Estrogen withdrawal alters oxytocin signaling in the paraventricular hypothalamus and dorsal raphe nucleus to increase postpartum anxiety

Hedges, V. L.; Heaton, E. C.; Amaral, C.; Benedetto, L. E.; Bodie, C. L.; D'Antonio, B. I.; Davila Portillo, D. R.; Lee, R. H.; Levine, M. T.; O'Sullivan, E. C.; Pisch, N. P.; Taveras, S.; Wild, H. R.; Ross, A. P.; Albers, H. E.; Been, L. E.

doi:10.1101/2020.06.16.154492

bioRxiv · 10.1101/2020.06.16.154492

Estrogen withdrawal alters oxytocin signaling in the paraventricular hypothalamus and dorsal raphe nucleus to increase postpartum anxiety

Hedges, V. L.·Heaton, E. C.·Amaral, C.·Benedetto, L. E.·Bodie, C. L.·D'Antonio, B. I.·Davila Portillo, D. R.·Lee, R. H.·Levine, M. T.·O'Sullivan, E. C.·Pisch, N. P.·Taveras, S.·Wild, H. R.·Ross, A. P.·Albers, H. E.·Been, L. E.

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Abstract

BackgroundEstrogen increases dramatically during pregnancy, but quickly drops below pre-pregnancy levels at birth and remains suppressed during the postpartum period. Clinical and rodent work suggests that this postpartum drop in estrogen results in an "estrogen withdrawal" state that is related to changes in affect, mood, and behavior. Most studies examining the effect of estrogen withdrawal on the brain have focused solely on the hippocampus. MethodsWe used a hormone-simulated pseudopregnancy model in Syrian hamsters, a first for this species. Ovariectomized females were given daily injections to approximate hormone levels during gestation and then withdrawn from estrogen to simulate postpartum estrogen withdrawal. Subjects were tested for behavioral assays of anxiety and anhedonia during estrogen withdrawal. Following sacrifice, neuroplasticity in oxytocin-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) and its efferent targets was measured. ResultsEstrogen-withdrawn females had increased anxiety-like behaviors in the elevated plus and open field, but did not differ from controls in sucrose preference. Furthermore, estrogen-withdrawn females had more oxytocin-immunoreactive cells and oxytocin mRNA in the PVH, as well as an increase in oxytocin receptor density in the dorsal raphe nucleus (DRN). Finally, blocking oxytocin receptors in the DRN during estrogen withdrawal prevented the high-anxiety behavioral phenotype in estrogen-withdrawn females. ConclusionsEstrogen withdrawal alters oxytocin signaling in the PVH and DRN to increase anxiety-like behavior during the postpartum period. More broadly, these experiments suggest Syrian hamsters as a novel organism in which to model the effects of postpartum estrogen withdrawal on the brain and anxiety-like behavior.

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Hedges, V. L., Heaton, E. C., Amaral, C., Benedetto, L. E., Bodie, C. L., D'Antonio, B. I., Davila Portillo, D. R., Lee, R. H., Levine, M. T., O'Sullivan, E. C., Pisch, N. P., Taveras, S., Wild, H. R., Ross, A. P., Albers, H. E., Been, L. E.. 2020-06-17. Estrogen withdrawal alters oxytocin signaling in the paraventricular hypothalamus and dorsal raphe nucleus to increase postpartum anxiety. https://doi.org/10.1101/2020.06.16.154492

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