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

Hedges, Valerie L.; Heaton, Elizabeth C.; Amaral, Claudia; Benedetto, Lauren E.; Bodie, Clio L.; D’Antonio, Breanna I.; Portillo, Dayana R. Davila; Lee, Rachel H.; Levine, Michael; O’Sullivan, Emily C.; Pisch, Natalie P.; Taveras, Shantal; Wild, Hannah; Grieb, Zachary A.; Ross, Amy P.; Albers, H. Elliott; Been, Laura E.

doi:10.1016/j.biopsych.2020.11.016

Cited by 33 publications

(24 citation statements)

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“…While sex differences in circulating oxytocin are not well established, there is evidence showing that intranasal (IN) oxytocin induces divergent, sex-specific behaviors and fMRI patterns in humans performing socio-emotional [ 170 , 171 ] and social reward [ 172 ] tasks. These observations, together with animal studies showing that estrogens [ 173 , 174 ] and androgens [ 175 , 176 ] can modulate PVN oxytocin neuron mRNA expression, support the hypothesis of sex differences in endogenous oxytocin status. Refinement of measurement techniques and adjustment for confounding factors affecting oxytocin physiology are needed to further research this question.…”

Section: Observational Studies In Humans-relation Of Oxytocin To Food Intake Weight Status and Metabolismsupporting

confidence: 65%

The Effects of Oxytocin on Appetite Regulation, Food Intake and Metabolism in Humans

Kerem

Lawson

2021

IJMS

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The hypothalamic peptide oxytocin and its receptor are involved in a range of physiological processes, including parturition, lactation, cell growth, wound healing, and social behavior. More recently, increasing evidence has established the effects of oxytocin on food intake, energy expenditure, and peripheral metabolism. In this review, we provide a comprehensive description of the central oxytocinergic system in which oxytocin acts to shape eating behavior and metabolism. Next, we discuss the peripheral beneficial effects oxytocin exerts on key metabolic organs, including suppression of visceral adipose tissue inflammation, skeletal muscle regeneration, and bone tissue mineralization. A brief summary of oxytocin actions learned from animal models is presented, showing that weight loss induced by chronic oxytocin treatment is related not only to its anorexigenic effects, but also to the resulting increase in energy expenditure and lipolysis. Following an in-depth discussion on the technical challenges related to endogenous oxytocin measurements in humans, we synthesize data related to the association between endogenous oxytocin levels, weight status, metabolic syndrome, and bone health. We then review clinical trials showing that in humans, acute oxytocin administration reduces food intake, attenuates fMRI activation of food motivation brain areas, and increases activation of self-control brain regions. Further strengthening the role of oxytocin in appetite regulation, we review conditions of hypothalamic insult and certain genetic pathologies associated with oxytocin depletion that present with hyperphagia, extreme weight gain, and poor metabolic profile. Intranasal oxytocin is currently being evaluated in human clinical trials to learn whether oxytocin-based therapeutics can be used to treat obesity and its associated sequela. At the end of this review, we address the fundamental challenges that remain in translating this line of research to clinical care.

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Section: Observational Studies In Humans-relation Of Oxytocin To Food Intake Weight Status and Metabolismsupporting

confidence: 65%

The Effects of Oxytocin on Appetite Regulation, Food Intake and Metabolism in Humans

Kerem

Lawson

2021

IJMS

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“…Our studies also showed that consistent with a generally anxiogenic role of serotonin [104–106], OTR knockdown in the DR further decreases postpartum anxiety-like behaviour in an elevated plus maze (figure 6; [147]). An anxiogenic role of DR OTRs was also recently demonstrated in pseudopregnant female Syrian hamsters [148], suggesting a conserved anxiogenic role of DR OTRs across rodent species. Finally, we found that OTR knockdown in the DR increases behavioural despair as measured by more time spent floating in a forced-swim test (figure 6; [147]).…”

Section: Oxytocin–serotonin Interactions In Maternal Nursing Aggressi...mentioning

confidence: 81%

Oxytocin interactions with central dopamine and serotonin systems regulate different components of motherhood

Grieb

Lonstein

2022

Phil. Trans. R. Soc. B

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The role of oxytocin in maternal caregiving and other postpartum behaviours has been studied for more than five decades. How oxytocin interacts with other neurochemical systems to enact these behavioural changes, however, is only slowly being elucidated. The best-studied oxytocin–neurotransmitter interaction is with the mesolimbic dopamine system, and this interaction is essential for maternal motivation and active caregiving behaviours such as retrieval of pups. Considerably less attention has been dedicated to investigating how oxytocin interacts with central serotonin to influence postpartum behaviour. Recently, it has become clear that while oxytocin–dopamine interactions regulate the motivational and pup-approach aspects of maternal caregiving behaviours, oxytocin–serotonin interactions appear to regulate nearly all other aspects including postpartum nursing, aggression, anxiety-like behaviour and stress coping strategy. Collectively, oxytocin's interactions with central dopamine and serotonin systems are thus critical for the entire suite of behavioural adaptations exhibited in the postpartum period, and these sites of interaction are potential pharmacological targets for where oxytocin could help to ameliorate deficits in maternal caregiving and poor postpartum mental health. This article is part of the theme issue ‘Interplays between oxytocin and other neuromodulators in shaping complex social behaviours’.

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“…Of note, oestrogen receptor α is present on both serotonergic and non‐serotonergic neurones in the DR, 31,32,35 suggesting that both populations of cells could contribute to the high peripartum OTR binding in the rostral DR. Furthermore, very recent work has found that chronic treatment with oestrogen followed by its rapid withdrawal (reminiscent of the natural pattern of this hormone at the end of pregnancy) increases OTR binding in the ovariectomised female hamster DR 62 . Given that the peripartum spike in circulating oestradiol in rats begins to fall 3‐6 hours after parturition, 63 the high OTR binding seen in the parturient females in the present study is likely the result of the rising then dropping oestrogens at the time we euthanised our subjects (i.e., within 3 hours after birth of the last pup).…”

Section: Discussionmentioning

confidence: 99%

Oxytocin receptor expression in the midbrain dorsal raphe is dynamic across female reproduction in rats

Grieb

Lonstein

2021

J Neuroendocrinology

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Central oxytocin receptor (OTR) expression is extremely sensitive to circulating steroid hormones and OTRs influence many of the neurobehavioural adaptations associated with female reproduction (e.g., postpartum caregiving, aggression, cognition, affective responses). Changes in central OTR expression across female reproduction have often been studied, but almost all of such research has focused on the forebrain, ignoring hormone-sensitive midbrain sites such as the serotonergic dorsal raphe (DR) that are also critical for postpartum behaviours. To investigate the effects of female reproductive state on OTRs in the DR, we first used autoradiography to examine OTR binding across four female reproductive states in laboratory rats: dioestrous virgin, pregnancy day 10, the day of parturition and postpartum day 7. OTR binding in the rostral DR (but not other DR subregions) was approximately 250% higher in parturient rats compared to dioestrous virgins and dropped back down to virgin levels by postpartum day 7. Given the chemical heterogeneity of the DR, we then examined OTR expression in the three most abundant neuronal phenotypes of the DR (i.e., serotonin, GABA and dopamine) in dioestrous virgins and recently parturient females. Using dual-label immunohistochemistry and in situ hybridisation, we found that twice as many dopaminergic cells in the parturient rostral DR contained OTR immunoreactivity compared to that found in virgins. On the other hand, mothers had fewer rostral DR GABAergic cells expressing OTRs than did virgins. OTR expression in serotonin cells did not differ between the two groups. Overall, these results suggest that the rostral subregion of the midbrain DR is uniquely sensitive to oxytocin around the time of parturition, with subpopulations of cells that become more sensitive (i.e., dopamine), less sensitive (i.e., GABA) and show no change (i.e., serotonin) to this neuropeptide. This dynamic OTR signalling in the female DR may help drive the numerous behavioural changes across female reproduction that are necessary for successful motherhood.

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

Cited by 33 publications

References 50 publications

The Effects of Oxytocin on Appetite Regulation, Food Intake and Metabolism in Humans

The Effects of Oxytocin on Appetite Regulation, Food Intake and Metabolism in Humans

Oxytocin interactions with central dopamine and serotonin systems regulate different components of motherhood

Oxytocin receptor expression in the midbrain dorsal raphe is dynamic across female reproduction in rats

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