Short-term maternal oxytocin administration may protect against poor outcomes of adverse childhood experiences in the offspring

Adverse childhood experiences (ACEs), such as early-life adverse events experienced by the mother and fetus during pregnancy (e.g. physical harm or chronic stress) or at early postnatal time points (such as maternal neglect or maternal separation), are major risk factors for future behavioral impairments, including anxiety, heightened pain sensitivity, social impairment, and depression during adolescence and adulthood [[1], [2], [3], [4]]. The long-lasting effects of these adverse experiences are thought to be partially mediated via modulation of the hypothalamic-pituitary-adrenal (HPA) axis [[5], [6], [7]]. HPA axis dysregulation, in turn, drives epigenetic alterations such as DNA methylation and histone modifications in the offspring's brain, leading to altered gene expression and ultimately impaired neuronal function and a high risk for neuropsychiatric disorders [[8], [9], [10], [11]].

Multiple lines of evidence suggest that ACE prevalence is high among adolescents and is more prevalent among certain demographic groups [12,13], hence placing a significant burden on society despite social support and trauma-informed therapy. Therefore, there is a need for therapeutics that will allow early intervention to minimize the potential lifelong effects of ACE. Such therapeutics should be implementable and safe for post-partum mothers and their babies.

In this issue of Neurotherapeutics, Harris et al. [14] explored the exciting possibility that short-term systemic administration of oxytocin to the dams may reduce ACE-induced behavioral abnormalities and aberrant gene expression in the hippocampus and the somatosensory cortex. They used a unique two-hit model of ACE in rats. The first hit was a mild traumatic brain injury, followed by non-fatal strangulation of the anesthetized pregnant rat. This part of the model aims to mimic the physical aspects of intimate partner violence, which is a common adverse experience for the mother and the fetus. The second hit was a daily 4-h maternal separation between postnatal days 2–11. This part of the model was used to mimic postnatal early-life stress. Each of these ‘hits’ was explored separately first by the researchers [15,16], and combining them allowed for modeling the experience of multiple ACEs, a common phenomenon known to significantly increase the risk for later life neuropsychiatric disorders, including anxiety and depression [17,18].

Next, the authors treated the rat dams with oxytocin for three consecutive days during postnatal days 14–16 and performed a comprehensive battery of behavioral tests, brain gene expression, oxytocin and CGRP serum levels, and telomere length. Maternal oxytocin increased the time dams spent grooming and nursing their pups. The ACE model had adverse effects on several behavioral domains, including anxiety- and depression-like behaviors, social impairments, and increased planar excision-induced nociception. Maternal oxytocin successfully mitigated some of these behavioral alterations, including the hypersensitivity to pain and the social impairments. Notably, while offspring of oxytocin-treated dams showed an expected slower weight gain, as oxytocin is a known anorexigenic, this effect was transient. This encouraging finding suggests that short-term maternal oxytocin administration is beneficial for the offspring's behavioral outcomes after ACE and does not cause growth retardation.

The ACE model also reduced offspring serum oxytocin levels and gene expression levels in the hippocampus and the somatosensory cortex of several genes with known roles in early life stress and epigenetic modulation, such as BDNF, DNMT3a, and MeCP2, among others. Maternal oxytocin also normalized the gene expression patterns, albeit some of these effects were sex- and planar surgery-dependent.

The authors should be commended for studying male and female offspring, as some effects were more pronounced in males while others were more pronounced in females, highlighting the need to include both males and females in ACE, stress, and pain-related studies [19,20]. The current study, however, did not explore the potential mechanism(s) by which short-period oxytocin administration to dams affects the offspring's behavior and brain gene expression. Poor maternal care has been associated with low serum oxytocin levels in dam mice [21] and with reduced oxytocin receptor levels across several brain regions in rats [22]. Additionally, acute and chronic stress can impair oxt (the Oxytocin/Neurophysin I Prepropeptide) and oxtr (the oxytocin receptor gene) DNA methylation levels [[23], [24], [25], [26]], potentially leading to increased anxiety, depression, and social impairment [27]. In the current study, ACE increased Dnmt3a and Mecp2 levels, and maternal oxytocin administration normalized their expression levels (mostly in males). Elevated levels of Dnmt3a and Mecp2 are likely to cause hypermethylation of the oxtr promoter to reduce its expression, alongside effects on the expression of many other relevant genes. Alternatively, this reduced oxytocin receptor activity can exert a downstream effect on Dnmt3a and Mecp2 as well as on neuronal activity and neuroplasticity-related gene expression (BDNF, Oxtr, ER alpha, 5HT1A, 5HT2A, GR, and more). These two plausible explanations can be examined by pharmacologically or genetically manipulating Dnmt3a and Mecp2 in the model and then inspecting DNA methylation levels and gene expression of the other affected genes after oxytocin treatment. If inhibiting Dnmt3a and Mecp2 would compromise the effects of oxytocin administration and alter DNA methylation levels in the other gene promoters, this will suggest that oxytocin exerts its impact on gene expression through the regulation of DNA methylation. If, on the other hand, oxytocin would affect gene expression despite Dnmt3a and Mecp2 inhibition or deletion, this would imply a more direct effect of oxytocin on gene expression in this ACE model.

It is also essential to consider that the elevated serum oxytocin levels in the offspring can originate from either direct transmission from the dam to the offspring via lactation, or it can be a result of the increased grooming and nursing provided by the oxytocin-treated dams [22,28]. It is also likely that these two possibilities are true. Oxytocin administration directly to the pups may help solve this question in the future.

Overall, short-term oxytocin administration to mothers who experience ACE might become a potentially beneficial and safe treatment to reduce the risk of future neurobehavioral and neuropsychiatric disorders for their offspring. However, further exploration of the underlying mechanisms and potential side effects is needed.

Author contribution

EL decided on the main points of the Commentary and wrote the manuscript.

Declaration of competing interest

The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Research in the lab of EL is funded by a grant from the Binational Israel-US Science Foundation (grant number: #2021123).