Skip to main content
SpringerLink
Log in

Childhood Separation Anxiety: Human and Preclinical Studies

  • Chapter
  • First Online:
Separation Anxiety in Adulthood

  • 103 Accesses

Abstract

Separation anxiety is ubiquitous in mammals, has a clear adaptive function, and is a source of individual differences. We adopt a reductionist approach, taking advantage of the interspecies, adversive nature of hypercapnia, and of the exaggerated response to CO2 stimulation proper of people with panic and separation anxiety disorders. We argue that the human developmental continuum from childhood separation anxiety disorder into adult panic disorder-agoraphobia can be modelled in murine studies of early maternal separation, with variance in respiratory parameters during CO2 stimulation as a key, non-inferential biomarker of anxiety.

We show how such preclinical models of early maternal separation led to identify differentially-expressed genes that correspond to differentially-methylated genes in human responders to CO2 stimulation. Specifically, we argue that: (a) brain acid-sensing ion channels (ASICs) are important to understand how mammals orchestrate enhanced homeostatic reactions in response to early adversities, and: (b) inhaled ASIC antagonist amiloride can be a viable treatment for some human anxiety disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. MacLean PD. Brain evolution relating to family, play, and the separation call. Arch Gen Psychiatry. 1985;42(4):405–17. https://doi.org/10.1001/archpsyc.1985.01790270095011.

    Article  CAS  PubMed  Google Scholar 

  2. Burmeister M, McInnis MG, Zöllner S. Psychiatric genetics: progress amid controversy. Nat Rev Genet. 2008;9(7):527–40. https://doi.org/10.1038/nrg2381.

    Article  PubMed  Google Scholar 

  3. Kendler KS, Zachar P, Craver C. What kinds of things are psychiatric disorders? Psychol Med. 2011;41(6):1143–50. https://doi.org/10.1017/S0033291710001844.

    Article  CAS  PubMed  Google Scholar 

  4. Kendler KS. The nature of psychiatric disorders. World Psychiatry. 2016;15(1):5–12. https://doi.org/10.1002/wps.20292.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Martin N, Boomsma D, Machin G. A twin-pronged attack on complex traits. Nat Genet. 1997;17(4):387–92. https://doi.org/10.1038/ng1297-387.

    Article  CAS  PubMed  Google Scholar 

  6. Ericsson AC, Crim MJ, Franklin CL. A brief history of animal modeling. Mo Med. 2013;110(3):201–5. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/23829102.

    PubMed  PubMed Central  Google Scholar 

  7. Chesselet M-F, Carmichael ST. Animal models of neurological disorders. Neurotherapeutics. 2012;9(2):241–4. https://doi.org/10.1007/s13311-012-0118-9.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hettema JM, Neale MC, Kendler KS. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatr. 2001;158(10):1568–78. https://doi.org/10.1176/appi.ajp.158.10.1568.

    Article  CAS  PubMed  Google Scholar 

  9. Klein DF, Fink MAX. Pychiatric reaction patterns to imipramine. Am J Psychiatr. 1962;119(5):432–8. https://doi.org/10.1176/ajp.119.5.432.

    Article  CAS  PubMed  Google Scholar 

  10. Schenberg LC. In: Nardi AE, Freire RCR, editors. A neural systems approach to the study of the respiratory-type panic disorder BT - panic disorder: neurobiological and treatment aspects. Cham: Springer; 2016. https://doi.org/10.1007/978-3-319-12538-1_2.

    Chapter  Google Scholar 

  11. Gittelman Klein R. Is panic disorder associated with childhood separation anxiety disorder? Clin Neuropharmacol. 1995;18. Retrieved from https://journals.lww.com/clinicalneuropharm/Fulltext/1995/18002/Is_Panic_Disorder_Associated_with_Childhood.3.aspx

  12. Gittelman R, Klein DF. Relationship between separation anxiety and panic and agoraphobic disorders. Psychopathology. 1984;17(Suppl. 1):56–65. https://doi.org/10.1159/000284078.

    Article  PubMed  Google Scholar 

  13. Klein RG, Koplewicz HS, Kanner A. Imipramine treatment of children with separation anxiety disorder. J Am Acad Child Adolesc Psychiatry. 1992;31(1):21–8. https://doi.org/10.1097/00004583-199201000-00005.

    Article  CAS  PubMed  Google Scholar 

  14. Kossowsky J, Pfaltz MC, Schneider S, Taeymans J, Locher C, Gaab J. The separation anxiety hypothesis of panic disorder revisited: a meta-analysis. Am J Psychiatr. 2013;170(7):768–81. https://doi.org/10.1176/appi.ajp.2012.12070893.

    Article  PubMed  Google Scholar 

  15. Klein DF. False suffocation alarms, spontaneous panics, and related conditions: an integrative hypothesis. Arch Gen Psychiatry. 1993;50(4):306–17. https://doi.org/10.1001/archpsyc.1993.01820160076009.

    Article  CAS  PubMed  Google Scholar 

  16. Pine DS, Klein RG, Coplan JD, Papp LA, Hoven CW, Martinez J, Kovalenko P, Mandell DJ, Moreau D, Klein DF, Gorman JM. Differential carbon dioxide sensitivity in childhood anxiety disorders and Nonill Comparison Group. Arch Gen Psychiatry. 2000;57(10):960–7. https://doi.org/10.1001/archpsyc.57.10.960.

    Article  CAS  PubMed  Google Scholar 

  17. Battaglia M, Ogliari A, D’Amato F, Kinkead R. Early-life risk factors for panic and separation anxiety disorder: insights and outstanding questions arising from human and animal studies of CO2 sensitivity. Neurosci Biobehav Rev. 2014;46:455–64. https://doi.org/10.1016/j.neubiorev.2014.04.005.

    Article  PubMed  Google Scholar 

  18. Rutter M. Why is the topic of the biological embedding of experiences important for translation? Dev Psychopathol. 2016;28(4pt2):1245–58. https://doi.org/10.1017/S0954579416000821.

    Article  PubMed  Google Scholar 

  19. Leakey MG, Feibel CS, McDougall I, Walker A. New four-million-year-old hominid species from Kanapoi and Allia Bay, Kenya. Nature. 1995;376(6541):565–71. https://doi.org/10.1038/376565a0.

    Article  CAS  PubMed  Google Scholar 

  20. Rosenberg K, Trevathan W. Birth, obstetrics and human evolution. BJOG Int J Obstet Gynaecol. 2002;109(11):1199–206. https://doi.org/10.1046/j.1471-0528.2002.00010.x.

    Article  Google Scholar 

  21. Rakic P. Evolution of the neocortex: a perspective from developmental biology. Nat Rev Neurosci. 2009;10(10):724–35. https://doi.org/10.1038/nrn2719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schick KD. Making silent stones speak: human evolution and the dawn of technology/Making Silent Stones Speak. London: Phoenix; 1993.

    Google Scholar 

  23. Ponce de León MS, Golovanova L, Doronichev V, Romanova G, Akazawa T, Kondo O, Ishida H, Zollikofer CPE. Neanderthal brain size at birth provides insights into the evolution of human life history. Proc Natl Acad Sci. 2008;105(37):13764–8. https://doi.org/10.1073/pnas.0803917105.

    Article  PubMed  PubMed Central  Google Scholar 

  24. DeSilva J, Lesnik J. Chimpanzee neonatal brain size: implications for brain growth in Homo erectus. J Hum Evol. 2006;51(2):207–12. https://doi.org/10.1016/j.jhevol.2006.05.006.

    Article  PubMed  Google Scholar 

  25. Leigh SR. Brain growth, life history, and cognition in primate and human evolution. Am J Primatol. 2004;62(3):139–64. https://doi.org/10.1002/ajp.20012.

    Article  CAS  PubMed  Google Scholar 

  26. Leigh SR. Brain ontogeny and life history in Homo erectus. J Hum Evol. 2006;50(1):104–8. https://doi.org/10.1016/j.jhevol.2005.02.008.

    Article  PubMed  Google Scholar 

  27. Martin RD. Human brain evolution in an ecological context (James Arthur lecture on the evolution of the human brain, no. 52, 1982). New York, NY: American Museum of Natural History; 1983.

    Google Scholar 

  28. Newman JD. Neural circuits underlying crying and cry responding in mammals. Behav Brain Res. 2007;182(2):155–65. https://doi.org/10.1016/j.bbr.2007.02.011.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Panksepp J, Biven L. The archaeology of mind: neuroevolutionary origins of human emotions (Norton series on interpersonal neurobiology). New York: WW Norton & Company; 2012.

    Google Scholar 

  30. Ainsworth MDS, Blehar MC, Waters E, Wall S. Patterns of attachment: a psychological study of the strange situation. In: Patterns of attachment: a psychological study of the strange situation. Oxford: Lawrence Erlbaum; 1978.

    Google Scholar 

  31. Copeland WE, Angold A, Shanahan L, Costello EJ. Longitudinal patterns of anxiety from childhood to adulthood: the Great Smoky Mountains Study. J Am Acad Child Adolesc Psychiatry. 2014;53(1):21–33. https://doi.org/10.1016/j.jaac.2013.09.017.

    Article  PubMed  Google Scholar 

  32. Ginsburg GS, Becker EM, Keeton CP, Sakolsky D, Piacentini J, Albano AM, Compton SN, Iyengar S, Sullivan K, Caporino N, Peris T, Birmaher B, Rynn M, March J, Kendall PC. Naturalistic follow-up of youths treated for pediatric anxiety disorders. JAMA Psychiatry. 2014;71(3):310–8. https://doi.org/10.1001/jamapsychiatry.2013.4186.

    Article  PubMed  PubMed Central  Google Scholar 

  33. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Washington, DC: American Psychiatric Association; 2013. https://doi.org/10.1176/appi.books.9780890425596.

    Book  Google Scholar 

  34. Scaini S, Ogliari A, Eley TC, Zavos HMS, Battaglia M. Genetic and environmental contributions to separation anxiety: a meta-analytic approach to twin data. Depress Anxiety. 2012;29(9):754–61. https://doi.org/10.1002/da.21941.

    Article  PubMed  Google Scholar 

  35. Cooper-Vince CE, Emmert-Aronson BO, Pincus DB, Comer JS. The diagnostic utility of separation anxiety disorder symptoms: an item response theory analysis. J Abnorm Child Psychol. 2014;42(3):417–28. https://doi.org/10.1007/s10802-013-9788-y.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Franz L, Angold A, Copeland W, Costello EJ, Towe-Goodman N, Egger H. Preschool anxiety disorders in pediatric primary care: prevalence and comorbidity. J Am Acad Child Adolesc Psychiatry. 2013;52(12):1294–1303.e1. https://doi.org/10.1016/j.jaac.2013.09.008.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Shear K, Jin R, Ruscio AM, Walters EE, Kessler RC. Prevalence and correlates of estimated DSM-IV child and adult separation anxiety disorder in the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163(6):1074–83. https://doi.org/10.1176/ajp.2006.163.6.1074.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Battaglia M, Touchette É, Garon-Carrier G, Dionne G, Côté SM, Vitaro F, Tremblay RE, Boivin M. Distinct trajectories of separation anxiety in the preschool years: persistence at school entry and early-life associated factors. J Child Psychol Psychiatry. 2016;57(1):39–46. https://doi.org/10.1111/jcpp.12424.

    Article  PubMed  Google Scholar 

  39. Petitclerc A, Boivin M, Dionne G, Zoccolillo M, Tremblay RE. Disregard for rules: the early development and predictors of a specific dimension of disruptive behavior disorders. J Child Psychol Psychiatry. 2009;50(12):1477–84. https://doi.org/10.1111/j.1469-7610.2009.02118.x.

    Article  PubMed  Google Scholar 

  40. Battaglia M, Garon-Carrier G, Côté SM, Dionne G, Touchette E, Vitaro F, Tremblay RE, Boivin M. Early childhood trajectories of separation anxiety: bearing on mental health, academic achievement, and physical health from mid-childhood to preadolescence. Depress Anxiety. 2017;34(10):918–27. https://doi.org/10.1002/da.22674.

    Article  PubMed  Google Scholar 

  41. Aschenbrand SG, Kendall PC, Webb A, Safford SM, Flannery-Schroeder E. Is childhood separation anxiety disorder a predictor of adult panic disorder and agoraphobia? A seven-year longitudinal study. J Am Acad Child Adolesc Psychiatry. 2003;42(12):1478–85. https://doi.org/10.1097/00004583-200312000-00015.

    Article  PubMed  Google Scholar 

  42. Bandelow B, Alvarez Tichauer G, Späth C, Broocks A, Hajak G, Bleich S, Rüther E. Separation anxiety and actual separation experiences during childhood in patients with panic disorder. Can J Psychiatry. 2001;46(10):948–52. https://doi.org/10.1177/070674370104601007.

    Article  CAS  PubMed  Google Scholar 

  43. Brückl TM, Wittchen H-U, Höfler M, Pfister H, Schneider S, Lieb R. Childhood separation anxiety and the risk of subsequent psychopathology: results from a community study. Psychother Psychosom. 2007;76(1):47–56. https://doi.org/10.1159/000096364.

    Article  PubMed  Google Scholar 

  44. Hayward C, Wilson KA, Lagle K, Killen JD, Taylor CB. Parent-reported predictors of adolescent panic attacks. J Am Acad Child Adolesc Psychiatry. 2004;43(5):613–20. https://doi.org/10.1097/00004583-200405000-00015.

    Article  PubMed  Google Scholar 

  45. Lewisohn PM, Holm-Denoma JM, Small JW, Seeley JR, Joiner TE. Separation anxiety disorder in childhood as a risk factor for future mental illness. J Am Acad Child Adolesc Psychiatry. 2008;47(5):548–55. https://doi.org/10.1097/CHI.0b013e31816765e7.

    Article  Google Scholar 

  46. Silove D, Manicavasagar V, Curtis J, Blaszczynski A. Is early separation anxiety a risk factor for adult panic disorder?: a critical review. Compr Psychiatry. 1996;37(3):167–79. https://doi.org/10.1016/S0010-440X(96)90033-4.

    Article  CAS  PubMed  Google Scholar 

  47. Battaglia M, Bertella S, Politi E, Bernardeschi L, Perna G, Gabriele A, Bellodi L. Age at onset of panic disorder: influence of familial liability to the disease and of childhood separation anxiety disorder. Am J Psychiatr. 1995;152(9):1362–4. https://doi.org/10.1176/ajp.152.9.1362.

    Article  CAS  PubMed  Google Scholar 

  48. Battaglia M, Bernardeschi L, Politi E, Bertella S, Bellodi L. Comorbidity of panic and somatization disorder: a genetic-epidemiological approach. Compr Psychiatry. 1995;36(6):411–20. https://doi.org/10.1016/S0010-440X(95)90248-1.

    Article  CAS  PubMed  Google Scholar 

  49. Battaglia M, Pesenti-Gritti P, Medland SE, Ogliari A, Tambs K, Spatola CAM. A genetically informed study of the association between childhood separation anxiety, sensitivity to CO2, panic disorder, and the effect of childhood parental loss. Arch Gen Psychiatry. 2009;66(1):64–71. https://doi.org/10.1001/archgenpsychiatry.2008.513.

    Article  PubMed  Google Scholar 

  50. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. Childhood parental loss and adult psychopathology in women. A twin study perspective. Arch Gen Psychiatry. 1992;49(2):109–16. https://doi.org/10.1001/archpsyc.1992.01820020029004.

    Article  CAS  PubMed  Google Scholar 

  51. Battaglia M. Separation anxiety: at the neurobiological crossroads of adaptation and illness. Dialogues Clin Neurosci. 2015;17(3):277–85. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/26487808.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Rutter M. Environmentally mediated risks for psychopathology: research strategies and findings. J Am Acad Child Adolesc Psychiatry. 2005;44(1):3–18. https://doi.org/10.1097/01.chi.0000145374.45992.c9.

    Article  PubMed  Google Scholar 

  53. Battaglia M. Gene-environment interaction in panic disorder and posttraumatic stress disorder. Can J Psychiatry. 2013;58(2):69–75. https://doi.org/10.1177/070674371305800202.

    Article  PubMed  Google Scholar 

  54. Battaglia M, Ogliari A, Harris J, Spatola CA, Pesenti-Gritti P, Reichborn-Kjennerud T, Torgersen S, Kringlen E, Tambs K. A genetic study of the acute anxious response to carbon dioxide stimulation in man. J Psychiatr Res. 2007;41(11):906–17. https://doi.org/10.1016/j.jpsychires.2006.12.002. Epub 2007 Jan 24. PMID: 17254605.

    Article  PubMed  Google Scholar 

  55. Battaglia M, Pesenti-Gritti P, Spatola CAM, Ogliari A, Tambs K. A twin study of the common vulnerability between heightened sensitivity to hypercapnia and panic disorder. Am J Med Genet B Neuropsychiatr Genet. 2008;147B(5):586–93. https://doi.org/10.1002/ajmg.b.30647.

    Article  PubMed  Google Scholar 

  56. Coryell W, Pine D, Fyer A, Klein D. Anxiety responses to CO2 inhalation in subjects at high-risk for panic disorder. J Affect Disord. 2006;92(1):63–70. https://doi.org/10.1016/j.jad.2005.12.045.

    Article  PubMed  Google Scholar 

  57. Battaglia M. Sensitivity to carbon dioxide and translational studies of anxiety disorders. Neuroscience. 2017;346:434–6. https://doi.org/10.1016/j.neuroscience.2017.01.053.

    Article  CAS  PubMed  Google Scholar 

  58. Rassovsky Y, Kushner MG. Carbon dioxide in the study of panic disorder: issues of definition, methodology, and outcome. J Anxiety Disord. 2003;17(1):1–32. https://doi.org/10.1016/S0887-6185(02)00181-0.

    Article  PubMed  Google Scholar 

  59. van Duinen MA, Schruers KRJ, Jaegers E, Maes M, Griez EJL. Hypothalamic–pituitary–adrenal axis function following a 35% CO2 inhalation in healthy volunteers. Prog Neuro-Psychopharmacol Biol Psychiatry. 2004;28(2):279–83. https://doi.org/10.1016/j.pnpbp.2003.10.005.

    Article  CAS  Google Scholar 

  60. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160(4):636–45. https://doi.org/10.1176/appi.ajp.160.4.636.

    Article  PubMed  Google Scholar 

  61. Battaglia M, Bertella S, Ogliari A, Bellodi L, Smeraldi E. Modulation by muscarinic antagonists of the response to carbon dioxide challenge in panic disorder. Arch Gen Psychiatry. 2001;58(2):114–9. https://doi.org/10.1001/archpsyc.58.2.114.

    Article  CAS  PubMed  Google Scholar 

  62. Roberson-Nay R, Klein DF, Klein RG, Mannuzza S, Moulton JL, Guardino M, Pine DS. Carbon dioxide hypersensitivity in separation-anxious offspring of parents with panic disorder. Biol Psychiatry. 2010;67(12):1171–7. https://doi.org/10.1016/j.biopsych.2009.12.014.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Roberson-Nay R, Moruzzi S, Ogliari A, Pezzica E, Tambs K, Kendler KS, Battaglia M. Evidence for distinct genetic effects associated with response to 35% CO2. Depress Anxiety. 2013;30(3):259–66. https://doi.org/10.1002/da.22038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ogliari A, Tambs K, Harris JR, Scaini S, Maffei C, Reichborn-Kjennerud T, Battaglia M. The relationships between adverse events, early antecedents, and carbon dioxide reactivity as an intermediate phenotype of panic disorder. Psychother Psychosom. 2010;79(1):48–55. https://doi.org/10.1159/000259417.

    Article  PubMed  Google Scholar 

  65. Battaglia M. Challenges in the appraisal and application of gene–environment interdependence. Eur J Dev Psychol. 2012;9(4):419–25. https://doi.org/10.1080/17405629.2012.689819.

    Article  Google Scholar 

  66. Spatola CAM, Scaini S, Pesenti-Gritti P, Medland SE, Moruzzi S, Ogliari A, Tambs K, Battaglia M. Gene–environment interactions in panic disorder and CO2 sensitivity: effects of events occurring early in life. Am J Med Genet B Neuropsychiatr Genet. 2011;156(1):79–88. https://doi.org/10.1002/ajmg.b.31144.

    Article  CAS  Google Scholar 

  67. Tractenberg SG, Levandowski ML, de Azeredo LA, Orso R, Roithmann LG, Hoffmann ES, Brenhouse H, Grassi-Oliveira R. An overview of maternal separation effects on behavioural outcomes in mice: evidence from a four-stage methodological systematic review. Neurosci Biobehav Rev. 2016;68:489–503. https://doi.org/10.1016/j.neubiorev.2016.06.021.

    Article  PubMed  Google Scholar 

  68. Wang D, Levine JLS, Avila-Quintero V, Bloch M, Kaffman A. Systematic review and meta-analysis: effects of maternal separation on anxiety-like behavior in rodents. Transl Psychiatry. 2020;10(1):174. https://doi.org/10.1038/s41398-020-0856-0.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Genest S-E, Gulemetova R, Laforest S, Drolet G, Kinkead R. Neonatal maternal separation and sex-specific plasticity of the hypoxic ventilatory response in awake rat. J Physiol. 2004;554(2):543–57. https://doi.org/10.1113/jphysiol.2003.052894.

    Article  CAS  PubMed  Google Scholar 

  70. Kinkead R, Gulemetova R, Bairam A. Neonatal maternal separation enhances phrenic responses to hypoxia and carotid sinus nerve stimulation in the adult anesthetized rat. J Appl Physiol (1985). 2005;99(1):189–96. https://doi.org/10.1152/japplphysiol.00070.2005.

    Article  PubMed  Google Scholar 

  71. Kinkead R, Joseph V, Lajeunesse Y, Bairam A. Neonatal maternal separation enhances dopamine D 2 -receptor and tyrosine hydroxylase mRNA expression levels in carotid body of rats. Can J Physiol Pharmacol. 2005;83(1):76–84. https://doi.org/10.1139/y04-106.

    Article  CAS  PubMed  Google Scholar 

  72. Kalinichev M, Easterling KW, Plotsky PM, Holtzman SG. Long-lasting changes in stress-induced corticosterone response and anxiety-like behaviors as a consequence of neonatal maternal separation in Long-Evans rats. Pharmacol Biochem Behav. 2002;73(1):131–40. https://doi.org/10.1016/s0091-3057(02)00781-5.

    Article  CAS  PubMed  Google Scholar 

  73. Kinkead R, Montandon G, Bairam A, Lajeunesse Y, Horner R. Neonatal maternal separation disrupts regulation of sleep and breathing in adult male rats. Sleep. 2009;32(12):1611–20. https://doi.org/10.1093/sleep/32.12.1611.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Macrì S. Neonatal corticosterone administration in rodents as a tool to investigate the maternal programming of emotional and immune domains. Neurobiol Stress. 2016;6:22–30. https://doi.org/10.1016/j.ynstr.2016.12.001.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Gulemetova R, Kinkead R. Neonatal stress increases respiratory instability in rat pups. Respir Physiol Neurobiol. 2011;176(3):103–9. https://doi.org/10.1016/j.resp.2011.01.014.

    Article  PubMed  Google Scholar 

  76. Vázquez DM. Stress and the developing limbic-hypothalamic-pituitary-adrenal axis. Psychoneuroendocrinology. 1998;23(7):663–700. https://doi.org/10.1016/s0306-4530(98)00029-8.

    Article  PubMed  Google Scholar 

  77. Buitelaar JK, Huizink AC, Mulder EJ, de Medina PGR, Visser GHA. Prenatal stress and cognitive development and temperament in infants. Neurobiol Aging. 2003;24 Suppl 1:S53–60.; discussion S67–8. https://doi.org/10.1016/s0197-4580(03)00050-2.

    Article  PubMed  Google Scholar 

  78. Charil A, Laplante DP, Vaillancourt C, King S. Prenatal stress and brain development. Brain Res Rev. 2010;65(1):56–79. https://doi.org/10.1016/j.brainresrev.2010.06.002.

    Article  PubMed  Google Scholar 

  79. Fumagalli F, Molteni R, Racagni G, Riva MA. Stress during development: impact on neuroplasticity and relevance to psychopathology. Prog Neurobiol. 2007;81(4):197–217. https://doi.org/10.1016/j.pneurobio.2007.01.002.

    Article  PubMed  Google Scholar 

  80. Graham YP, Heim C, Goodman SH, Miller AH, Nemeroff CB. The effects of neonatal stress on brain development: implications for psychopathology. Dev Psychopathol. 1999;11(3):545–65. https://doi.org/10.1017/S0954579499002205.

    Article  CAS  PubMed  Google Scholar 

  81. Dumont FS, Biancardi V, Kinkead R. Hypercapnic ventilatory response of anesthetized female rats subjected to neonatal maternal separation: insight into the origins of panic attacks? Respir Physiol Neurobiol. 2011;175(2):288–95. https://doi.org/10.1016/j.resp.2010.12.004.

    Article  PubMed  Google Scholar 

  82. Kinkead R, Gulemetova R. Neonatal maternal separation and neuroendocrine programming of the respiratory control system in rats. Biol Psychol. 2010;84(1):26–38. https://doi.org/10.1016/j.biopsycho.2009.09.001.

    Article  PubMed  Google Scholar 

  83. Kinkead R, Tenorio L, Drolet G, Bretzner F, Gargaglioni L. Respiratory manifestations of panic disorder in animals and humans: a unique opportunity to understand how supramedullary structures regulate breathing. Respir Physiol Neurobiol. 2014;204:3–13. https://doi.org/10.1016/j.resp.2014.06.013.

    Article  PubMed  Google Scholar 

  84. Soliz J, Tam R, Kinkead R. Neonatal maternal separation augments carotid body response to hypoxia in adult males but not female rats. Front Physiol. 2016;7:432. Retrieved from https://www.frontiersin.org/article/10.3389/fphys.2016.00432.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Feinstein JS, Buzza C, Hurlemann R, Follmer RL, Dahdaleh NS, Coryell WH, Welsh MJ, Tranel D, Wemmie JA. Fear and panic in humans with bilateral amygdala damage. Nat Neurosci. 2013;16(3):270–2. https://doi.org/10.1038/nn.3323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Macrì S, Würbel H. Developmental plasticity of HPA and fear responses in rats: a critical review of the maternal mediation hypothesis. Horm Behav. 2006;50(5):667–80. https://doi.org/10.1016/j.yhbeh.2006.06.015.

    Article  CAS  PubMed  Google Scholar 

  87. Millstein RA, Holmes A. Effects of repeated maternal separation on anxiety- and depression-related phenotypes in different mouse strains. Neurosci Biobehav Rev. 2007;31(1):3–17. https://doi.org/10.1016/j.neubiorev.2006.05.003.

    Article  PubMed  Google Scholar 

  88. Buxbaum LU, DeRitis PC, Chu N, Conti PA. Eliminating murine norovirus by cross-fostering. J Am Assoc Lab Anim Sci. 2011;50(4):495–9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21838978

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Landers MS, Sullivan RM. The development and neurobiology of infant attachment and fear. Dev Neurosci. 2012;34(2–3):101–14. https://doi.org/10.1159/000336732.

    Article  CAS  PubMed  Google Scholar 

  90. Bartolomucci A, Gioiosa L, Chirieleison A, Ceresini G, Parmigiani S, Palanza P. Cross fostering in mice: behavioral and physiological carry-over effects in adulthood. Genes Brain Behav. 2004;3(2):115–22. https://doi.org/10.1111/j.1601-183X.2003.00059.x.

    Article  CAS  PubMed  Google Scholar 

  91. Dickinson AL, Leach MC, Flecknell PA. Influence of early neonatal experience on nociceptive responses and analgesic effects in rats. Lab Anim. 2009;43(1):11–6. https://doi.org/10.1258/la.2007.007078.

    Article  CAS  PubMed  Google Scholar 

  92. Leussis MP, Heinrichs SC. Quality of rearing guides expression of behavioral and neural seizure phenotypes in EL mice. Brain Res. 2009;1260:84–93. https://doi.org/10.1016/j.brainres.2009.01.007.

    Article  CAS  PubMed  Google Scholar 

  93. Lu L, Mamiya T, Lu P, Niwa M, Mouri A, Zou L-B, Nagai T, Hiramatsu M, Nabeshima T. The long-lasting effects of cross-fostering on the emotional behavior in ICR mice. Behav Brain Res. 2009;198(1):172–8. https://doi.org/10.1016/j.bbr.2008.10.031.

    Article  PubMed  Google Scholar 

  94. Malkesman O, Lavi-Avnon Y, Maayan R, Weizman A. A cross-fostering study in a genetic animal model of depression: maternal behavior and depression-like symptoms. Pharmacol Biochem Behav. 2008;91(1):1–8. https://doi.org/10.1016/j.pbb.2008.06.004.

    Article  CAS  PubMed  Google Scholar 

  95. Matthews PA, Samuelsson A-M, Seed P, Pombo J, Oben JA, Poston L, Taylor PD. Fostering in mice induces cardiovascular and metabolic dysfunction in adulthood. J Physiol. 2011;589(16):3969–81. https://doi.org/10.1113/jphysiol.2011.212324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. D’Amato FR, Zanettini C, Lampis V, Coccurello R, Pascucci T, Ventura R, Puglisi-Allegra S, Spatola CA, Pesenti-Gritti P, Oddi D, Moles A, Battaglia M. Unstable maternal environment, separation anxiety, and heightened CO2 sensitivity induced by gene-by-environment interplay. PLoS One. 2011;6(4):e18637. https://doi.org/10.1371/journal.pone.0018637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Giannese F, Luchetti A, Barbiera G, Lampis V, Zanettini C, Knudsen GP, Scaini S, Lazarevic D, Cittaro D, D’Amato FR, Battaglia M. Conserved DNA methylation signatures in early maternal separation and in twins discordant for CO2 sensitivity. Sci Rep. 2018;8(1):2258. https://doi.org/10.1038/s41598-018-20457-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Luchetti A, Oddi D, Lampis V, Centofante E, Felsani A, Battaglia M, D’Amato FR. Early handling and repeated cross-fostering have opposite effect on mouse emotionality. Front Behav Neurosci. 2015;9:93. https://doi.org/10.3389/fnbeh.2015.00093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Spiacci A, Vilela-Costa HH, Sant’Ana AB, Fernandes GG, Frias AT, da Silva GSF, Antunes-Rodrigues J, Zangrossi H. Panic-like escape response elicited in mice by exposure to CO2, but not hypoxia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2018;81:178–86. https://doi.org/10.1016/j.pnpbp.2017.10.018.

    Article  CAS  Google Scholar 

  100. Ventura R, Coccurello R, Andolina D, Latagliata EC, Zanettini C, Lampis V, Battaglia M, D’Amato FR, Moles A. Postnatal aversive experience impairs sensitivity to natural rewards and increases susceptibility to negative events in adult life. Cereb Cortex. 2013;23(7):1606–17. https://doi.org/10.1093/cercor/bhs145.

    Article  PubMed  Google Scholar 

  101. Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2012;13(2):97–109. https://doi.org/10.1038/nrg3142.

    Article  CAS  PubMed  Google Scholar 

  102. Xie L, Korkmaz KS, Braun K, Bock J. Early life stress-induced histone acetylations correlate with activation of the synaptic plasticity genes Arc and Egr1 in the mouse hippocampus. J Neurochem. 2013;125(3):457–64. https://doi.org/10.1111/jnc.12210.

    Article  CAS  PubMed  Google Scholar 

  103. Zhou VW, Goren A, Bernstein BE. Charting histone modifications and the functional organization of mammalian genomes. Nat Rev Genet. 2011;12(1):7–18. https://doi.org/10.1038/nrg2905.

    Article  CAS  PubMed  Google Scholar 

  104. Battaglia M. Epigenomic landscapes and their relationship to variation, fitness, and evolution. Neurosci Biobehav Rev. 2020;109:90–1. https://doi.org/10.1016/j.neubiorev.2020.01.002.

    Article  CAS  PubMed  Google Scholar 

  105. Cittaro D, Lampis V, Luchetti A, Coccurello R, Guffanti A, Felsani A, Moles A, Stupka E, D’Amato FR, Battaglia M. Histone modifications in a mouse model of early adversities and panic disorder: role for Asic1 and neurodevelopmental genes. Sci Rep. 2016;6:25131. https://doi.org/10.1038/srep25131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Barski A, Cuddapah S, Cui K, Roh T-Y, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129(4):823–37. https://doi.org/10.1016/j.cell.2007.05.009.

    Article  CAS  PubMed  Google Scholar 

  107. Wemmie JA, Taugher RJ, Kreple CJ. Acid-sensing ion channels in pain and disease. Nat Rev Neurosci. 2013;14(7):461–71. https://doi.org/10.1038/nrn3529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ziemann AE, Allen JE, Dahdaleh NS, Drebot II, Coryell MW, Wunsch AM, Lynch CM, Faraci FM, Wemmie JA. The amygdala is a chemosensor that detects carbon dioxide and acidosis to elicit fear behavior. Cell. 2009;139(5):1012–21. https://doi.org/10.1016/j.cell.2009.10.029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Savage JE, McMichael O, Gorlin EI, Beadel JR, Teachman B, Vladimirov VI, Hettema JM, Roberson-Nay R. Validation of candidate anxiety disorder genes using a carbon dioxide challenge task. Biol Psychol. 2015;109:61–6. https://doi.org/10.1016/j.biopsycho.2015.04.006.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Smoller JW, Gallagher PJ, Duncan LE, McGrath LM, Haddad SA, Holmes AJ, Cohen BM. The human ortholog of acid-sensing ion channel gene ASIC1a is associated with panic disorder and amygdala structure and function. Biol Psychiatry. 2014;76(11):902–10. https://doi.org/10.1016/j.biopsych.2013.12.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Luchetti A, Battaglia M, D’Amato FR. Repeated cross-fostering protocol as a mouse model of early environmental instability. Bio-Protocol. 2016;6(4):e1734. https://doi.org/10.21769/BioProtoc.1734.

    Article  Google Scholar 

  112. Battaglia M, Rossignol O, Bachand K, D’Amato FR, Koninck YD. Amiloride modulation of carbon dioxide hypersensitivity and thermal nociceptive hypersensitivity induced by interference with early maternal environment. J Psychopharmacol. 2018;33(1):101–8. https://doi.org/10.1177/0269881118784872.

    Article  CAS  PubMed  Google Scholar 

  113. Dunn KM, Jordan KP, Mancl L, Drangsholt MT, Le Resche L. Trajectories of pain in adolescents: a prospective cohort study. Pain. 2011;152(1):66–73. https://doi.org/10.1016/j.pain.2010.09.006.

    Article  PubMed  PubMed Central  Google Scholar 

  114. King S, Chambers CT, Huguet A, MacNevin RC, McGrath PJ, Parker L, MacDonald AJ. The epidemiology of chronic pain in children and adolescents revisited: a systematic review. Pain. 2011;152(12):2729–38. https://doi.org/10.1016/j.pain.2011.07.016.

    Article  PubMed  Google Scholar 

  115. Battaglia M, Garon-Carrier G, Brendgen M, Feng B, Dionne G, Vitaro F, Tremblay RE, Boivin M. Trajectories of pain and anxiety in a longitudinal cohort of adolescent twins. Depress Anxiety. 2020;37(5):475–84. https://doi.org/10.1002/da.22992.

    Article  PubMed  Google Scholar 

  116. McWilliams LA, Goodwin RD, Cox BJ. Depression and anxiety associated with three pain conditions: results from a nationally representative sample. Pain. 2004;111(1–2):77–83. https://doi.org/10.1016/j.pain.2004.06.002.

    Article  PubMed  Google Scholar 

  117. Noel M, Groenewald CB, Beals-Erickson SE, Gebert JT, Palermo TM. Chronic pain in adolescence and internalizing mental health disorders: a nationally representative study. Pain. 2016;157(6):1333–8. https://doi.org/10.1097/j.pain.0000000000000522.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Schechter NL. Functional pain: time for a new name. JAMA Pediatr. 2014;168(8):693–4. https://doi.org/10.1001/jamapediatrics.2014.530.

    Article  PubMed  Google Scholar 

  119. Khan WU, Michelini G, Battaglia M. Twin studies of the covariation of pain with depression and anxiety: a systematic review and re-evaluation of critical needs. Neurosci Biobehav Rev. 2020;111:135–48. https://doi.org/10.1016/j.neubiorev.2020.01.015.

    Article  PubMed  Google Scholar 

  120. Scaini S, Michelini G, De Francesco S, Fagnani C, Medda E, Stazi M, Battaglia M. Adolescent pain, anxiety and depressive problems: a twin study of their co-occurrence and the relationship to substance use. Pain. 2022;163(3):e488–94.

    Article  PubMed  Google Scholar 

  121. You DS, Albu S, Lisenbardt H, Meagher MW. Cumulative childhood adversity as a risk factor for common chronic pain conditions in young adults. Pain Med. 2019;20(3):486–94. https://doi.org/10.1093/pm/pny106.

    Article  PubMed  Google Scholar 

  122. Wang H-J, Xu X, Zhang P-A, Li M, Zhou Y-L, Xu Y-C, Jiang XH, Xu G-Y. Epigenetic upregulation of acid-sensing ion channel 1 contributes to gastric hypersensitivity in adult offspring rats with prenatal maternal stress. Pain. 2020;161(5):989–1004. https://doi.org/10.1097/j.pain.0000000000001785.

    Article  CAS  PubMed  Google Scholar 

  123. Battaglia M, Quinn PD, Groenewald CB. Consideration of adolescent pain in responses to the opioid crisis. JAMA Psychiatry. 2021;78(1):5–6. https://doi.org/10.1001/jamapsychiatry.2020.1694.

    Article  Google Scholar 

  124. Volkow ND, McLellan AT. Opioid abuse in chronic pain — misconceptions and mitigation strategies. N Engl J Med. 2016;374(13):1253–63. https://doi.org/10.1056/NEJMra1507771.

    Article  CAS  PubMed  Google Scholar 

  125. McCabe SE, Veliz PT, Dickinson K, Schepis TS, Schulenberg JE. Trajectories of prescription drug misuse during the transition from late adolescence into adulthood in the USA: a national longitudinal multicohort study. Lancet Psychiatry. 2019;6(10):840–50. https://doi.org/10.1016/S2215-0366(19)30299-8.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Azzeh M, Battaglia M, Davies S, Strauss J, Dogra P, Yellepeddi V. Novel intranasal treatment for anxiety disorders using amiloride, an acid-sensing ion channel antagonist: pharmacokinetic modeling and simulation. Int J Clin Pharmacol Ther. 2022;60(6):253–63. https://doi.org/10.5414/CP204217. PMID: 35445658.

    Article  CAS  PubMed  Google Scholar 

  127. Yellepeddi VK, Battaglia M, Davies SJC, Alt J, Ashby S, Shipman P, Anderson DJ, Rower JE, Reilly C, Voight M, Mim SR. Pharmacokinetics of intranasal amiloride in healthy volunteers. Clin Transl Sci. 2023. https://doi.org/10.1111/cts.13514. Epub ahead of print. PMID: 36932683.

  128. Yellepeddi V, Sayre C, Burrows A, Watt K, Davies S, Strauss J, Battaglia M. Stability of extemporaneously compounded amiloride nasal spray. PLoS One. 2020;15(7):e0232435. https://doi.org/10.1371/journal.pone.0232435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Richey JA, Schmidt NB, Hofmann SG, Timpano KR. Temporal and structural dynamics of anxiety sensitivity in predicting fearful responding to a 35% CO2 challenge. J Anxiety Disord. 2010;24(4):423–32. https://doi.org/10.1016/j.janxdis.2010.02.007.

    Article  PubMed  Google Scholar 

  130. Fluharty ME, Attwood AS, Munafò MR. Anxiety sensitivity and trait anxiety are associated with response to 7.5% carbon dioxide challenge. J Psychopharmacol (Oxford, England). 2016;30(2):182–7. https://doi.org/10.1177/0269881115615105.

    Article  CAS  Google Scholar 

  131. Tay TL, Savage JC, Hui CW, Bisht K, Tremblay M-È. Microglia across the lifespan: from origin to function in brain development, plasticity and cognition. J Physiol. 2017;595(6):1929–45. https://doi.org/10.1113/JP272134.

    Article  CAS  PubMed  Google Scholar 

  132. Vollmer LL, Ghosal S, McGuire JL, Ahlbrand RL, Li K-Y, Santin JM, Ratliff-Rang CA, Patrone LG, Rush J, Lewkowich IP, Herman JP, Putnam RW, Sah R. Microglial acid sensing regulates carbon dioxide-evoked fear. Biol Psychiatry. 2016;80(7):541–51. https://doi.org/10.1016/j.biopsych.2016.04.022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Knowles MR, Church NL, Waltner WE, Yankaskas JR, Gilligan P, King M, Edwards LJ, Helms RW, Boucher RC. A pilot study of aerosolized amiloride for the treatment of lung disease in cystic fibrosis. N Engl J Med. 1990;322(17):1189–94. https://doi.org/10.1056/NEJM199004263221704.

    Article  CAS  PubMed  Google Scholar 

  134. Tipton AF, Tarash I, McGuire B, Charles A, Pradhan AA. The effects of acute and preventive migraine therapies in a mouse model of chronic migraine. Cephalalgia. 2016;36(11):1048–56. https://doi.org/10.1177/0333102415623070.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Xu Y, Jiang Y-Q, Li C, He M, Rusyniak WG, Annamdevula N, Ochoa J, Leavesley SJ, Xu J, Rich TC, Lin MT, Zha X-M. Human ASIC1a mediates stronger acid-induced responses as compared with mouse ASIC1a. FASEB J. 2018;32(7):3832–43. https://doi.org/10.1096/fj.201701367R.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Battaglia M, Rossignol O, Lorenzo L-E, Deguire J, Godin AJ, D’Amato FR, De Koninck Y. Enhanced harm detection following maternal separation: transgenerational transmission and reversibility by inhaled Amiloride. Sci Adv. in press 2023.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre for Addiction and Mental Health, Toronto, ON, Canada

    Maximilian Strauss & Marco Battaglia

  2. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Marco Battaglia

  3. Cundill Centre for Child and Youth Depression, Toronto, ON, Canada

    Marco Battaglia

Authors
  1. Maximilian Strauss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marco Battaglia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marco Battaglia .

Editor information

Editors and Affiliations

  1. Dept Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Stefano Pini

  2. Psychiatry and Behavioral Sc. (PRIME), Albert Einstein College of Medicine, New York, NY, USA

    Barbara Milrod

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Strauss, M., Battaglia, M. (2023). Childhood Separation Anxiety: Human and Preclinical Studies. In: Pini, S., Milrod, B. (eds) Separation Anxiety in Adulthood. Springer, Cham. https://doi.org/10.1007/978-3-031-37446-3_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-37446-3_2

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-031-37445-6

  • Online ISBN: 978-3-031-37446-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation