxious-depressive behavior in rats in health and after early proinflammatory stress. Zh. Vyssh. Nerv. Deyat. 2021;71(5):690–709. [Google Scholar]
- Peterman JL, White JD, Calcagno A, et al. Prolonged isolation stress accelerates the onset of Alzheimer’s disease-related pathology in 5xFAD mice despite running wheels and environmental enrichment. Behav. Brain Res. 2020;379:112366. doi: 10.1016/j.bbr.2019.112366. [DOI] [PubMed] [Google Scholar]
- Pietropaolo S, Feldon J, Alleca E, et al. The role of voluntary exercise in enriched rearing: a behavioral analysis. Behav. Neurosci. 2006;4:787–803. doi: 10.1037/0735-7044.120.4.787. [DOI] [PubMed] [Google Scholar]
- Pietropaolo S, Singer P, Feldon J, Yee BK. The postweaning social isolation in C57BL/6 mice: preferential vulnerability in the male sex. Psychopharmacology. 2008;197:613–628. doi: 10.1007/s00213-008-1081-3. [DOI] [PubMed] [Google Scholar]
- Pisu MG, Garau A, Boero G, et al. Sex differences in the outcome of juvenile social isolation on HPA axis function in rats. Neuroscience. 2016;320:172–82. doi: 10.1016/j.neuroscience.2016.02.009. [DOI] [PubMed] [Google Scholar]
- Powell SB, Geyer MA, Preece MA, et al. Dopamine depletion of the nucleus accumbens reverses isolation-induced deficits in prepulse inhibition in rats. Neuroscience. 2003;119:233–240. doi: 10.1016/S0306-4522(03)00122-2. [DOI] [PubMed] [Google Scholar]
- Pritchard LM, Van Kempen TA, Zimmerberg B. Behavioral effects of repeated handling differ in rats reared in social isolation and environmental enrichment. Neurosci. Lett. 2013;536:47–51. doi: 10.1016/j.neulet.2012.12.048. [DOI] [PubMed] [Google Scholar]
- Ramírez LA, Pérez-Padilla EA, García-Oscos F, et al. A new theory of depression based on the serotonin/kynurenine relationship and the hypothalamic pituitary-adrenal axis. Biomedica. 2018;38(3):437–450. doi: 10.7705/biomedica.v38i3.3688. [DOI] [PubMed] [Google Scholar]
- Ramos-Ortolaza DL, Doreste-Mendez RJ, Alvarado-Torres JK, Torres-Reveron A. Ovarian hormones modify anxiety behavior and glucocorticoid receptors after chronic social isolation stress. Behav. Brain Res. 2017;328:115–122. doi: 10.1016/j.bbr.2017.04.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ren QG, Gong WG, Wang YJ, et al. Citalopram attenuates tau hyperphosphorylation and spatial memory deficit induced by social isolation rearing in middle-aged rats. J. Mol. Neurosci. 2015;56(1):145–153. doi: 10.1007/s12031-014-0475-4. [DOI] [PubMed] [Google Scholar]
- Ridnour LA, Thomas DD, Mancardi D, Espey MG, Miranda KM, Paolocci N, Feelisch M, Fukuto J, Wink DA. The chemistry of nitrosative stress induced by nitric oxide and reactive nitrogen oxide species. Putting perspective on stressful biological situations. Biol. Chem. 2004;385:1–10. doi: 10.1515/BC.2004.001. [DOI] [PubMed] [Google Scholar]
- Rivera-Irizarry JK, Skelly MJ, Pleil KE. Social isolation stress in adolescence, but not adulthood, produces hypersocial behavior in adult male and female C57BL/6J Mice. Front. Behav. Neurosci. 2020;14:129. doi: 10.3389/fnbeh.2020.00129. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Roeckner AR, Bowling A, Butler TR. Chronic social instability increases anxiety-like behavior and ethanol preference in male Long Evans rats. Physiol. Behav. 2017;73:179–187. doi: 10.1016/j.physbeh.2017.02.010. [DOI] [PubMed] [Google Scholar]
- Santarelli S, Zimmermann C, Kalideris G, et al. An adverse early life environment can enhance stress resilience in adulthood. Psychoneuroendocrinology. 2017;78:213–221. doi: 10.1016/j.psyneuen.2017.01.021. [DOI] [PubMed] [Google Scholar]
- Scaccianoce S, Del Bianco P, Paolone G, et al. Social isolation selectively reduces hippocampal brain-derived neurotrophic factor without altering plasma corticosterone. Behav. Brain Res. 2006;68:323–325. doi: 10.1016/j.bbr.2005.04.024. [DOI] [PubMed] [Google Scholar]
- Scala F, Nenov MN, Crofton EJ, et al. Environmental enrichment and social isolation mediate neuroplasticity of medium spiny neurons through the GSK3 pathway. Cell Rep. 2018;23(2):555–567. doi: 10.1016/j.celrep.2018.03.062. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schrijver NC, Bahr NI, Weiss IC, Würbel H. Dissociable effects of isolation rearing and environmental enrichment on exploration, spatial learning and HPA activity in adult rats. Pharmacol. Biochem. Behav. 2002;73(1):209–224. doi: 10.1016/S0091-3057(02)00790-6. [DOI] [PubMed] [Google Scholar]
- Sequeira-Cordero A, Salas-Bastos A, Fornaguera J, Brenes JC. Behavioural characterisation of chronic unpredictable stress based on ethologically relevant paradigms in rats. Sci. Rep. 2019;9(1):17403. doi: 10.1038/s41598-019-53624-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Serra M, Sanna E, Mostallino MC, Biggio G. Social isolation stress and neuroactive steroids. Eur. Neuropsychopharmacol. 2007;17:1–11. doi: 10.1016/j.euroneuro.2006.03.004. [DOI] [PubMed] [Google Scholar]
- Shao F, Han X, Shao S, Wang W. Adolescent social isolation influences cognitive function in adult rats. Neural Regen. Res. 2013;8(11):1025–1030. doi: 10.3969/j.issn.1673-5374.2013.11.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shao Y, Yan G, Xuan Y, et al. Chronic social isolation decreases glutamate and glutamine levels and induces oxidative stress in the rat hippocampus. Behav. Brain Res. 2015;282:201–208. doi: 10.1016/j.bbr.2015.01.005. [DOI] [PubMed] [Google Scholar]
- Skelly MJ, Chappell AE, Carter E, Weiner JL. Adolescent social isolation increases anxiety-like behavior and ethanol intake and impairs fear extinction in adulthood: Possible role of disrupted noradrenergic signaling. Neuropharmacology. 2015;97:149–159. doi: 10.1016/j.neuropharm.2015.05.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Spasojevic N, Gavrilovic L, Varagic VV, Dronjak S. Effects of chronic diazepam treatments on behavior on individually housed rats. Arch. Biol. Sci. 2007;59:113–117. doi: 10.2298/ABS0702113S. [DOI] [Google Scholar]
- Spiers JG, Chen H-JC, Sernia C, Lavidis NA. Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress. Front. Neurosci. 2015;8:456. doi: 10.3389/fnins.2014.00456. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stevenson JR, McMahon EK, Boner W, Haussmann MF. Oxytocin administration prevents cellular aging caused by social isolation. Psychoneuroendocrinology. 2019;103:52–60. doi: 10.1016/j.psyneuen.2019.01.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takatsu-Coleman AL, Patti CL, Zanin KA, et al. Short-term social isolation induces depressive-like behaviour and reinstates the retrieval of an aversive task: mood-congruent memory in male mice? J. Psychiatry Neurosci. 2013;38(4):259–268. doi: 10.1503/jpn.120050. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thorsell A, Slawecki CJ, El Khoury A, et al. The effects of social isolation on neuropeptide Y levels, exploratory and anxiety related behaviors in rats. Pharmacol. Biochem. Behav. 2006;83:28–34. doi: 10.1016/j.pbb.2005.12.005. [DOI] [PubMed] [Google Scholar]
- Todorović N, Filipović D. The antidepressant- and anxiolytic-like effects of fluoxetine and clozapine in chronically isolated rats involve inhibition of hippocampal TNF-α. Pharmac. Biochem. Behav. 2017;163:57. doi: 10.1016/j.pbb.2017.10.006. [DOI] [PubMed] [Google Scholar]
- Todorović, N., Boškovicć, M., and Filipović, D., “Fluoxetine failed to prevent isolation-induced changes of glutathione-dependent defense in rat hippocampus,” Physical Chemistry. 2014. 12th Int. Conf. on Fundamental And Applied Aspects of Physical Chemistry (2014), Vol. 3, pp. 1121–1124.
- Tulogdi A, Tóth M, Barsvári B, et al. Effects of resocialization on post-weaning social isolation-induced abnormal aggression and social deficits in rats. Dev. Psychobiol. 2014;56(1):49–57. doi: 10.1002/dev.21090. [DOI] [PubMed] [Google Scholar]
- Vesce S, Rossi D, Brambilla L, Volterra A. Glutamate release from astrocytes in physiological conditions and in neurodegenerative disorders characterized by neuroinflammation. Int. Rev. Neurobiol. 2007;82:57–71. doi: 10.1016/S0074-7742(07)82003-4. [DOI] [PubMed] [Google Scholar]
- Viana Borges J, Souza de Freitas B, Antoniazzi V, et al. Social isolation and social support at adulthood affect epigenetic mechanisms, brain-derived neurotrophic factor levels and behavior of chronically stressed rats. Behav. Brain Res. 2019;366:36–44. doi: 10.1016/j.bbr.2019.03.025. [DOI] [PubMed] [Google Scholar]
- Vieira PR, Garcia LP, Maciel ELN. The increase in domestic violence during the social isolation: what does it reveals? Rev. Bras. Epidemiol. 2020;22(23):e200033. doi: 10.1590/1980-549720200033. [DOI] [PubMed] [Google Scholar]
- Villa A, Vegeto E, Poletti A, Maggi A. Estrogens, neuroinflammation, and neurodegeneration. Endocrine Rev. 2016;37(4):372–402. doi: 10.1210/er.2016-1007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Võikar V, Polus A, Vasar E, Rauvala H. Long-term individual housing in C57BL/6J and DBA/2 mice: assessment of behavioral consequences. Genes Brain Behav. 2005;4(4):240–52. doi: 10.1111/j.1601-183X.2004.00106.x. [DOI] [PubMed] [Google Scholar]
- Walker DM, Cunningham AM, Gregory JK, Nestler EJ. Long-term behavioral effects of post-weaning social isolation in males and females. Front. Behav. Neurosci. 2019;13:66. doi: 10.3389/fnbeh.2019.00066. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wallace DL, Han M-H, Graham DL, et al. CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral defi cits. Nat. Neurosci. 2009;12:200–209. doi: 10.1038/nn.2257. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang B, Wu Q, Lei L, et al. Long-term social isolation inhibits autophagy activation, induces postsynaptic dysfunctions and impairs spatial memory. Exp. Neurol. 2019;311:213–224. doi: 10.1016/j.expneurol.2018.09.009. [DOI] [PubMed] [Google Scholar]
- Wang HT, Huang FL, Hu ZL, et al. Early-life social isolation-induced depressive-like behavior in rats results in microglial activation and neuronal histone methylation that are mitigated by minocycline. Neurotox. Res. 2017;31(4):505–520. doi: 10.1007/s12640-016-9696-3. [DOI] [PubMed] [Google Scholar]
- Weintraub A, Singaravelu J, Bhatnagar S. Enduring and sex-specific effects of adolescent social isolation in rats on adult stress reactivity. Brain Res. 2010;1343:83–92. doi: 10.1016/j.brainres.2010.04.068. [DOI] [PubMed] [Google Scholar]
- Weiss IC, Pryce CR, Jongen-Rêlo AL, et al. Effect of social isolation on stress-related behavioural and neuroendocrine state in the rat. J. Behav. Brain Res. 2004;152(2):279–295. doi: 10.1016/j.bbr.2003.10.015. [DOI] [PubMed] [Google Scholar]
- Whitaker LR, Degoulet M, Morikawa H. Social deprivation enhances VTA synaptic plasticity and drug-induced contextual learning. Neuron. 2013;77(2):335–345. doi: 10.1016/j.neuron.2012.11.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wolffgramm J, Heyne A. Social behavior, dominance, and social deprivation of rats determine drug choice. Pharmacol. Biochem. Behav. 1991;38(2):389–399. doi: 10.1016/0091-3057(91)90297-F. [DOI] [PubMed] [Google Scholar]
- Wright IK, Upton N, Marsden CA. Resocialisation of isolation-reared rats does not alter their anxiogenic profile on the elevated X-maze model of anxiety. Physiol. Behav. 1991;50:1129–1132. doi: 10.1016/0031-9384(91)90572-6. [DOI] [PubMed] [Google Scholar]
- Yildirim E, Erol K, Ulupinar E. Effects of sertraline on behavioral alterations caused by environmental enrichment and social isolation. Pharmacol. Biochem. Behav. 2012;101(2):278–87. doi: 10.1016/j.pbb.2011.12.017. [DOI] [PubMed] [Google Scholar]
- Zafir A, Banu N. Induction of oxidative stress by restraint stress and corticosterone treatments in rats. Ind. J. Biochem. Biophys. 2009;46:53–58. [PubMed] [Google Scholar]
- Zhang Y, Zu X, Luo W, et al. Social isolation produces anxiety-like behaviors and changes PSD-95 levels in the forebrain. Neurosci. Lett. 2012;514:27–30. doi: 10.1016/j.neulet.2012.02.043. [DOI] [PubMed] [Google Scholar]
- Zlatković J, Filipović D. Bax and B-cell-lymphoma 2 mediate proapoptotic signaling following chronic isolation stress in rat brain. Neuroscience. 2012;223:238–245. doi: 10.1016/j.neuroscience.2012.08.005. [DOI] [PubMed] [Google Scholar]
- Zlatković J, Todorović N, Bošković M, et al. Different susceptibility of prefrontal cortex and hippocampus to oxidative stress following chronic social isolation stress. Mol. Cell Biochem. 2014;393:43–57. doi: 10.1007/s11010-014-2045-z. [DOI] [PubMed] [Google Scholar]
- Zorzo C, Méndez-López M, Méndez M, Arias JL. Adult social isolation leads to anxiety and spatial memory impairment: Brain activity pattern of COX and c-Fos. Behav. Brain Res. 2019;365:170. doi: 10.1016/j.bbr.2019.03.011. [DOI] [PubMed] [Google Scholar]