Unstable maternal environment, separation anxiety, and heightened CO2 sensitivity induced by gene-by-environment interplay

PLoS One. 2011 Apr 8;6(4):e18637. doi: 10.1371/journal.pone.0018637.


Background: In man, many different events implying childhood separation from caregivers/unstable parental environment are associated with heightened risk for panic disorder in adulthood. Twin data show that the occurrence of such events in childhood contributes to explaining the covariation between separation anxiety disorder, panic, and the related psychobiological trait of CO(2) hypersensitivity. We hypothesized that early interference with infant-mother interaction could moderate the interspecific trait of response to CO(2) through genetic control of sensitivity to the environment.

Methodology: Having spent the first 24 hours after birth with their biological mother, outbred NMRI mice were cross-fostered to adoptive mothers for the following 4 post-natal days. They were successively compared to normally-reared individuals for: number of ultrasonic vocalizations during isolation, respiratory physiology responses to normal air (20%O(2)), CO(2)-enriched air (6% CO(2)), hypoxic air (10%O(2)), and avoidance of CO(2)-enriched environments.

Results: Cross-fostered pups showed significantly more ultrasonic vocalizations, more pronounced hyperventilatory responses (larger tidal volume and minute volume increments) to CO(2)-enriched air and heightened aversion towards CO(2)-enriched environments, than normally-reared individuals. Enhanced tidal volume increment response to 6%CO(2) was present at 16-20, and 75-90 postnatal days, implying the trait's stability. Quantitative genetic analyses of unrelated individuals, sibs and half-sibs, showed that the genetic variance for tidal volume increment during 6%CO(2) breathing was significantly higher (Bartlett χ = 8.3, p = 0.004) among the cross-fostered than the normally-reared individuals, yielding heritability of 0.37 and 0.21 respectively. These results support a stress-diathesis model whereby the genetic influences underlying the response to 6%CO(2) increase their contribution in the presence of an environmental adversity. Maternal grooming/licking behaviour, and corticosterone basal levels were similar among cross-fostered and normally-reared individuals.

Conclusions: A mechanism of gene-by-environment interplay connects this form of early perturbation of infant-mother interaction, heightened CO(2) sensitivity and anxiety. Some non-inferential physiological measurements can enhance animal models of human neurodevelopmental anxiety disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects
  • Animals
  • Anxiety, Separation / complications
  • Anxiety, Separation / genetics*
  • Anxiety, Separation / physiopathology
  • Behavior, Animal / drug effects
  • Carbon Dioxide / pharmacology*
  • Corticosterone / metabolism
  • Environment*
  • Female
  • Genes / genetics*
  • Humans
  • Male
  • Mice
  • Panic / drug effects
  • Phenotype
  • Reproducibility of Results
  • Respiration / drug effects
  • Tidal Volume / drug effects


  • Carbon Dioxide
  • Corticosterone