Abstract
Early-life stress is a potent risk factor for development of psychiatric conditions such as depression. The underlying mechanisms remain poorly understood. Here, we used the early-life social isolation (ESI) model of early-life stress in rats to characterize development of depressive-like behavior, the role of microglia, levels of histone methylation, as well as expression of glutamate receptor subunits in the hippocampus. We found that depressive-like behavior was induced after ESI as determined by sucrose preference and forced swimming tests. Increased expression of microglial activation marker, Iba1, was observed in the hippocampus of the ESI group, while expression of the microglial CD200 receptor, which promotes microglial quiescence, significantly decreased. In addition, increased levels of proinflammatory cytokines, interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were observed in the hippocampus of the ESI group. Moreover, ESI increased levels of neuronal H3K9me2 (a repressive marker of transcription) and its associated “writer” enzymes, G9a and G9a-like protein, in the hippocampus. ESI also decreased expression of hippocampal NMDA receptor subunits, NR1, and AMPA receptor subunits, GluR1 and GluR2, which are involved in synaptic plasticity, but it did not affect expression of PSD95 and NR2B. Interestingly, treatment with minocycline to block microglial activation induced by ESI inhibited increases in hippocampal microglia and prevented ESI-induced depressive-like behavior as well as increases in IL-1β, IL-6, and TNF-α. Notably, minocycline also triggered downregulation of H3K9me2 expression and restored expression of NR1, GluR1, and GluR2. These results suggest that ESI induces depressive-like behavior, which may be mediated by microglial signaling.
Similar content being viewed by others
References
Akbarian S, Ruehl MG, Bliven E, Luiz LA, Peranelli AC, Baker SP, Roberts RC, Bunney WJ, Conley RC, Jones EG et al (2005) Chromatin alterations associated with down-regulated metabolic gene expression in the prefrontal cortex of subjects with schizophrenia. Arch Gen Psychiatry 62:829–840
Arakawa H (2003) The effects of isolation rearing on open-field behavior in male rats depends on developmental stages. Dev Psychobiol 43:11–19
Beumer W, Gibney SM, Drexhage RC, Pont-Lezica L, Doorduin J, Klein HC, Steiner J, Connor TJ, Harkin A, Versnel MA, Drexhage HA (2012) The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J Leukoc Biol 92:959–975
Bilbo SD, Schwarz JM (2009) Early-life programming of later-life brain and behavior: a critical role for the immune system. Front Behav Neurosci 3:14
Bosch OJ, Nair HP, Ahern TH, Neumann ID, Young LJ (2009) The CRF system mediates increased passive stress-coping behavior following the loss of a bonded partner in a monogamous rodent. NEUROPSYCHOPHARMACOL 34:1406–1415
Cao W, Duan J, Wang X, Zhong X, Hu Z, Huang F, Wang H, Zhang J, Li F, Zhang J et al (2014) Early enriched environment induces an increased conversion of proBDNF to BDNF in the adult rat’s hippocampus. Behav Brain Res 265:76–83
Chourbaji S, Vogt MA, Fumagalli F, Sohr R, Frasca A, Brandwein C, Hortnagl H, Riva MA, Sprengel R, Gass P (2008) AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression. FASEB J 22:3129–3134
Covington HR, Maze I, LaPlant QC, Vialou VF, Ohnishi YN, Berton O, Fass DM, Renthal W, Rush AR, Wu EY et al (2009) Antidepressant actions of histone deacetylase inhibitors. J Neurosci 29:11451–11460
Covington HR, Maze I, Sun H, Bomze HM, DeMaio KD, Wu EY, Dietz DM, Lobo MK, Ghose S, Mouzon E et al (2011) A role for repressive histone methylation in cocaine-induced vulnerability to stress. Neuron 71:656–670
Das S, Mishra MK, Ghosh J, Basu A (2008) Japanese encephalitis virus infection induces IL-18 and IL-1beta in microglia and astrocytes: correlation with in vitro cytokine responsiveness of glial cells and subsequent neuronal death. J Neuroimmunol 195:60–72
de Kloet ER, Sibug RM, Helmerhorst FM, Schmidt MV (2005) Stress, genes and the mechanism of programming the brain for later life. Neurosci Biobehav Rev 29:271–281
Dean B (2011) Understanding the role of inflammatory-related pathways in the pathophysiology and treatment of psychiatric disorders: evidence from human peripheral studies and CNS studies. Int J Neuropsychopharmacol 14:997–1012
Domercq M, Matute C (2004) Neuroprotection by tetracyclines. Trends Pharmacol Sci 25:609–612
Dulac C (2010) Brain function and chromatin plasticity. Nature 465:728–735
Einon DF, Morgan MJ (1977) A critical period for social isolation in the rat. Dev Psychobiol 10:123–132
Ferdman N, Murmu RP, Bock J, Braun K, Leshem M (2007) Weaning age, social isolation, and gender, interact to determine adult explorative and social behavior, and dendritic and spine morphology in prefrontal cortex of rats. Behav Brain Res 180:174–182
Fone KC, Porkess MV (2008) Behavioural and neurochemical effects of post-weaning social isolation in rodents—relevance to developmental neuropsychiatric disorders. Neurosci Biobehav Rev 32:1087–1102
Franklin TB, Saab BJ, Mansuy IM (2012) Neural mechanisms of stress resilience and vulnerability. Neuron 75:747–761
Frick LR, Williams K, Pittenger C (2013) Microglial dysregulation in psychiatric disease. CLIN DEV IMMUNOL 2013:608654
Fujimaki K, Ogihara T, Morris DL, Oda H, Iida H, Fujitani Y, Mirmira RG, Evans-Molina C, Watada H (2015) SET7/9 enzyme regulates cytokine-induced expression of inducible nitric-oxide synthase through methylation of lysine 4 at histone 3 in the islet β cell. J Biol Chem 290:16607–16618
Ganguly P, Brenhouse HC (2015) Broken or maladaptive? Altered trajectories in neuroinflammation and behavior after early life adversity. Dev Cogn Neurosci 11:18–30
Goshen I, Yirmiya R (2009) Interleukin-1 (IL-1): a central regulator of stress responses. Front Neuroendocrinol 30:30–45
Grippo AJ, Lamb DG, Carter CS, Porges SW (2007) Social isolation disrupts autonomic regulation of the heart and influences negative affective behaviors. Biol Psychiatry 62:1162–1170
Gupta S, Kim SY, Artis S, Molfese DL, Schumacher A, Sweatt JD, Paylor RE, Lubin FD (2010) Histone methylation regulates memory formation. J Neurosci 30:3589–3599
Haj-Mirzaian A, Amiri S, Kordjazy N, Rahimi-Balaei M, Haj-Mirzaian A, Marzban H, Aminzadeh A, Dehpour AR, Mehr SE (2015) Blockade of NMDA receptors reverses the depressant, but not anxiogenic effect of adolescence social isolation in mice. Eur J Pharmacol 750:160–166
Halassa MM, Haydon PG (2010) Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Annu Rev Physiol 72:335–355
Hall FS (1998) Social deprivation of neonatal, adolescent, and adult rats has distinct neurochemical and behavioral consequences. Crit Rev Neurobiol 12:129–162
Hammen C (2005) Stress and depression. Annu Rev Clin Psychol 1:293–319
Hashimoto K (2009) Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res Rev 61:105–123
Heim C, Nemeroff CB (2001) The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry 49:1023–1039
Hinwood M, Morandini J, Day TA, Walker FR (2012) Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex. Cereb Cortex 22:1442–1454
Hoyo-Becerra C, Schlaak JF, Hermann DM (2014) Insights from interferon-alpha-related depression for the pathogenesis of depression associated with inflammation. Brain Behav Immun 42:222–231
Iseme RA, McEvoy M, Kelly B, Agnew L, Attia J, Walker FR (2014) Autoantibodies and depression: evidence for a causal link? Neurosci Biobehav Rev 40:62–79
Jahng JW, Yoo SB, Ryu V, Lee JH (2012) Hyperphagia and depression-like behavior by adolescence social isolation in female rats. Int J Dev Neurosci 30:47–53
Jankord R, Herman JP (2008) Limbic regulation of hypothalamo-pituitary-adrenocortical function during acute and chronic stress. Ann N Y Acad Sci 1148:64–73
Kendler KS, Karkowski LM, Prescott CA (1999) Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry 156:837–841
Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553
Kim HS, Suh YH (2009) Minocycline and neurodegenerative diseases. Behav Brain Res 196:168–179
Kreisel T, Frank MG, Licht T, Reshef R, Ben-Menachem-Zidon O, Baratta MV, Maier SF, Yirmiya R (2013) Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. MOL PSYCHIATR 19:699–709
Lapiz MD, Fulford A, Muchimapura S, Mason R, Parker T, Marsden CA (2003) Influence of postweaning social isolation in the rat on brain development, conditioned behavior, and neurotransmission. Neurosci Behav Physiol 33:13–29
Leng A, Feldon J, Ferger B (2004) Long-term social isolation and medial prefrontal cortex: dopaminergic and cholinergic neurotransmission. Pharmacol Biochem Behav 77:371–379
Li CQ, Xu JM, Liu D, Zhang JY, Dai RP (2008) Brain derived neurotrophic factor (BDNF) contributes to the pain hypersensitivity following surgical incision in the rats. Mol Pain 4:27
Li F, Li M, Cao W, Xu Y, Luo Y, Zhong X, Zhang J, Dai R, Zhou XF, Li Z, Li C (2012) Anterior cingulate cortical lesion attenuates food foraging in rats. Brain Res Bull 88:602–608
Li CQ, Luo YW, Bi FF, Cui TT, Song L, Cao WY, Zhang JY, Li F, Xu JM, Hao W et al (2014) Development of anxiety-like behavior via hippocampal IGF-2 signaling in the offspring of parental morphine exposure: effect of enriched environment. NEUROPSYCHOPHARMACOL 39:2777–2787
Luo Y, Xu Y, Cao W, Zhong X, Duan J, Wang X, Hu Z, Li F, Zhang J, Zhou M et al (2015) Insulin-like growth factor 2 mitigates depressive behavior in a rat model of chronic stress. Neuropharmacology 89:318–324
Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G, Kubera M, Bob P, Lerer B, Maj M (2009) The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis 24:27–53
Margueron R, Trojer P, Reinberg D (2005) The key to development: interpreting the histone code? CURR OPIN GENET DEV 15:163–176
Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 6:838–849
Maze I, Covington HR, Dietz DM, LaPlant Q, Renthal W, Russo SJ, Mechanic M, Mouzon E, Neve RL, Haggarty SJ et al (2010) Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science 327:213–216
Maze I, Noh KM, Allis CD (2013) Histone regulation in the CNS: basic principles of epigenetic plasticity. NEUROPSYCHOPHARMACOL 38:3–22
McCullumsmith RE, Kristiansen LV, Beneyto M, Scarr E, Dean B, Meador-Woodruff JH (2007) Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder. Brain Res 1127:108–118
McInnis OA, Matheson K, Anisman H (2014) Living with the unexplained: coping, distress, and depression among women with chronic fatigue syndrome and/or fibromyalgia compared to an autoimmune disorder. Anxiety Stress Coping 27:601–618
Muchimapura S, Fulford AJ, Mason R, Marsden CA (2002) Isolation rearing in the rat disrupts the hippocampal response to stress. Neuroscience 112:697–705
Muchimapura S, Mason R, Marsden CA (2003) Effect of isolation rearing on pre- and post-synaptic serotonergic function in the rat dorsal hippocampus. Synapse 47:209–217
Musazzi L, Treccani G, Mallei A, Popoli M (2013) The action of antidepressants on the glutamate system: regulation of glutamate release and glutamate receptors. Biol Psychiatry 73:1180–1188
Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM (2002) Neurobiology of depression. Neuron 34:13–25
Ng HH, Robert F, Young RA, Struhl K (2003) Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity. Mol Cell 11:709–719
Pae CU, Marks DM, Han C, Patkar AA (2008) Does minocycline have antidepressant effect? BIOMED PHARMACOTHER 62:308–311
Peter CJ, Akbarian S (2011) Balancing histone methylation activities in psychiatric disorders. Trends Mol Med 17:372–379
Qiang M, Danny A, Lieu M, Carreon S, Li J (2011) Histone H3K9 modifications are a local chromatin event involved in ethanol-induced neuroadaptation of the NR2B gene. EPIGENETICS 6:1095–1104
Réus GZ, Fries GR, Stertz L, Badawy M, Passos IC, Barichello T, Kapczinski F, Quevedo J (2015) The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience 300:141–154
Riazi K, Galic MA, Kentner AC, Reid AY, Sharkey KA, Pittman QJ (2015) Microglia-dependent alteration of glutamatergic synaptic transmission and plasticity in the hippocampus during peripheral inflammation. J Neurosci 35:4942–4952
Robbins TW, Jones GH, Wilkinson LS (1996) Behavioural and neurochemical effects of early social deprivation in the rat. J Psychopharmacol 10:39–47
Sanacora G, Treccani G, Popoli M (2012) Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62:63–77
Santos-Rosa H, Schneider R, Bannister AJ, Sherriff J, Bernstein BE, Emre NC, Schreiber SL, Mellor J, Kouzarides T (2002) Active genes are tri-methylated at K4 of histone H3. Nature 419:407–411
Schaefer A, Sampath SC, Intrator A, Min A, Gertler TS, Surmeier DJ, Tarakhovsky A, Greengard P (2009) Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron 64:678–691
Schneider R, Bannister AJ, Myers FA, Thorne AW, Crane-Robinson C, Kouzarides T (2004) Histone H3 lysine 4 methylation patterns in higher eukaryotic genes. Nat Cell Biol 6:73–77
Schroeder FA, Lin CL, Crusio WE, Akbarian S (2007) Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol Psychiatry 62:55–64
Shively CA, Williams JK, Laber-Laird K, Anton RF (2002) Depression and coronary artery atherosclerosis and reactivity in female cynomolgus monkeys. Psychosom Med 64:699–706
Sims RR, Nishioka K, Reinberg D (2003) Histone lysine methylation: a signature for chromatin function. Trends Genet 19:629–639
Smith RS (1991) The macrophage theory of depression. Med Hypotheses 35:298–306
Takaki J, Fujimori K, Miura M, Suzuki T, Sekino Y, Sato K (2012) L-glutamate released from activated microglia downregulates astrocytic L-glutamate transporter expression in neuroinflammation: the ‘collusion’ hypothesis for increased extracellular L-glutamate concentration in neuroinflammation. J Neuroinflammation 9:275
Takatsu-Coleman AL, Patti CL, Zanin KA, Zager A, Carvalho RC, Borcoi AR, Ceccon LM, Berro LF, Tufik S, Andersen ML, Frussa-Filho R (2013) 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 38:259–268
Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A (2011a) The role of microglia in the healthy brain. J Neurosci 31:16064–16069
Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9:519–525
Vermeulen M, Mulder KW, Denissov S, Pijnappel WW, van Schaik FM, Varier RA, Baltissen MP, Stunnenberg HG, Mann M, Timmers HT (2007) Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell 131:58–69
Wake H, Moorhouse AJ, Miyamoto A, Nabekura J (2013) Microglia: actively surveying and shaping neuronal circuit structure and function. Trends Neurosci 36:209–217
Weber K, Rockstroh B, Borgelt J, Awiszus B, Popov T, Hoffmann K, Schonauer K, Watzl H, Propster K (2008) Stress load during childhood affects psychopathology in psychiatric patients. BMC PSYCHIATRY 8:63
Weiss IC, Pryce CR, Jongen-Relo AL, Nanz-Bahr NI, Feldon J (2004) Effect of social isolation on stress-related behavioural and neuroendocrine state in the rat. Behav Brain Res 152:279–295
Wohleb ES, Franklin T, Iwata M, Duman RS (2016) Integrating neuroimmune systems in the neurobiology of depression. NAT REV NEUROSCI 17:497–511
Yirmiya R, Rimmerman N, Reshef R (2015) Depression as a microglial disease. Trends Neurosci 38:637–658
Zhang X, Wang Q, Wang Y, Hu J, Jiang H, Cheng W, Ma Y, Liu M, Sun A, Zhang X, Li X (2016) Duloxetine prevents the effects of prenatal stress on depressive-like and anxiety-like behavior and hippocampal expression of pro-inflammatory cytokines in adult male offspring rats. Int J Dev Neurosci 55:41–48
Zhao X, Sun L, Jia H, Meng Q, Wu S, Li N, He S (2009) Isolation rearing induces social and emotional function abnormalities and alters glutamate and neurodevelopment-related gene expression in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 33:1173–1177
Zhao Q, Xie X, Fan Y, Zhang J, Jiang W, Wu X, Yan S, Chen Y, Peng C, You Z (2015) Phenotypic dysregulation of microglial activation in young offspring rats with maternal sleep deprivation-induced cognitive impairment. SCI REP-UK 5:9513
Acknowledgments
We wish to thank Xin-Fu Zhou from the University of South Australia for his critical reading of the manuscript.
Authors’ Contributions
HW performed behavioral testing, immunofluorescence, immunohistochemical staining, and western blot experiments, and wrote the manuscript. FH was involved in qPCR experiments, data collection, and data analysis. ZH, WZ, and XQ participated in data collection and data analysis. YH helped with performing the minocycline manipulations. RD provided experimental suggestions and assisted in writing the manuscript. The corresponding authors FL and CL supervised, designed the project, interpreted the work, revised the manuscript, and provided funds. All authors contributed to the study and have approved the final manuscript.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Funding
This study was supported by the National Natural Science Foundation of China (Grant No: 31171151 and 31371212 to Chang-Qi Li, Grant No: 81471372 to Fang Li).
Availability of Data and Materials
There is no data, software, database, and application/tool available apart from that reported in the present study. All data is provided in the manuscript.
Conflict of Interest
The authors declare that they have no competing interests.
Consent for Publication
Not applicable.
Ethics Approval and Consent to Participate
All animal procedures performed in this study were reviewed and approved by the Animal Care and Use Committee of Central South University and were conducted in accordance with the guidelines of the International Association for the Study of Depression.
Additional information
Hong-Tao Wang and Fu-Lian Huang contributed equally to this work.
Rights and permissions
About this article
Cite this article
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 31, 505–520 (2017). https://doi.org/10.1007/s12640-016-9696-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-016-9696-3