Oxytocin receptor gene loss influences expression of the oxytocin gene in C57BL/6J mice in a sex‐ and age‐dependent manner

Dec 18, 2019Journal of neuroendocrinology

Loss of oxytocin receptor gene changes oxytocin gene activity in mice depending on sex and age

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Abstract

By postnatal day 8, OXTR KO mice show significantly decreased Oxt mRNA expression in the hypothalamus compared to wild-type littermates.

Oxt mRNA levels in OXTR KO mice were similar to wild-type littermates from postnatal day 0 to day 6.
By postnatal day 14, OXTR KO mice exhibited significantly decreased Oxt mRNA expression in the paraventricular nucleus, but not in the supraoptic nucleus, compared to wild-type mice.
In adulthood, male OXTR KO mice displayed reduced Oxt expression in the paraventricular nucleus compared to male wild-type mice, whereas both male and female OXTR KO adults had increased Oxt levels in the supraoptic nucleus.
More OXT-immunoreactive cells were observed in the paraventricular nucleus of OXTR KO mice, but they had significantly fewer c-Fos immunoreactive cells.
There were no differences in immunoreactivity for OXT or c-Fos activity in the supraoptic nucleus at postnatal day 14.

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Parental care and sensory stimulation are critical environmental factors that influence oxytocin (OXT) and its receptor (OXTR). Because developmental Oxt mRNA expression is enhanced by sensory-rich early life experience and reduced by sensory deprivation, we predicted that compared to wild-type (WT) littermates, mice with congenital loss of OXTR (OXTR KO), as a genetically induced deprivation, would show impaired Oxt mRNA expression in the offspring hypothalamus during development. Oxt mRNA levels of male and female OXTR KO mice were not different from WT littermates from postnatal day (P)0 to P6, although, by P8, OXTR KO showed significantly decreased Oxt mRNA expression in the hypothalamus compared to WT littermates. At P14, male and female OXTR KO mice had significantly decreased Oxt mRNA expression specifically in the paraventricular nucleus (PVN), but not the supraoptic nucleus (SON), compared to WT littermates. We investigated whether this effect persisted in adulthood (P90) and found a significant genotype by sex interaction where male OXTR KO mice displayed a reduction in Oxt expression specific to the PVN compared to male WT littermates. By contrast, male and female OXTR KO adults had increased Oxt mRNA levels in the SON. These findings suggest that OXTR plays a role in developmental Oxt mRNA expression with sex by genotype interactions apparent at adulthood. We then measured OXT and neural activation in the PVN and SON at P14. We observed more OXT-immunoreactive cells in the PVN of OXTR KO mice but significantly fewer c-Fos immunoreactive cells. There were no genotype differences in immunoreactivity for OXT and no c-Fos activity in the SON at P14. Combined, these data suggest that OXTR WT P14 mice have more PVN activity and are more likely to release OXT than OXTR KO mice. Future experiments are warranted to understand which OXTR-expressing neural circuits modulate the development of the PVN oxytocin system.

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Oxytocin receptor gene loss influences expression of the oxytocin gene in C57BL/6J mice in a sex‐ and age‐dependent manner

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