Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Differential transcriptome expression in human nucleus accumbens as a function of loneliness

Molecular Psychiatry volume 22, pages 1069–1078 (2017)Cite this article

Subjects

Abstract

Loneliness is associated with impaired mental and physical health. Studies of lonely individuals reported differential expression of inflammatory genes in peripheral leukocytes and diminished activation in brain reward regions such as nucleus accumbens, but could not address gene expression in the human brain. Here, we examined genome-wide RNA expression in post-mortem nucleus accumbens from donors (N=26) with known loneliness measures. Loneliness was associated with 1710 differentially expressed transcripts and genes from 1599 genes (DEGs; false discovery rate P<0.05, fold change ⩾|2|, controlling for confounds) previously associated with behavioral processes, neurological disease, psychological disorders, cancer, organismal injury and skeletal and muscular disorders, as well as networks of upstream RNA regulators. Furthermore, a number of DEGs were associated with Alzheimer’s disease (AD) genes (that was correlated with loneliness in this sample, although gene expression analyses controlled for AD diagnosis). These results identify novel targets for future mechanistic studies of gene networks in nucleus accumbens and gene regulatory mechanisms across a variety of diseases exacerbated by loneliness.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Peplau LA, Perlman D. Perspectives on loneliness. In: Peplau LA, Perlman D (eds). Loneliness: A Sourcebook of Current Theory, Research, and Therapy. Wiley-Interscience: New York, 1982, pp 1–18.

    Google Scholar 

  2. Cacioppo JT, Ernst JM, Burleson MH, McClintock MK, Malarkey WB, Hawkley LC et al. Lonely traits and concomitant physiological processes: the MacArthur social neuroscience studies. Int J Psychophysiol 2000; 35: 143–154.

    Article  CAS  Google Scholar 

  3. Russell DW . UCLA Loneliness Scale (Version 3): reliability, validity, and factor structure. J Pers Assess 1996; 66: 20–40.

    Article  CAS  Google Scholar 

  4. Masi CM, Chen HY, Hawkley LC, Cacioppo JT . A meta-analysis of interventions to reduce loneliness. Pers Soc Psychol Rev 2011; 15: 219–266.

    Article  Google Scholar 

  5. Boomsma DI, Willemsen G, Dolan CV, Hawkley LC, Cacioppo JT . Genetic and environmental contributions to loneliness in adults: the Netherlands twin register study. Behav Genet 2005; 35: 745–752.

    Article  Google Scholar 

  6. Hawkley LC, Cacioppo JT . Loneliness matters: a theoretical and empirical review of consequences and mechanisms. Ann Behav Med 2010; 40: 218–227.

    Article  Google Scholar 

  7. Bekhet AK, Zauszniewski JA . Mental health of elders in retirement communities: is loneliness a key factor? Arch Psychiatr Nurs 2012; 26: 214–224.

    Article  Google Scholar 

  8. Cacioppo JT, Hughes ME, Waite LJ, Hawkley LC, Thisted RA . Loneliness as a specific risk factor for depressive symptoms: cross-sectional and longitudinal analyses. Psychol Aging 2006; 21: 140–151.

    Article  Google Scholar 

  9. Shankar A, Hamer M, McMunn A, Steptoe A . Social isolation and loneliness: relationships with cognitive function during 4 years of follow-up in the English Longitudinal Study of Ageing. Psychosom Med 2013; 75: 161–170.

    Article  Google Scholar 

  10. Wilson RS, Krueger KR, Arnold SE, Schneider JA, Kelly JF, Barnes LL et al. Loneliness and risk of Alzheimer disease. Arch Gen Psychiatry 2007; 64: 234–240.

    Article  Google Scholar 

  11. Tilvis RS, Kahonen-Vare MH, Jolkkonen J, Valvanne J, Pitkala KH, Strandberg TE . Predictors of cognitive decline and mortality of aged people over a 10-year period. J Gerontol A Biol Sci Med Sci 2004; 59: 268–274.

    Article  Google Scholar 

  12. Holwerda TJ, Deeg DJ, Beekman AT, van Tilburg TG, Stek ML, Jonker C et al. Feelings of loneliness, but not social isolation, predict dementia onset: results from the Amsterdam Study of the Elderly (AMSTEL). J Neurol Neurosurg Psychiatry 2014; 85: 135–142.

    Article  Google Scholar 

  13. Buchman AS, Boyle PA, Wilson RS, James BD, Leurgans SE, Arnold SE et al. Loneliness and the rate of motor decline in old age: the Rush Memory and Aging Project, a community-based cohort study. BMC Geriatr 2010; 10: 77.

    Article  Google Scholar 

  14. Nausheen B, Gidron Y, Peveler R, Moss-Morris R . Social support and cancer progression: a systematic review. J Psychosom Res 2009; 67: 403–415.

    Article  Google Scholar 

  15. Antoni MH, Lutgendorf SK, Cole SW, Dhabhar FS, Sephton SE, McDonald PG et al. The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer 2006; 6: 240–248.

    Article  CAS  Google Scholar 

  16. Hawkley LC, Thisted RA, Masi CM, Cacioppo JT . Loneliness predicts increased blood pressure: 5-year cross-lagged analyses in middle-aged and older adults. Psychol Aging 2010; 25: 132–141.

    Article  Google Scholar 

  17. Sorkin D, Rook KS, Lu JL . Loneliness, lack of emotional support, lack of companionship, and the likelihood of having a heart condition in an elderly sample. Ann Behav Med 2002; 24: 290–298.

    Article  Google Scholar 

  18. Herlitz J, Wiklund I, Caidahl K, Hartford M, Haglid M, Karlsson BW et al. The feeling of loneliness prior to coronary artery bypass grafting might be a predictor of short-and long-term postoperative mortality. Eur J Vasc Endovasc Surg 1998; 16: 120–125.

    Article  CAS  Google Scholar 

  19. Luanaigh CO, Lawlor BA . Loneliness and the health of older people. Int J Geriatr Psychiatry 2008; 23: 1213–1221.

    Article  Google Scholar 

  20. Cohen S, Doyle WJ, Skoner DP, Rabin BS, Gwaltney JM Jr . Social ties and susceptibility to the common cold. JAMA 1997; 277: 1940–1944.

    Article  CAS  Google Scholar 

  21. Cole SW, Kemeny ME, Fahey JL, Zack JA, Naliboff BD . Psychological risk factors for HIV pathogenesis: mediation by the autonomic nervous system. Biol Psychiatry 2003; 54: 1444–1456.

    Article  Google Scholar 

  22. Cole SW, Hawkley LC, Arevalo JM, Sung CY, Rose RM, Cacioppo JT . Social regulation of gene expression in human leukocytes. Genome Biol 2007; 8: R189.

    Article  Google Scholar 

  23. Bennett DA, Schneider JA, Buchman AS, Barnes LL, Boyle PA, Wilson RS . Overview and findings from the rush Memory and Aging Project. Curr Alzheimer Res 2012; 9: 646–663.

    Article  CAS  Google Scholar 

  24. Rilling JK, Gutman D, Zeh T, Pagnoni G, Berns G, Kilts C . A neural basis for social cooperation. Neuron 2002; 35: 395–405.

    Article  CAS  Google Scholar 

  25. Guroglu B, Haselager GJ, van Lieshout CF, Takashima A, Rijpkema M, Fernandez G . Why are friends special? Implementing a social interaction simulation task to probe the neural correlates of friendship. Neuroimage 2008; 39: 903–910.

    Article  Google Scholar 

  26. Davey CG, Allen NB, Harrison BJ, Dwyer DB, Yucel M . Being liked activates primary reward and midline self-related brain regions. Hum Brain Mapp 2010; 31: 660–668.

    PubMed  Google Scholar 

  27. Cacioppo JT, Norris CJ, Decety J, Monteleone G, Nusbaum H . In the eye of the beholder: individual differences in perceived social isolation predict regional brain activation to social stimuli. J Cogn Neurosci 2008; 21: 83–92.

    Article  Google Scholar 

  28. Bennett DA, Schneider JA, Aggarwal NT, Arvanitakis Z, Shah RC, Kelly JF et al. Decision rules guiding the clinical diagnosis of Alzheimer's disease in two community-based cohort studies compared to standard practice in a clinic-based cohort study. Neuroepidemiology 2006; 27: 169–176.

    Article  Google Scholar 

  29. Boyle PA, Wilson RS, Aggarwal NT, Tang Y, Bennett DA . Mild cognitive impairment: risk of Alzheimer disease and rate of cognitive decline. Neurology 2006; 67: 441–445.

    Article  CAS  Google Scholar 

  30. Schneider JA, Arvanitakis Z, Bang W, Bennett DA . Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 2007; 69: 2197–2204.

    Article  Google Scholar 

  31. Wilson RS, Schneider JA, Arnold SE, Tang Y, Boyle PA, Bennett DA . Olfactory identification and incidence of mild cognitive impairment in older age. Arch Gen Psychiatry 2007; 64: 802–808.

    Article  Google Scholar 

  32. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.

    Article  CAS  Google Scholar 

  33. Blalock EM, Geddes JW, Chen KC, Porter NM, Markesbery WR, Landfield PW . Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc Natl Acad Sci USA 2004; 101: 2173–2178.

    Article  CAS  Google Scholar 

  34. Oliveros JC (2007–2015) Venny. An interactive tool for comparing lists with Venn's diagrams. Available at: http://bioinfogp.cnb.csic.es/tools/venny/.

  35. 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: 3080–3085.

    Article  CAS  Google Scholar 

  36. Stednitz JN, Epkins CC . Girls' and mothers' social anxiety, social skills, and loneliness: associations after accounting for depressive symptoms. J Clin Child Adolesc Psychol 2006; 35: 148–154.

    Article  Google Scholar 

  37. Stanek LM . Cocaine- and amphetamine related transcript (CART) and anxiety. Peptides 2006; 27: 2005–2011.

    Article  CAS  Google Scholar 

  38. Chaki S, Kawashima N, Suzuki Y, Shimazaki T, Okuyama S . Cocaine- and amphetamine-regulated transcript peptide produces anxiety-like behavior in rodents. Eur J Pharmacol 2003; 464: 49–54.

    Article  CAS  Google Scholar 

  39. Koylu EO, Balkan B, Kuhar MJ, Pogun S . Cocaine and amphetamine regulated transcript (CART) and the stress response. Peptides 2006; 27: 1956–1969.

    Article  CAS  Google Scholar 

  40. Hubert GW, Jones DC, Moffett MC, Rogge G, Kuhar MJ . CART peptides as modulators of dopamine and psychostimulants and interactions with the mesolimbic dopaminergic system. Biochem Pharmacol 2008; 75: 57–62.

    Article  CAS  Google Scholar 

  41. Jaworski JN, Kozel MA, Philpot KB, Kuhar MJ . Intra-accumbal injection of CART (cocaine-amphetamine regulated transcript) peptide reduces cocaine-induced locomotor activity. J Pharmacol Exp Ther 2003; 307: 1038–1044.

    Article  CAS  Google Scholar 

  42. Hawkley LC, Preacher KJ, Cacioppo JT Multilevel modeling of social interactions and mood in lonely and socially connected individuals: the MacArthur social neuroscience studies. In: Ong DA, van Dulmen M (eds). Oxford Handbook of Methods in Positive Psychology. Oxford University Press: New York, 2007, pp 559–575.

    Google Scholar 

  43. Swerdlow RH, Burns JM, Khan SM . The Alzheimer's disease mitochondrial cascade hypothesis. J Alzheimers Dis 2010; 20 (Suppl 2): S265–S279.

    Article  Google Scholar 

  44. Swerdlow RH, Khan SM . The Alzheimer's disease mitochondrial cascade hypothesis: an update. Exp Neurol 2009; 218: 308–315.

    Article  CAS  Google Scholar 

  45. Swerdlow RH, Khan SM . A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease. Med Hypotheses 2004; 63: 8–20.

    Article  CAS  Google Scholar 

  46. Rapoport SI . Coupled reductions in brain oxidative phosphorylation and synaptic function can be quantified and staged in the course of Alzheimer disease. Neurotox Res 2003; 5: 385–398.

    Article  Google Scholar 

  47. Chandrasekaran K, Hatanpaa K, Brady DR, Rapoport SI . Evidence for physiological down-regulation of brain oxidative phosphorylation in Alzheimer's disease. Exp Neurol 1996; 142: 80–88.

    Article  CAS  Google Scholar 

  48. Ihara Y, Morishima-Kawashima M, Nixon R . The ubiquitin-proteasome system and the autophagic-lysosomal system in Alzheimer disease. Cold Spring Harb Perspect Med 2012; 2: 1–27.

    Article  Google Scholar 

  49. Bannon MJ, Johnson MM, Michelhaugh SK, Hartley ZJ, Halter SD, David JA et al. A molecular profile of cocaine abuse includes the differential expression of genes that regulate transcription, chromatin, and dopamine cell phenotype. Neuropsychopharmacology 2014; 39: 2191–2199.

    Article  CAS  Google Scholar 

  50. Counts SE, Alldred MJ, Che S, Ginsberg SD, Mufson EJ . Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment. Neuropharmacology 2014; 79: 172–179.

    Article  CAS  Google Scholar 

  51. Cole SW . Social regulation of leukocyte homeostasis: the role of glucocorticoid sensitivity. Brain Behav Immun 2008; 22: 1049–1055.

    Article  CAS  Google Scholar 

  52. Steptoe A, Owen N, Kunz-Ebrecht SR, Brydon L . Loneliness and neuroendocrine, cardiovascular, and inflammatory stress responses in middle-aged men and women. Psychoneuroendocrinology 2004; 29: 593–611.

    Article  CAS  Google Scholar 

  53. Adam EK . Transactions among adolescent trait and state emotion and diurnal and momentary cortisol activity in naturalistic settings. Psychoneuroendocrinology 2006; 31: 664–679.

    Article  CAS  Google Scholar 

  54. Duman EA, Canli T . Influence of life stress, 5-HTTLPR genotype, and SLC6A4 methylation on gene expression and stress response in healthy Caucasian males. Biol Mood Anxiety Disord [Internet] 2015; 5: 2.

    Article  Google Scholar 

  55. Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci 2013; 16: 33–41.

    Article  CAS  Google Scholar 

  56. McGowan PO, Sasaki A, D'Alessio AC, Dymov S, Labonte B, Szyf M et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 2009; 12: 342–348.

    Article  CAS  Google Scholar 

  57. Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR et al. Epigenetic programming by maternal behavior. Nat Neurosci 2004; 7: 847–854.

    Article  CAS  Google Scholar 

  58. Massart R, Barnea R, Dikshtein Y, Suderman M, Meir O, Hallett M et al. Role of DNA methylation in the nucleus accumbens in incubation of cocaine craving. J Neurosci 2015; 35: 8042–8058.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by funding from NIA R01 AG034578-01 and NSF BCS-0843346 to TC, and RF1AG15819, R01AG17917 and R01AG36042 to DAB.

Author information

Authors and Affiliations

  1. Department of Psychology, Integrative Neuroscience, Stony Brook University, Stony Brook, NY, USA

    T Canli & A Mikhailik

  2. Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA

    R Wen

  3. Preventive Medicine, School of Medicine, Stony Brook Medicine, Stony Brook, NY, USA

    X Wang

  4. Rush Alzheimer's Disease Center and Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

    L Yu, D Fleischman, R S Wilson & D A Bennett

Authors
  1. T Canli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Mikhailik
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Fleischman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R S Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D A Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Canli.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Canli, T., Wen, R., Wang, X. et al. Differential transcriptome expression in human nucleus accumbens as a function of loneliness. Mol Psychiatry 22, 1069–1078 (2017). https://doi.org/10.1038/mp.2016.186

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2016.186

This article is cited by

Search

Advanced search

Quick links