Region‐specific sex modulation of central oxytocin receptor by gut microbiota: An ontogenic study

Abstract

Oxytocin (OT) is a developmentally important neuropeptide recognized to play a dominant role in social functioning and stress‐related behaviors, in a sex‐dependent manner. Nonetheless, the underlining factors driving OT and OT receptor (OTR) early brain development remain unclear. Recent evidence highlight the critical influence of gut microbiota and its bidirectional interaction with the brain on neurodevelopment via the gut microbiota‐brain axis. Therefore, we aimed to determine the impact of gut microbiota on the OTR system of the rat brain at different developmental stages in a pilot study. Quantitative OTR [125I]‐OVTA autoradiographic binding was carried out in the forebrain of male and female conventional (CON) and germ‐free (GF) rats at postnatal days (PND) 8, 22, and 116–150. OTR binding was also assessed in the eyes of PND 1 and PND 4 GF female rats. Significant “microbiota × sex × region” interaction and age‐dependent effects on OTR binding were demonstrated. Microbiota status influenced OTR levels in males but not females with higher levels of OTR observed in GF versus CON rats in the cingulate, prelimbic, and lateral/medial/ventral orbital cortex, and septum across all age groups, while sex differences were observed in GF, but not in CON rats. Interestingly, OTRs present in the eyes of CON rats were abolished in GF rats. This is the first study to uncover a sex‐specific role of gut microbiota on the central OTR system, which may have implications in understanding the developmental neuroadaptations critical for behavioral regulation and the etiology of certain neurodevelopmental disorders.

Sex‐dependent impact of microbiota status on cerebral μ‐opioid receptor density in fischer rats

“…The microbiota effect on MOPr binding was restricted to male rats, and the presence of sex differences in the microbiome‐gut‐brain axis is in agreement with multiple studies (Coretti et al, 2017; Davis et al, 2017; Leclercq et al, 2017; Sylvia et al, 2017). This sex‐dependent microbiota effect is consistent with our recent findings demonstrating an identical oxytocin receptor density regulation pattern in male GF rats (Effah et al, 2021). The mechanism underlining the increased sensitivity of microbiota regulation of MOPr in males and its resistance in females remains to be elucidated.…”

“…For detailed justification of the selection of these specific age groups as well as for the selection of the GF model, rather than the antibiotic‐treated one to assess the impact of gut microbiota on MOPr ontogeny, the reader is directed to our recent publication (Effah et al, 2021) and the discussion of this manuscript.…”

Microbes, oxytocin and stress: Converging players regulating eating behavior

“…In contrast, there were no significant differences between conventional (CONV) and germ‐free (GF, animals raised without a microbiota) animals 54 . Another study, however, reported an increase of OXTR protein levels in specific cortical regions from male, but not female, GF rats 55 . To date, to the best of our knowledge, it is not known how microbial depletion affects blood Oxt levels.…”

Emerging roles for microglia and microbiota in the development of social circuits

“…Do shifts in the gut microbiome following early life insults influence these processes? Interestingly, germ-free male, but not female rats, have higher densities of OTR in the prefrontal cortex and septum as compared to conventionally housed rats ( Effah et al., 2021 ). Rodent species such as prairie voles could also prove to be incredibly useful in these investigations given that they exhibit complex social behaviors (such as pair bond formation) and that the social circuits underlying these behaviors have been well characterized in voles ( Loth and Donaldson, 2021 ; Walum and Young, 2018 ).…”