The promotion of parental behavior by the neurosteroid allopregnanediol - Summary Around 15% of women suffer from postpartum depression, which negatively impacts their motivation to care for their infants. Beyond postpartum depression, more than 600,000 children suffer from parental abuse or neglect (largely by parents themselves) in the United States, every year. Given how important parental care is to child development, it is thus critical to understand what shapes the motivation to care for young. Yet, the molecular and cellular mechanisms that contribute to interindividual differences in parental care are largely unknown. Here, we propose to characterize the mechanisms of action of the neurosteroid Allodiol, which promotes parental behavior in mice and is nearly identical to allopregnanolone, the only drug approved to treat postpartum depression in humans. Variation in parental behavior between males and females, and within individuals across their life, is partly due to differences in levels of steroid hormones such as progesterone and estradiol. However, empirical knowledge about the effects of these hormones is largely restricted to two species of murid rodents: house mice and brown rats. Critically, males of these promiscuous species display little to no parental care, making it difficult to study the full spectrum of parental care. To expand the investigation of the hormonal modulation of parental care, we turned to mice of the genus Peromyscus. We have shown how this genus contains a pair of sister species that are genetically similar but behaviorally divergent: the deer mouse is promiscuous and only the mother shows parental care, whereas the oldfield mouse is monogamous and both mother and father show robust parental care, as is typical in monogamous species. Altogether, the extreme interspecific differences in behavior among these closely related Peromyscus species, coupled to the availability of molecular tools provide an extraordinary opportunity to discover novel aspects of parental behavior biology that have remained obscure as a result of the focus on the two classic laboratory rodents. We recently discovered that the adrenal cortex of the oldfield mice is 8× larger than that of deer mice; that it contains a cell type that is not present in deer mice; that this cell type produces the poorly-studied steroid hormone 20⍺-hydroxyprogesterone (20⍺-OHP) and that plasma 20⍺-OHP levels are much higher in oldfield mice. We found that 20⍺-OHP is converted in the brain into allopregnanediol (Allodiol), and that a single dose of Allodiol is enough to induce parental behavior within just one hour. Both 20⍺-OHP and Allodiol are weak ligands of the progesterone receptor. However, our electrophysiology experiments suggest that Allodiol, but not 20⍺-OHP, functionally antagonizes extrasynaptic GABAA receptors containing the δ subunit (δGABAAR). These results suggest that Allodiol is a neurosteroid metabolite of 20⍺-OHP, active both on parental behavior and on the physiology of neurons. Here, we propose to follow up on these intriguing findings to discover where and how Allodiol acts in the brain to modulate parental care.
