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The developmental origins of anxiety

Nature Reviews Neuroscience volume 5, pages 545–552 (2004)Cite this article

Key Points

  • Anxiety is a mental state that is a normal reaction to potential threat. Excessive or inappropriate anxiety can become an illness. Early developmental mechanisms are thought to contribute to the susceptibility of the adult to anxiety. Developmental mechanisms under both genetic and environmental control set the tendency of an organism to express anxiety in certain situations.

  • Drugs such as benzodiazepines and selective serotonin re-uptake inhibitors (SSRIs) have been used to treat excessive anxiety. These drugs target GABAA (γ-aminobutyric acid, type A) receptors and block the re-uptake of serotonin, respectively.

  • A small number of genetic variations have been linked to increased anxiety in humans. Studies have shown a small, but significant, increase in anxiety in both infants and adults that carry a variant of the serotonin transporter (5-HTT) gene, indicating that 5-HTT influences anxiety-related behaviour.

  • Twin studies indicate that reduced hippocampal volume increases susceptibility to environmental stresses that presage the onset of anxiety-related behaviours such as post-traumatic stress disorder. Whether reductions of hippocampal volume have genetic or environmental origins is not yet known.

  • The MAOA gene has been implicated in the mechanism by which early-life trauma influences subsequent psychopathology. In boys that have been maltreated, carrying the low-activity allele of the MAOA gene increases the probability that they will develop antisocial behaviour as an adult. However, maltreated boys with the high-activity allele are not at increased risk of behaving in an antisocial manner at maturity.

  • Studies of genetically modified mice have made it possible to investigate the consequences on anxiety-related behaviour of manipulating specific genes. Anxiety-related behaviour is altered in mice bearing mutations in specific genes, including 5-HT1A.

  • In summary, lifelong susceptibility to anxiety can be determined by the combined influence of genetic and environmental factors on early development.

Abstract

Anxiety is a mental state that is elicited in anticipation of threat or potential threat. Sensations of anxiety are a normal part of human experience, but excessive or inappropriate anxiety can become an illness. In this review, we consider the evidence for anxiety as a product of early environmental experiences, the impacts of which are modulated by genetic susceptibility factors. We propose that such interactions can induce persistent structural and functional changes in the brain that underlie susceptibility to anxiety. Investigation of the molecular nature of these factors and the plastic changes that they induce has the potential to reveal why different individuals experience different levels of anxiety.

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Figure 1: A comparison of the occurrence of mental illness in monozygotic and dizygotic twins reveals the influence of genetic factors.
Figure 2: Post-traumatic stress disorder (PTSD) can develop as a result of a traumatic experience, such as military combat, and is associated with a reduction in hippocampal volume.
Figure 3: Rats raised by mothers that display low licking-and-grooming behaviour exhibit more anxiety-related behaviour than rats raised by high licking-and-grooming mothers.
Figure 4: Serotonin receptor espression and anxiety.
Figure 5: During development, genetic and environmental influences interact to modulate neuronal maturation and determine levels of anxiety.

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Acknowledgements

We thank D. Leonardo, J. Gordon, A. Dranovsky, M. Rogan, K. Klemenhagen, J. Monckton, L. Santarelli and V. Carola for helpful comments and discussions.

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Authors and Affiliations

  1. Mouse Biology Programme, European Molecular Biology Laboratory, Via Ramarini 32, Monterotondo (Rome), 00016, Italy

    Cornelius Gross

  2. Center for Neurobiology and Behavior, Columbia University, 722 West 168th Street, New York, 10032, New York, USA

    Rene Hen

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DATABASES

Entrez Gene

BDNF

CREB

5-HTT

MAOA

OMIM

OCD

panic disorder

FURTHER INFORMATION

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Hen's homepage

Glossary

OBSESSIVE–COMPULSIVE DISORDER

A psychological disorder in which the person is burdened by recurrent, persistent thoughts or ideas, and/or feels compelled to carry out a repetitive, ritualized behaviour. Anxiety is increased by attempts to resist the compulsion and is relieved by giving way to it.

AMYGDALA

A small almond-shaped structure, comprising 13 nuclei, buried in the anterior medial section of each temporal lobe.

MONOZYGOTIC

Twins that develop from a single fertilized egg cell through its division into two genetically identical parts.

DIZYGOTIC

Twins that develop during the same pregnancy as the result of two separate eggs being fertilized by two separate sperm.

NEUROTICISM

One of five domains of the NEO-Personality Inventory psychological assessment tool. Neuroticism comprises six facets: anxiety, depression, angry hostility, self-consciousness, impulsivity and vulnerability.

AGREEABLENESS

One of five domains of the NEO-Personality Inventory psychological assessment tool. Agreeableness comprises six facets: trust, straightforwardness, altruism, compliance, modesty and tender-mindedness.

POLYMORPHISM

Variation in DNA sequence between individuals.

GLUCOCORTICOID

Hormones produced by the adrenal cortex, which are involved in carbohydrate and protein metabolism, but also affect brain function. Cortisol (human) and corticosterone (rodent) are examples.

METHYLATION

A chemical modification of a molecule involving the covalent attachment of a CH3 group. Methylation of the DNA encoding a gene can alter its expression.

OCULAR DOMINANCE

In the mature primary visual cortex of mammals, most neurons respond predominantly to visual inputs from one eye or the other. Cells that respond to a given eye are arranged in stripes — the ocular dominance columns — that alternate with stripes of neurons that respond to the other eye.

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Gross, C., Hen, R. The developmental origins of anxiety. Nat Rev Neurosci 5, 545–552 (2004). https://doi.org/10.1038/nrn1429

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