Effects of Neonatal Treatment with Valproic Acid on Vasopressin Immunoreactivity and Olfactory Behaviour in Mice

Abstract

Recent findings demonstrate that epigenetic modifications are required for the sexual differentiation of the brain. For example, neonatal administration of the histone deacetylase inhibitor, valproic acid, blocks masculinisation of cell number in the principal nucleus of the bed nucleus of the stria terminalis (BNST). In the present study, we examined the effects of valproic acid on neurochemistry and behaviour, focusing on traits that are sexually dimorphic and linked to the BNST. Newborn mice were treated with saline or valproic acid and the effect on vasopressin immunoreactivity and olfactory preference behaviour was examined in adulthood. As expected, males had more vasopressin immunoreactive fibres than females in the lateral septum and medial dorsal thalamus, which are two projection sites of BNST vasopressin neurones. Neonatal valproic acid increased vasopressin fibre density specifically in females in the lateral septum, thereby reducing the sex difference, and increased vasopressin fibres in both sexes in the medial dorsal thalamus. The effects were not specific to BNST vasopressin projections, however, because valproic acid also significantly increased vasopressin immunoreactivity in the anterior hypothalamic area in both sexes. Subtle sex-specific effects of neonatal valproic acid treatment were observed on olfactory behaviour. As predicted, males showed a preference for investigating female-soiled bedding, whereas females showed a preference for male-soiled bedding. Valproic acid did not significantly alter olfactory preference, per se, although it increased the number of visits females made to female-soiled bedding and the overall time females spent investigating soiled versus clean bedding. Taken together, these results suggest that a transient disruption of histone deacetylation at birth does not have generalised effects on sexual differentiation, although it does produce lasting effects on brain neurochemistry and behaviour.