Abstract
There is increasing recognition that many psychiatric disorders including anxiety disorders are neurodevelopmental in their origins. Here, we review and integrate data from human studies and from animal models that point to a critical period during which neural circuits that mediate anxiety develop. We then postulate that this highly plastic critical period is a time of heightened responsiveness that is particularly susceptible to adverse events. We discuss these concepts in the context the current heightened interest in gene by environment interactions in psychiatric illness emphasizing the importance of the temporal relationship between gene action and environmental milieu.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Albert PR, Lemonde S (2004). 5-HT1A receptors, gene repression, and depression: guilt by association. Neuroscientist 10: 575–593.
Altman J, Sudarshan K (1975). Postnatal development of locomotion in the laboratory rat. Anim Behav 23: 896–920.
American Psychiatric Association, American Psychiatric Association. Task Force on DSM-IV (2000). Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR, 4th edn. American Psychiatric Association: Washington, DC, 37: 943 pp.
Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA (2004). Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 306: 879–881. Demonstrates how even a transient loss of gene function during a critical period in development can have long-term behavioral consequences. The data presented here nicely complement data on the effects of human 5-HTT polymorphisms on early life adverse events.
Ba A, Seri BV (1993). Functional development of central nervous system in the rat: ontogeny of nociceptive thresholds. Physiol Behav 54: 403–405.
Beauregard M, Malkova L, Bachevalier J (1995). Stereotypies and loss of social affiliation after early hippocampectomy in primates. Neuroreport 6: 2521–2526.
Benes FM, Taylor JB, Cunningham MC (2000). Convergence and plasticity of monoaminergic systems in the medial prefrontal cortex during the postnatal period: implications for the development of psychopathology. Cereb Cortex 10: 1014–1027.
Bowlby J (1969). Attachment and Loss: Vol. 1. Attachment. Basic Books: New York. pp 321–330.
Breslau N, Schultz L, Peterson E (1995). Sex differences in depression: a role for preexisting anxiety. Psychiatry Res 58: 1–12.
Carroll JC, Boyce-Rustay JM, Millstein R, Yang R, Wiedholz LM, Murphy DL et al (2007). Effects of mild early life stress on abnormal emotion-related behaviors in 5-HTT knockout mice. Behav Genet 37: 214–222.
Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW et al (2002). Role of genotype in the cycle of violence in maltreated children. Science 297: 851–854.
Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H et al (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301: 386–389.
Chorpita BF, Brown TA, Barlow DH (1998). Perceived control as a mediator of family environment in etiological models of childhood anxiety. Behav Ther 29: 457–476.
Chrousos GP (1998). Stressors, stress, and neuroendocrine integration of the adaptive response. The 1997 Hans Selye Memorial Lecture. Ann NY Acad Sci 851: 311–335.
Cole DA, Turner Jr JE (1993). Models of cognitive mediation and moderation in child depression. J Abnorm Psychol 102: 271–281.
Cooper JR, Bloom FE, Roth RH (2003). The Biochemical Basis of Neuropharmacology, 8th edn. Oxford University Press: Oxford, New York, 7: 40 pp.
Danglot L, Triller A, Marty S (2006). The development of hippocampal interneurons in rodents. Hippocampus 16: 1032–1060.
Emde RN, Harmon RJ, Gaensbauer TJ (1976). Emotional Expression in Infancy: A Biobehavioral Study. International Universities Press: New York, 11: 19 pp.
Fox K (1992). A critical period for experience-dependent synaptic plasticity in rat barrel cortex. J Neurosci 12: 1826–1838.
Gray JA, McNaughton N (2000). The Neuropsychology of Anxiety: An Enquiry into The Functions of The Septo-Hippocampal System, 2nd edn. Oxford University Press: Oxford, New York, 16: 424 pp.
Greenberg PE, Sisitsky T, Kessler RC, Finkelstein SN, Berndt ER, Davidson JR et al (1999). The economic burden of anxiety disorders in the 1990s. J Clin Psychiatry 60: 427–435.
Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, Kirby L et al (2002). Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416: 396–400. Demonstrates the requirement for 5-HT1AR function in the forebrain during early postnatal development in order to establish normal anxiety circuits. Also demonstrates that expression of the receptor in the adult animal is unable to reverse the developmental phenotype.
Hammen C, Adrian C, Hiroto D (1988). A longitudinal test of the attributional vulnerability model in children at risk for depression. Br J Clin Psychol 27: 37–46.
Hensch TK (2004). Critical period regulation. Annu Rev Neurosci 27: 549–579.
Hettema JM, Neale MC, Kendler KS (2001). A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 158: 1568–1578.
Hettema JM, Prescott CA, Myers JM, Neale MC, Kendler KS (2005). The structure of genetic and environmental risk factors for anxiety disorders in men and women. Arch Gen Psychiatry 62: 182–189.
Hirshfeld DR, Rosenbaum JF, Biederman J, Bolduc EA, Faraone SV, Snidman N et al (1992). Stable behavioral inhibition and its association with anxiety disorder. J Am Acad Child Adolesc Psychiatry 31: 103–111.
Kagan J, Reznick JS, Snidman N (1988). Biological bases of childhood shyness. Science 240: 167–171. Longitudinal study that demonstrates the stability of behavioral inhibition as initially assessed at age 2 over time.
Kagan J, Snidman N (1999). Early childhood predictors of adult anxiety disorders. Biol Psychiatry 46: 1536–1541.
Kagan J, Snidman N, Arcus D (1995). The role of temperament in social development. Ann NY Acad Sci 771: 485–490.
Kagan J, Snidman N, Arcus D (1998). Childhood derivatives of high and low reactivity in infancy. Child Dev 69: 1483–1493.
Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ (1992). Major depression and generalized anxiety disorder. Same genes, (partly) different environments? Arch Gen Psychiatry 49: 716–722.
Kendler KS, Prescott CA, Myers J, Neale MC (2003). The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Arch Gen Psychiatry 60: 929–937.
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arc Gen Psychiatry 62: 593–602.
Kessler RC, Wittchen HU (2002). Patterns and correlates of generalized anxiety disorder in community samples. J Clin Psychiatry 63(Suppl 8): 4–10.
Klemenhagen KC, Gordon JA, David DJ, Hen R, Gross CT (2006). Increased fear response to contextual cues in mice lacking the 5-HT1A receptor. Neuropsychopharmacology 31: 101–111.
Knudsen EI (2004). Sensitive periods in the development of the brain and behavior. J Cogn Neurosci 16: 1412–1425.
Loizou LA (1972). The postnatal ontogeny of monoamine-containing neurones in the central nervous system of the albino rat. Brain Res 40: 395–418.
Moffitt TE, Caspi A, Harrington H, Milne BJ, Melchior M, Goldberg D et al (2007). Generalized anxiety disorder and depression: childhood risk factors in a birth cohort followed to age 32. Psychol Med 37: 441–452. Prospective study demonstrating that early life risk factors are overrepresented in people with a lifetime anxiety disorder and co-morbid anxiety and depression but not in those with depression alone.
Murrin LC, Sanders JD, Bylund DB (2007). Comparison of the maturation of the adrenergic and serotonergic neurotransmitter systems in the brain: implications for differential drug effects on juveniles and adults. Biochem Pharmacol 73: 1225–1236.
Nakamura K, Koyama Y, Takahashi K, Tsurui H, Xiu Y, Ohtsuji M et al (2006). Requirement of tryptophan hydroxylase during development for maturation of sensorimotor gating. J Mol Biol 363: 345–354.
Ninan PT, Berger J (2001). Symptomatic and syndromal anxiety and depression. Depress Anxiety 14: 79–85.
Nolen-Hoeksema S, Girgus JS, Seligman MEP (1992). Predictors and consequences of childhood depressive symptoms a 5-year longitudinal study. J Abnorm Psychol 101: 405–422.
Parker G, Wilhelm K, Mitchell P, Austin MP, Roussos J, Gladstone G (1999). The influence of anxiety as a risk to early onset major depression. J Affect Disord 52: 11–17.
Parks CL, Robinson PS, Sibille E, Shenk T, Toth M (1998). Increased anxiety of mice lacking the serotonin1A receptor. Proc Natl Acad Sci USA 95: 10734–10739.
Pokorny J, Yamamoto T (1981). Postnatal ontogenesis of hippocampal CA1 area in rats. II. Development of ultrastructure in stratum lacunosum and molecular. Brain Res Bull 7: 121–130.
Ramboz S, Oosting R, Amara DA, Kung HF, Blier P, Mendelsohn M et al (1998). Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proc Natl Acad Sci USA 95: 14476–14481.
Roy MA, Neale MC, Pedersen NL, Mathe AA, Kendler KS (1995). A twin study of generalized anxiety disorder and major depression. Psychol Med 25: 1037–1049.
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S et al (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301: 805–809.
Schwartz CE, Snidman N, Kagan J (1999). Adolescent social anxiety as an outcome of inhibited temperament in childhood. J Am Acad Child Adolesc Psychiatry 38: 1008–1015.
Sullivan PF, Neale MC, Kendler KS (2000). Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 157: 1552–1562.
Tansey EP, Chow A, Rudy B, McBain CJ (2002). Developmental expression of potassium-channel subunit Kv3.2 within subpopulations of mouse hippocampal inhibitory interneurons. Hippocampus 12: 137–148.
Van Ameringen M, Mancini C, Oakman JM (1998). The relationship of behavioral inhibition and shyness to anxiety disorder. J Nerv Ment Dis 186: 425–431.
Weissman MM, Wickramaratne P, Nomura Y, Warner V, Verdeli H, Pilowsky DJ et al (2005). Families at high and low risk for depression: a 3-generation study. Arch Gen Psychiatry 62: 29–36. Demonstrates that anxiety disorders are the early markers of psychopathology in families with familial depression.
Westerga J, Gramsbergen A (1990). The development of locomotion in the rat. Brain Res Dev Brain Res 57: 163–174.
Wittchen HU, Kessler RC, Pfister H, Lieb M (2000). Why do people with anxiety disorders become depressed? A prospective-longitudinal community study. Acta Psychiatr Scand 102(Suppl): 14–23.
Author information
Authors and Affiliations
Corresponding author
PowerPoint slides
Rights and permissions
About this article
Cite this article
Leonardo, E., Hen, R. Anxiety as a Developmental Disorder. Neuropsychopharmacol 33, 134–140 (2008). https://doi.org/10.1038/sj.npp.1301569
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.npp.1301569
Keywords
This article is cited by
-
Spatiotemporal expression patterns of anxiety disorder-associated genes
Translational Psychiatry (2023)
-
Gabrb3 endothelial cell-specific knockout mice display abnormal blood flow, hypertension, and behavioral dysfunction
Scientific Reports (2022)
-
Maternal Intake of Probiotics to Program Offspring Health
Current Nutrition Reports (2022)
-
Effects of chronic fluoxetine treatment on anxiety- and depressive-like behaviors in adolescent rodents – systematic review and meta-analysis
Pharmacological Reports (2022)
-
Generalized and social anxiety disorder interactomes show distinctive overlaps with striosome and matrix interactomes
Scientific Reports (2021)
