Anxiety-related behavior and postnatal dentate gyrus development: Regulation by parental and offspring genotypes

Anxiety in humans is thought to have both genetic and environmental components. To gain insight into the neurobiological basis of anxiety, genetically modified mice can be used as a model to link anxiety-related behavioral phenotypes with specific cellular and molecular changes in the brain. Here, we use two mouse models of altered anxiety-related behavior, each with a single gene deletion, to determine how parental and offspring genotypes regulate postnatal development and anxiety-related behavior. The serotonin 1A receptor (5-HT 1AR) knockout mouse displays significant anxiety-related behavior. Importantly, the 5-HT1AR gene has been linked to anxiety disorders in humans. Conversely, mice with a knockout of the cytokine tumor necrosis factor alpha (TNFalpha) display reduced anxiety-related behavior.;We show that even genetically normal (wild type) mice raised by 5-HT 1AR deficient mothers demonstrate increased anxiety-related behavior in highly stressful environments and increased stress reactivity. However, increased anxiety in moderately stressful situations is due purely to genetic factors. Additionally, we use postnatal and embryonic cross-fostering to distinguish prenatal and postnatal maternal effects on stress-related behaviors. The reduced anxiety-related behaviors in the TNFalpha knockout (KO) mouse are also maternal in origin, due specifically to the complete absence of maternal TNFalpha (Zupan 2009).;We find that these mouse lines show alterations in the development of the ventral hippocampus, a brain area implicated in anxiety. Offspring of 5-HT1AR deficient mothers have increased granule cell layer volume and delayed maturation of granule cells in the first postnatal week, whereas offspring of TNFalpha KO mothers display increased proliferation of precursor cells in the dentate gyrus at the end of the second postnatal week, and increased ectopic neurogenesis in the hilus. We argue that these changes in postnatal hippocampal development contribute to the specific alterations of anxiety-related behavior in these mice.