Estrogen Withdrawal Increases Postpartum Anxiety via Oxytocin Plasticity in the Paraventricular Hypothalamus and Dorsal Raphe Nucleus

Published:November 23, 2020DOI:



      Estrogen increases dramatically during pregnancy but quickly drops below prepregnancy 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. How estrogen withdrawal affects oxytocin (OT) neurocircuitry has not been examined.


      We used a hormone-simulated pseudopregnancy followed by estrogen withdrawal 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 Ovariectomized females were given daily injections to approximate hormone levels during gestation and then withdrawn from estrogen to simulate postpartum estrogen withdrawal. These hamsters were tested for behavioral assays of anxiety and anhedonia during estrogen withdrawal. Neuroplasticity in OT-producing neurons in the paraventricular nucleus of the hypothalamus and its efferent targets was measured.


      Estrogen-withdrawn females had increased anxiety-like behaviors in the elevated plus maze and open field tests but did not differ from control females in sucrose preference. Furthermore, estrogen-withdrawn females had more OT-immunoreactive cells and OT messenger RNA in the paraventricular nucleus of the hypothalamus and an increase in OT receptor density in the dorsal raphe nucleus. Finally, blocking OT receptors in the dorsal raphe nucleus during estrogen withdrawal prevented the high-anxiety behavioral phenotype in estrogen-withdrawn females.


      Estrogen withdrawal induces OT neuroplasticity in the paraventricular nucleus of the hypothalamus and dorsal raphe nucleus 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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        • Hendrick V.
        • Altshuler L.L.
        • Suri R.
        Hormonal changes in the postpartum and implications for postpartum depression.
        Psychosomatics. 1998; 39: 93-101
        • McNeilly A.S.
        Lactational control of reproduction.
        Reprod Fertil Dev. 2001; 13: 583-590
        • Bloch M.
        • Daly R.C.
        • Rubinow D.R.
        Endocrine factors in the etiology of postpartum depression.
        Compr Psychiatry. 2003; 44: 234-246
        • Sichel D.A.
        • Cohen L.S.
        • Robertson L.M.
        • Ruttenberg A.
        • Rosenbaum J.F.
        Prophylactic estrogen in recurrent postpartum affective disorder.
        Biol Psychiatry. 1995; 38: 814-818
        • Ahokas A.
        • Kaukoranta J.
        • Wahlbeck K.
        • Aito M.
        Estrogen deficiency in severe postpartum depression: Successful treatment with sublingual physiologic 17beta-estradiol: A preliminary study.
        J Clin Psychiatry. 2001; 62: 332-336
        • Gregoire A.J.
        • Kumar R.
        • Everitt B.
        • Henderson A.F.
        • Studd J.W.
        Transdermal oestrogen for treatment of severe postnatal depression.
        Lancet. 1996; 347: 930-933
        • Galea L.A.
        • Wide J.K.
        • Barr A.M.
        Estradiol alleviates depressive-like symptoms in a novel animal model of post-partum depression.
        Behav Brain Res. 2001; 122: 1-9
        • Green A.D.
        • Barr A.M.
        • Galea L.A.
        Role of estradiol withdrawal in ‘anhedonic’ sucrose consumption: A model of postpartum depression.
        Physiol Behav. 2009; 97: 259-265
        • Schiller C.E.
        • O’Hara M.W.
        • Rubinow D.R.
        • Johnson A.K.
        Estradiol modulates anhedonia and behavioral despair in rats and negative affect in a subgroup of women at high risk for postpartum depression.
        Physiol Behav. 2013; 119: 137-144
        • Stoffel E.C.
        • Craft R.M.
        Ovarian hormone withdrawal-induced “depression” in female rats.
        Physiol Behav. 2004; 83: 505-513
        • Suda S.
        • Segi-Nishida E.
        • Newton S.S.
        • Duman R.S.
        A postpartum model in rat: Behavioral and gene expression changes induced by ovarian steroid deprivation.
        Biol Psychiatry. 2008; 64: 311-319
        • Navarre B.M.
        • Laggart J.D.
        • Craft R.M.
        Anhedonia in postpartum rats.
        Physiol Behav. 2010; 99: 59-66
        • Baka J.
        • Csakvari E.
        • Huzian O.
        • Dobos N.
        • Siklos L.
        • Leranth C.
        • et al.
        Stress induces equivalent remodeling of hippocampal spine synapses in a simulated postpartum environment and in a female rat model of major depression.
        Neuroscience. 2017; 343: 384-397
        • Zhang Z.
        • Hong J.
        • Zhang S.
        • Zhang T.
        • Sha S.
        • Yang R.
        • et al.
        Postpartum estrogen withdrawal impairs hippocampal neurogenesis and causes depression- and anxiety-like behaviors in mice.
        Psychoneuroendocrinology. 2016; 66: 138-149
        • Yang R.
        • Zhang B.
        • Chen T.
        • Zhang S.
        • Chen L.
        Postpartum estrogen withdrawal impairs GABAergic inhibition and LTD induction in basolateral amygdala complex via down-regulation of GPR30.
        Eur Neuropsychopharmacol. 2017; 27: 759-772
        • Qin C.
        • Li J.
        • Tang K.
        The paraventricular nucleus of the hypothalamus: Development, function, and human diseases.
        Endocrinology. 2018; 159: 3458-3472
        • Brunton P.J.
        • Russell J.A.
        Endocrine induced changes in brain function during pregnancy.
        Brain Res. 2010; 1364: 198-215
        • Jurek B.
        • Neumann I.D.
        The oxytocin receptor: From intracellular signaling to behavior.
        Physiol Rev. 2018; 98: 1805-1908
        • Ross A.P.
        • McCann K.E.
        • Larkin T.E.
        • Song Z.
        • Grieb Z.A.
        • Huhman K.L.
        • Albers H.E.
        Sex-dependent effects of social isolation on the regulation of arginine-vasopressin (AVP) V1a, oxytocin (OT) and serotonin (5HT) 1a receptor binding and aggression.
        Horm Behav. 2019; 116: 104578
        • McCarthy M.M.
        Estrogen modulation of oxytocin and its relation to behavior.
        Adv Exp Med Biol. 1995; 395: 235-245
        • Rosenblatt J.S.
        • Mayer A.D.
        • Giordano A.L.
        Hormonal basis during pregnancy for the onset of maternal behavior in the rat.
        Psychoneuroendocrinology. 1988; 13: 29-46
        • Siegel H.I.
        • Rosenblatt J.S.
        Estrogen-induced maternal behavior in hysterectomized-overiectomized virgin rats.
        Physiol Behav. 1975; 14: 465-471
        • Mayer A.D.
        • Ahdieh H.B.
        • Rosenblatt J.S.
        Effects of prolonged estrogen-progesterone treatment and hypophysectomy on the stimulation of short-latency maternal behavior and aggression in female rats.
        Horm Behav. 1990; 24: 152-173
        • Siegel H.I.
        • Rosenblatt J.S.
        Hormonal and behavioral aspects of maternal care in the hamster: A review.
        Neurosci Biobehav Rev. 1980; 4: 17-26
        • Gannon R.L.
        • Lungwitz E.
        • Batista N.
        • Hester I.
        • Huntley C.
        • Peacock A.
        • et al.
        The benzodiazepine diazepam demonstrates the usefulness of Syrian hamsters as a model for anxiety testing: Evaluation of other classes of anxiolytics in comparison to diazepam.
        Behav Brain Res. 2011; 218: 8-14
        • Manning M.
        • Misicka A.
        • Olma A.
        • Bankowski K.
        • Stoev S.
        • Chini B.
        • et al.
        Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics.
        J Neuroendocrinol. 2012; 24: 609-628
        • Morin L.P.
        • Wood R.I.
        A Stereotaxic Atlas of the Golden Hamster Brain.
        Academic Press, London2001
        • Gilbert A.N.
        Postpartum and lactational estrus: A comparative analysis in rodentia.
        J Comp Psychol. 1984; 98: 232-245
        • Feigin M.B.
        • Sclafani A.
        • Sunday S.R.
        Species differences in polysaccharide and sugar taste preferences.
        Neurosci Biobehav Rev. 1987; 11: 231-240
        • National Research Council
        Nutrient Requirements of Laboratory Animals.
        4th rev ed. National Academies Press, Washington, DC1995
        • Caldwell J.D.
        • Greer E.R.
        • Johnson M.F.
        • Prange Jr., A.J.
        • Pedersen C.A.
        Oxytocin and vasopressin immunoreactivity in hypothalamic and extrahypothalamic sites in late pregnant and postpartum rats.
        Neuroendocrinology. 1987; 46: 39-47
        • Jirikowski G.F.
        • Caldwell J.D.
        • Pilgrim C.
        • Stumpf W.E.
        • Pedersen C.A.
        Changes in immunostaining for oxytocin in the forebrain of the female rat during late pregnancy, parturition and early lactation.
        Cell Tissue Res. 1989; 256: 411-417
        • Caba M.
        • Silver R.
        • González-Mariscal G.
        • Jiménez A.
        • Beyer C.
        Oxytocin and vasopressin immunoreactivity in rabbit hypothalamus during estrus, late pregnancy, and postpartum.
        Brain Res. 1996; 720: 7-16
        • Broad K.D.
        • Kendrick K.M.
        • Sirinathsinghji D.J.
        • Keverne E.B.
        Changes in oxytocin immunoreactivity and mRNA expression in the sheep brain during pregnancy, parturition and lactation and in response to oestrogen and progesterone.
        J Neuroendocrinol. 1993; 5: 435-444
        • Grieb Z.A.
        • Ford E.G.
        • Manfredsson F.P.
        • Lonstein J.S.
        Dorsal raphe oxytocin receptors regulate the neurobehavioral consequences of social touch.
        bioRxiv doi. 2019;
        • Steinman M.Q.
        • Duque-Wilckens N.
        • Trainor B.C.
        Complementary neural circuits for divergent effects of oxytocin: Social approach versus social anxiety.
        Biol Psychiatry. 2019; 85: 792-801
        • Yip S.H.
        • Romanò N.
        • Gustafson P.
        • Hodson D.J.
        • Williams E.J.
        • Kokay I.C.
        • et al.
        Elevated prolactin during pregnancy drives a phenotypic switch in mouse hypothalamic dopaminergic neurons.
        Cell Rep. 2019; 26: 1787-1799.e5
        • Burbach J.P.
        • Luckman S.M.
        • Murphy D.
        • Gainer H.
        Gene regulation in the magnocellular hypothalamo-neurohypophysial system.
        Physiol Rev. 2001; 81: 1197-1267
        • Bale T.L.
        • Dorsa D.M.
        Transcriptional regulation of the oxytocin receptor gene.
        in: Zingg H.H. Bourque C.W. Bichet D.G. Vasopressin and Oxytocin: Molecular, Cellular, and Clinical Advances. 449. Springer, Boston, MA1998: 307-315
        • Geerling J.C.
        • Shin J.W.
        • Chimenti P.C.
        • Loewy A.D.
        Paraventricular hypothalamic nucleus: Axonal projections to the brainstem.
        J Comp Neurol. 2010; 518: 1460-1499
        • Lu J.
        • Jhou T.C.
        • Saper C.B.
        Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter.
        J Neurosci. 2006; 26: 193-202
        • Hasue R.H.
        • Shammah-Lagnado S.J.
        Origin of the dopaminergic innervation of the central extended amygdala and accumbens shell: A combined retrograde tracing and immunohistochemical study in the rat.
        J Comp Neurol. 2002; 454: 15-33
        • Shin J.W.
        • Geerling J.C.
        • Loewy A.D.
        Inputs to the ventrolateral bed nucleus of the stria terminalis.
        J Comp Neurol. 2008; 511: 628-657
        • Abrams J.K.
        • Johnson P.L.
        • Hollis J.H.
        • Lowry C.A.
        Anatomic and functional topography of the dorsal raphe nucleus.
        Ann N Y Acad Sci. 2004; 1018: 46-57
        • Yoshida M.
        • Takayanagi Y.
        • Inoue K.
        • Kimura T.
        • Young L.J.
        • Onaka T.
        • Nishimori K.
        Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in mice.
        J Neurosci. 2009; 29: 2259-2271
        • Ludwig M.
        • Stern J.
        Multiple signalling modalities mediated by dendritic exocytosis of oxytocin and vasopressin.
        Philos Trans R Soc Lond B Biol Sci. 2015; 370: 20140182