Interleukin-1 receptor on hippocampal neurons drives social withdrawal and cognitive deficits after chronic social stress

  • A Correction to this article was published on 30 June 2020

Abstract

Chronic stress contributes to the development of psychiatric disorders including anxiety and depression. Several inflammatory-related effects of stress are associated with increased interleukin-1 (IL-1) signaling within the central nervous system and are mediated by IL-1 receptor 1 (IL-1R1) on several distinct cell types. Neuronal IL-1R1 is prominently expressed on the neurons of the dentate gyrus, but its role in mediating behavioral responses to stress is unknown. We hypothesize that IL-1 acts on this subset of hippocampal neurons to influence cognitive and mood alterations with stress. Here, mice subjected to psychosocial stress showed reduced social interaction and impaired working memory, and these deficits were prevented by global IL-1R1 knockout. Stress-induced monocyte trafficking to the brain was also blocked by IL-1R1 knockout. Selective deletion of IL-1R1 in glutamatergic neurons (nIL-1R1−/−) abrogated the stress-induced deficits in social interaction and working memory. In addition, viral-mediated selective IL-1R1 deletion in hippocampal neurons confirmed that IL-1 receptor in the hippocampus was critical for stress-induced behavioral deficits. Furthermore, selective restoration of IL-1R1 on glutamatergic neurons was sufficient to reestablish the impairments of social interaction and working memory after stress. RNA-sequencing of the hippocampus revealed that stress increased several canonical pathways (TREM1, NF-κB, complement, IL-6 signaling) and upstream regulators (INFγ, IL-1β, NF-κB, MYD88) associated with inflammation. The inductions of TREM1 signaling, complement, and leukocyte extravasation with stress were reversed by nIL-1R1−/−. Collectively, stress-dependent IL-1R1 signaling in hippocampal neurons represents a novel mechanism by which inflammation is perpetuated and social interactivity and working memory are modulated.

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Fig. 1: Stress-induced social withdrawal and working memory deficits are dependent on IL-1R1.
Fig. 2: IL-1R1 is required for vascular adhesion and monocyte accumulation with social stress.
Fig. 3: IL-1R1 on glutamatergic neurons is sufficient for stress-induced social withdrawal and working memory deficits.
Fig. 4: Hippocampal-specific knockout of the neuronal IL-1 receptor is sufficient to eliminate stress-induced behavioral changes.
Fig. 5: Stress-induced hippocampal gene expression is mediated by IL-1R1 on glutamatergic neurons.

Data availability

The RNA-sequencing data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus (DiSabato et al., 2020) and are accessible through GEO Series accession number GSE149195 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE149195).

Change history

  • 30 June 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

References

  1. 1.

    Kendler KS, Hettema JM, Butera F, Gardner CO, Prescott CA. Life event dimensions of loss, humiliation, entrapment, and danger in the prediction of onsets of major depression and generalized anxiety. Arch Gen Psychiatry. 2003;60:789–96.

    PubMed  Google Scholar 

  2. 2.

    Kendler KS, Karkowski LM, Prescott CA. Stressful life events and major depression: risk period, long-term contextual threat, and diagnostic specificity. J Nerv Ment Dis. 1998;186:661–9.

    CAS  PubMed  Google Scholar 

  3. 3.

    Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology. 2012;37:137–62.

    CAS  PubMed  Google Scholar 

  5. 5.

    Beumer W, Gibney SM, Drexhage RC, Pont-Lezica L, Doorduin J, Klein HC, et al. The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J Leukoc Biol. 2012;92:959–75.

    CAS  PubMed  Google Scholar 

  6. 6.

    Dantzer R. Cytokine, sickness behavior, and depression. Immunol Allergy Clin N Am. 2009;29:247–64.

    Google Scholar 

  7. 7.

    Jakobsson J, Bjerke M, Sahebi S, Isgren A, Ekman CJ, Sellgren C, et al. Monocyte and microglial activation in patients with mood-stabilized bipolar disorder. J Psychiatry Neurosci. 2015;40:250–8.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Cole SW, Hawkley LC, Arevalo JM, Cacioppo JT. Transcript origin analysis identifies antigen-presenting cells as primary targets of socially regulated gene expression in leukocytes. Proc Natl Acad Sci USA. 2011;108:3080–5.

    CAS  PubMed  Google Scholar 

  9. 9.

    Wohleb ES, Powell ND, Godbout JP, Sheridan JF. Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J Neurosci. 2013;33:13820–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Wohleb ES, McKim DB, Sheridan JF, Godbout JP. Monocyte trafficking to the brain with stress and inflammation: a novel axis of immune-to-brain communication that influences mood and behavior. Front Neurosci. 2014;8:447.

    PubMed  Google Scholar 

  11. 11.

    McKim DB, Weber MD, Niraula A, Sawicki CM, Liu X, Jarrett BL, et al. Microglial recruitment of IL-1beta-producing monocytes to brain endothelium causes stress-induced anxiety. Mol Psychiatry. 2018;23:1421–31.

    CAS  PubMed  Google Scholar 

  12. 12.

    Pfau ML, Menard C, Cathomas F, Desland F, Kana V, Chan KL, et al. Role of monocyte-derived microRNA106b approximately 25 in resilience to social stress. Biological Psychiatry. 2019;86:474–82.

    CAS  PubMed  Google Scholar 

  13. 13.

    Golden SA, Covington HE 3rd, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6:1183–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Stewart AM, Roy S, Wong K, Gaikwad S, Chung KM, Kalueff AV. Cytokine and endocrine parameters in mouse chronic social defeat: implications for translational ‘cross-domain’ modeling of stress-related brain disorders. Behav Brain Res. 2015;276:84–91.

    CAS  PubMed  Google Scholar 

  15. 15.

    Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D, et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA. 2014;111:16136–41.

    CAS  PubMed  Google Scholar 

  16. 16.

    Avitsur R, Stark JL, Dhabhar FS, Sheridan JF. Social stress alters splenocyte phenotype and function. J Neuroimmunol. 2002;132:66–71.

    CAS  PubMed  Google Scholar 

  17. 17.

    Avitsur R, Stark JL, Dhabhar FS, Kramer KA, Sheridan JF. Social experience alters the response to social stress in mice. Brain Behav Immun. 2003;17:426–37.

    PubMed  Google Scholar 

  18. 18.

    McKim DB, Yin W, Wang Y, Cole SW, Godbout JP, Sheridan JF. Social stress mobilizes hematopoietic stem cells to establish persistent splenic myelopoiesis. Cell Rep. 2018;25:2552–62.e3.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Ramirez K, Fornaguera-Trias J, Sheridan JF. Stress-induced microglia activation and monocyte trafficking to the brain underlie the development of anxiety and depression. Curr Top Behav Neurosci. 2017;31:155–72.

    CAS  PubMed  Google Scholar 

  20. 20.

    Reader BF, Jarrett BL, McKim DB, Wohleb ES, Godbout JP, Sheridan JF. Peripheral and central effects of repeated social defeat stress: monocyte trafficking, microglial activation, and anxiety. Neuroscience. 2015;289:429–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Niraula A, Sheridan JF, Godbout JP. Microglia priming with aging and stress. Neuropsychopharmacol. 2017;42:318–33.

    Google Scholar 

  22. 22.

    Niraula A, Witcher KG, Sheridan JF, Godbout JP. Interleukin-6 induced by social stress promotes a unique transcriptional signature in the monocytes that facilitate anxiety. Biol Psychiatry. 2019;85:679–89.

    CAS  PubMed  Google Scholar 

  23. 23.

    Wohleb ES, Patterson JM, Sharma V, Quan N, Godbout JP, Sheridan JF. Knockdown of interleukin-1 receptor type-1 on endothelial cells attenuated stress-induced neuroinflammation and prevented anxiety-like behavior. J Neurosci. 2014;34:2583–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Liu X, Nemeth DP, McKim DB, Zhu L, DiSabato DJ, Berdysz O, et al. Cell-type-specific interleukin 1 receptor 1 signaling in the brain regulates distinct neuroimmune activities. Immunity. 2019;50:764–6.

    CAS  PubMed  Google Scholar 

  25. 25.

    Zhu L, Liu X, Nemeth DP, DiSabato DJ, Witcher KG, McKim DB, et al. Interleukin-1 causes CNS inflammatory cytokine expression via endothelia-microglia bi-cellular signaling. Brain Behav Immun. 2019;81:292–304.

    CAS  PubMed  Google Scholar 

  26. 26.

    Liu X, Yamashita T, Chen Q, Belevych N, McKim DB, Tarr AJ, et al. Interleukin 1 type 1 receptor restore: a genetic mouse model for studying interleukin 1 receptor-mediated effects in specific cell types. J Neurosci. 2015;35:2860–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    McKim DB, Patterson JM, Wohleb ES, Jarrett BL, Reader BF, Godbout JP, et al. Sympathetic release of splenic monocytes promotes recurring anxiety following repeated social defeat. Biol Psychiatry. 2016;79:803–13.

    CAS  PubMed  Google Scholar 

  28. 28.

    Wohleb ES, McKim DB, Shea DT, Powell ND, Tarr AJ, Sheridan JF, et al. Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain. Biol Psychiatry. 2014;75:970–81.

    CAS  PubMed  Google Scholar 

  29. 29.

    Hughes RN. The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci Biobehav Rev. 2004;28:497–505.

    CAS  PubMed  Google Scholar 

  30. 30.

    Miedel CJ, Patton JM, Miedel AN, Miedel ES, Levenson JM. Assessment of spontaneous alternation, novel object recognition and limb clasping in transgenic mouse models of amyloid-beta and tau neuropathology. J Vis Exp. 2017:55523. https://doi.org/10.3791/55523.

  31. 31.

    Niraula A, Wang Y, Godbout JP, Sheridan JF. Corticosterone production during repeated social defeat causes monocyte mobilization from the bone marrow, glucocorticoid resistance, and neurovascular adhesion molecule expression. J Neurosci. 2018;38:2328–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Sawicki CM, McKim DB, Wohleb ES, Jarrett BL, Reader BF, Norden DM, et al. Social defeat promotes a reactive endothelium in a brain region-dependent manner with increased expression of key adhesion molecules, selectins and chemokines associated with the recruitment of myeloid cells to the brain. Neuroscience. 2015;302:151–64.

    CAS  PubMed  Google Scholar 

  33. 33.

    Clarkson BDS, Kahoud RJ, McCarthy CB, Howe CL. Inflammatory cytokine-induced changes in neural network activity measured by waveform analysis of high-content calcium imaging in murine cortical neurons. Sci Rep. 2017;7:9037.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Menard C, Pfau ML, Hodes GE, Kana V, Wang VX, Bouchard S, et al. Social stress induces neurovascular pathology promoting depression. Nat Neurosci. 2017;20:1752–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Ambree O, Ruland C, Scheu S, Arolt V, Alferink J. Alterations of the innate immune system in susceptibility and resilience after social defeat stress. Front Behav Neurosci. 2018;12:141.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Stankiewicz AM, Goscik J, Swiergiel AH, Majewska A, Wieczorek M, Juszczak GR, et al. Social stress increases expression of hemoglobin genes in mouse prefrontal cortex. BMC Neurosci. 2014;15:130.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Shaftel SS, Carlson TJ, Olschowka JA, Kyrkanides S, Matousek SB, O’Banion MK. Chronic interleukin-1beta expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood brain barrier permeability without overt neurodegeneration. J Neurosci. 2007;27:9301–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    McKim DB, Niraula A, Tarr AJ, Wohleb ES, Sheridan JF, Godbout JP. Neuroinflammatory dynamics underlie memory impairments after repeated social defeat. J Neurosci. 2016;36:2590–604.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Qian J, Zhu L, Li Q, Belevych N, Chen Q, Zhao F, et al. Interleukin-1R3 mediates interleukin-1-induced potassium current increase through fast activation of Akt kinase. Proc Natl Acad Sci USA. 2012;109:12189–94.

    CAS  PubMed  Google Scholar 

  40. 40.

    Sheline YI, Mittler BL, Mintun MA. The hippocampus and depression. Eur Psychiatry. 2002;17(Suppl 3):300–5.

    Google Scholar 

  41. 41.

    Fanselow MS, Dong HW. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron. 2010;65:7–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Avital A, Goshen I, Kamsler A, Segal M, Iverfeldt K, Richter-Levin G, et al. Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity. Hippocampus. 2003;13:826–34.

    CAS  PubMed  Google Scholar 

  43. 43.

    Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun. 2011;25:181–213.

    CAS  PubMed  Google Scholar 

  44. 44.

    Gaikwad S, Stewart A, Hart P, Wong K, Piet V, Cachat J, et al. Acute stress disrupts performance of zebrafish in the cued and spatial memory tests: the utility of fish models to study stress-memory interplay. Behav Process. 2011;87:224–30.

    Google Scholar 

  45. 45.

    Yun J, Koike H, Ibi D, Toth E, Mizoguchi H, Nitta A, et al. Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4. J Neurochemistry. 2010;114:1840–51.

    CAS  Google Scholar 

  46. 46.

    Gareau MG, Wine E, Rodrigues DM, Cho JH, Whary MT, Philpott DJ, et al. Bacterial infection causes stress-induced memory dysfunction in mice. Gut. 2011;60:307–17.

    PubMed  Google Scholar 

  47. 47.

    Skinner RA, Gibson RM, Rothwell NJ, Pinteaux E, Penny JI. Transport of interleukin-1 across cerebromicrovascular endothelial cells. Br J Pharmacol. 2009;156:1115–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Nakamura Y, Si QS, Kataoka K. Lipopolysaccharide-induced microglial activation in culture: temporal profiles of morphological change and release of cytokines and nitric oxide. Neurosci Res. 1999;35:95–100.

    CAS  PubMed  Google Scholar 

  49. 49.

    Amaral DG, Scharfman HE, Lavenex P. The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies). Prog Brain Res. 2007;163:3–22.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Finnell JE, Lombard CM, Melson MN, Singh NP, Nagarkatti M, Nagarkatti P, et al. The protective effects of resveratrol on social stress-induced cytokine release and depressive-like behavior. Brain Behav Immun. 2017;59:147–57.

    CAS  PubMed  Google Scholar 

  51. 51.

    Finnell JE, Lombard CM, Padi AR, Moffitt CM, Wilson LB, Wood CS, et al. Physical versus psychological social stress in male rats reveals distinct cardiovascular, inflammatory and behavioral consequences. PLoS ONE. 2017;12:e0172868.

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Engler H, Dawils L, Hoves S, Kurth S, Stevenson JR, Schauenstein K, et al. Effects of social stress on blood leukocyte distribution: the role of alpha- and beta-adrenergic mechanisms. J Neuroimmunol. 2004;156:153–62.

    CAS  PubMed  Google Scholar 

  53. 53.

    Reznikov R, Bambico FR, Diwan M, Raymond RJ, Nashed MG, Nobrega JN, et al. Prefrontal cortex deep brain stimulation improves fear and anxiety-like behavior and reduces basolateral amygdala activity in a preclinical model of posttraumatic stress disorder. Neuropsychopharmacology. 2018;43:1099–106.

    PubMed  Google Scholar 

  54. 54.

    Ghosal S, Duman CH, Liu RJ, Wu M, Terwilliger R, Girgenti MJ, et al. Ketamine rapidly reverses stress-induced impairments in GABAergic transmission in the prefrontal cortex in male rodents. Neurobiol Dis. 2020;134:104669.

    PubMed  Google Scholar 

  55. 55.

    Francis TC, Chandra R, Gaynor A, Konkalmatt P, Metzbower SR, Evans B, et al. Molecular basis of dendritic atrophy and activity in stress susceptibility. Mol Psychiatry. 2017;22:1512–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Bakunina N, Pariante CM, Zunszain PA. Immune mechanisms linked to depression via oxidative stress and neuroprogression. Immunology. 2015;144:365–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Liu WX, Wang J, Xie ZM, Xu N, Zhang GF, Jia M, et al. Regulation of glutamate transporter 1 via BDNF-TrkB signaling plays a role in the anti-apoptotic and antidepressant effects of ketamine in chronic unpredictable stress model of depression. Psychopharmacol. 2016;233:405–15.

    CAS  Google Scholar 

  58. 58.

    Boulle F, Pawluski JL, Homberg JR, Machiels B, Kroeze Y, Kumar N, et al. Prenatal stress and early-life exposure to fluoxetine have enduring effects on anxiety and hippocampal BDNF gene expression in adult male offspring. Dev Psychobiol. 2016;58:427–38.

    CAS  PubMed  Google Scholar 

  59. 59.

    Licznerski P, Jonas EA. BDNF signaling: harnessing stress to battle mood disorder. Proc Natl Acad Sci USA. 2018;115:3742–4.

    CAS  PubMed  Google Scholar 

  60. 60.

    Femenia T, Gomez-Galan M, Lindskog M, Magara S. Dysfunctional hippocampal activity affects emotion and cognition in mood disorders. Brain Res. 2012;1476:58–70.

    CAS  PubMed  Google Scholar 

  61. 61.

    Campbell S, Macqueen G. The role of the hippocampus in the pathophysiology of major depression. J Psychiatry Neurosci. 2004;29:417–26.

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Kirkby LA, Luongo FJ, Lee MB, Nahum M, Van Vleet TM, Rao VR, et al. An amygdala-hippocampus subnetwork that encodes variation in human mood. Cell. 2018;175:1688–1700.e14.

    CAS  PubMed  Google Scholar 

  63. 63.

    Hammond SL, Leek AN, Richman EH, Tjalkens RB. Cellular selectivity of AAV serotypes for gene delivery in neurons and astrocytes by neonatal intracerebroventricular injection. PLoS ONE. 2017;12:e0188830.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Connor B, Sun Y, von Hieber D, Tang SK, Jones KS, Maucksch C. AAV1/2-mediated BDNF gene therapy in a transgenic rat model of Huntington’s disease. Gene Ther. 2016;23:283–95.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This research was supported by NIMH R01-MH-109165 and R21-MH-099482 (to NQ), NIMH R01-MH-119670 and NIMH R01-MH-116670 (to JPG and JFS), and NIA R01-AG-051902 (to JPG). DJD, DPN, and SO were supported by a National Institute of Dental and Craniofacial Research Training Grant T32-DE-014320 (to JFS). XL and KGW were supported by the OSU Presidential Fellowship. Our RNA-sequencing was made possible by an allotment of resources from the Ohio Supercomputing Center.

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DiSabato, D.J., Nemeth, D.P., Liu, X. et al. Interleukin-1 receptor on hippocampal neurons drives social withdrawal and cognitive deficits after chronic social stress. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-0788-3

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