Injection of oxytocin into paraventricular nucleus reverses depressive-like behaviors in the postpartum depression rat model

Wang, Tong; Shi, Cuige; Li, Xiaoxiao; Zhang, Pan; Liu, Bo; Wang, Hao; Wang, Yongjun; Yang, Yutao; Wu, Yan; Li, Hui; Xu, Zhi‐Qing David

doi:10.1016/j.bbr.2017.09.012

Cited by 56 publications

(42 citation statements)

References 42 publications

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“…Caldwell et al also found increased OTimmunoreactivity in the SON of postpartum female rats, which differs from our findings using the HSP model; this suggests that while OT levels in the PVH and SON are both dynamic during the peripartum period, only PVH OT levels are likely to be mediated by estrogen levels. Of interest, a recent study that used a gestational stress model of postpartum depression found 20 that postpartum rats who had undergone restraint stress during pregnancy had decreased OT immunoreactivity and OT mRNA expression in the PVH (37). On the surface, this conflicts with our finding that OT immunoreactivity and OT mRNA levels are increased following estrogen withdrawal; however, the gestational stress study only compared postpartum females with and without gestational stress, so it is unclear whether postpartum OT levels are higher or lower relative to pregnant, cycling, or ovariectomized females.…”

Section: Discussionmentioning

confidence: 99%

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

Hedges

Heaton

Amaral

et al. 2020

Preprint

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Background: 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. Most studies examining the effect of estrogen withdrawal on the brain have focused solely on the hippocampus. Methods: We 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this species.Ovariectomized females were given daily injections to approximate hormone levels during gestation and then withdrawn from estrogen to simulate postpartum estrogen withdrawal.Subjects were tested for behavioral assays of anxiety and anhedonia during estrogen withdrawal.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.Results: Estrogen-withdrawn females had increased anxiety-like behaviors in the elevated plus and open field, but did not differ from controls in sucrose preference. Furthermore, estrogenwithdrawn 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. Conclusions: Estrogen 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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Section: Discussionmentioning

confidence: 99%

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

Hedges

Heaton

Amaral

et al. 2020

Preprint

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“…Gestating females subjected to 2-hour restraint stress and injected with 20 ng or 5 ng OT bilaterally into PVN for 5 days did not differ in anxiety levels in the OF relative to controls, even though they exhibited less depressive-like behavior (Wang et al, 2018). Similarly, on day 7 of ICV chronic OT (10 ng/hr) administration, no significant differences in EPM behavior were detected between groups of male rats (Havranek et al, 2015).…”

Section: The Role Of Oxytocin In the Regulation Of Anxietymentioning

confidence: 93%

Oxytocin facilitates adaptive fear and attenuates anxiety responses in animal models and human studies—potential interaction with the corticotropin-releasing factor (CRF) system in the bed nucleus of the stria terminalis (BNST)

Janeček

Dabrowska

2018

Cell Tissue Res

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Despite its relatively well-understood role as a reproductive and pro-social peptide, oxytocin (OT) tells a more convoluted story in terms of its modulation of fear and anxiety. This nuanced story has been obscured by a great deal of research into the therapeutic applications of exogenous OT, driving more than 400 ongoing clinical trials. Drawing from animal models and human studies, we review the complex evidence concerning OT’s role in fear learning and anxiety, clarifying the existing confusion about modulation of fear versus anxiety. We discuss animal models and human studies demonstrating the prevailing role of OT in strengthening fear memory to a discrete signal or cue, which allows accurate and rapid threat detection that facilitates survival. We also review ostensibly contrasting behavioral studies that nonetheless provide compelling evidence of OT attenuating sustained contextual fear and anxiety-like behavior, arguing that these OT effects on the modulation of fear vs. anxiety are not mutually exclusive. To disambiguate how endogenous OT modulates fear and anxiety, an understudied area compared to exogenous OT, we survey behavioral studies utilizing OT receptor (OTR) antagonists. Based on emerging evidence about the role of OTR in rat dorsolateral bed nucleus of stria terminalis (BNST) and elsewhere, we postulate that OT plays a critical role in facilitating accurate discrimination between stimuli representing threat and safety. Supported by human studies, we demonstrate that OT uniquely facilitates adaptive fear but reduces maladaptive anxiety. Furthermore, we show that the effects of OT are primarily observed in conditions of novelty or elevated stress level. Last, we explore the limited literature on endogenous OT and its interaction with corticotropin-releasing factor (CRF) with a special emphasis on the dorsolateral BNST, which may hold the key to the neurobiology of phasic fear and sustained anxiety.

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“…Rats in PPD_E group were tested 2 h after the injection. The FST was carried out on rats as described in our earlier study ( 18 ), with slight modifications. Briefly, rats were individually placed in a transparent glass cylinder (64 cm height and 22 cm diameter) filled with tap water with depth of 30 cm at 25 ± 2°C.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of GALR1 in PFC Alleviates Depressive-Like Behaviors in Postpartum Depression Rat Model by Upregulating CREB-BNDF and 5-HT Levels

Wang

Shi³

et al. 2018

Front. Psychiatry

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Estrogen (E2) withdrawal is a core pathology mechanism for postpartum depression (PPD). Galanin (GAL), an estrogen-inducible neuropeptide has also been reported to be associated with depression. However, it still remains unclear which GAL receptors (GALRs) are involved in PPD pathologic process. In the present study, we discovered that the expression of GALR1, rather than GALR2/3, was upregulated with a region-specific pattern in the prefrontal cortex (PFC) of E2 withdrawal induced PPD model rats. Meanwhile, c-fos was also upregulated only in PFC in the same animal model. Injection of GALR1-siRNA into the bilateral PFC ameliorated depressive-like behavior of PPD rats, suggesting that the upregulation of GALR1 in PFC is involved in PPD. Moreover, Western Blot and HPLC assays demonstrated that the downregulation of CREB-BDNF signaling and 5-HT levels in the PFC of PPD rats were reversed after GALR1-siRNA injection. These comprehensive results suggest that the knock down of GALR1 in PFC alleviates depressive-like behaviors and reverse downregulation of CREB-BDNF and 5-HT levels in PPD rat model.HIGHLIGHTS Expression level of GALR1 mRNA was significantly increased in PFC of estrogen withdraw-induced PPD rats.Injecting GALR1-siRNA into PFC alleviated depressive-like behavior and reversed the decrease of 5-HT level and CREB/BDNF signaling in PFC of PPD rats.

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Injection of oxytocin into paraventricular nucleus reverses depressive-like behaviors in the postpartum depression rat model

Cited by 56 publications

References 42 publications

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

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

Oxytocin facilitates adaptive fear and attenuates anxiety responses in animal models and human studies—potential interaction with the corticotropin-releasing factor (CRF) system in the bed nucleus of the stria terminalis (BNST)

Inhibition of GALR1 in PFC Alleviates Depressive-Like Behaviors in Postpartum Depression Rat Model by Upregulating CREB-BNDF and 5-HT Levels

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