Dorsal raphe oxytocin receptors regulate the neurobehavioral consequences of social touch

Grieb, Zachary A.; Ford, Emma G.; Manfredsson, Fredric P.; Lonstein, Joseph S.

doi:10.1101/850271

Cited by 3 publications

(6 citation statements)

References 71 publications

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“…Our finding that OTR autoradiographic binding is increased in the DRN of estrogen withdrawn females is also supported by recent data from naturally-parturient females showing that OTR autoradiographic binding and OT-ir fibers are increased in the DRN of postpartum rats (38). What's more, viral-mediated knockdown of OTR mRNA in the DRN of postpartum rats decreases anxiety-like behavior in the elevated plus (38), mirroring our finding that pharmacological blockade of OTRs in the DRN decreased anxiety-like behavior in the elevated plus during estrogen withdrawal. When coupled with previous data, this suggests that 1) oxytocin in the DRN has anxiogenic effects on behavior and 2) these effects may depend on postpartum estrogen withdrawal.…”

Section: Discussionsupporting

confidence: 91%

“…These dopaminergic DRN cells have been associated with arousal (42), and project to nuclei in the extended amygdala that are known to regulate anxiety (43,44). Recent work by Grieb et al (2019) demonstrates that approximately one third of these dopamine cells express OTRs, and the number and percentage of dopamine cells expressing OTRs were higher in postpartum rats than in diestrus virgin rats (38). In addition to dopaminergic cells, the raphe nuclei, including the DRN, are the primary source of forebrain-projecting serotonin in the brain (45).…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 91%

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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“…Such oxytocin‐induced changes in DR serotonin and dopamine release could be critical for the periparturitional transition to motherhood. In fact, we have recent data showing that shRNA‐mediated knockdown of OTRs in the DR beginning in pregnancy disrupts the later display of most postpartum caregiving behaviors and increases mothers' behavioural despair 92 …”

Section: Discussionmentioning

confidence: 99%

“…In fact, we have recent data showing that shRNA-mediated knockdown of OTRs in the DR beginning in pregnancy disrupts the later display of most postpartum caregiving behaviors and increases mothers' behavioural despair. 92…”

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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“…Most research investigating how oxytocin influences maternal nurturance relates to oxytocin's upregulation by oestradiol, a well-known driver of postpartum caregiving. Indeed, estrogen-dependent oxytocin signalling has often been positively linked with maternal motivation [6,7], caregiving behaviours toward pups [8,9], as well as low postpartum anxiety- [10] and depressive-like [11,12] behaviours. However, there has been considerably less work examining downstream neurochemical systems through which oxytocin leads to these behavioural effects.…”

Section: Introductionmentioning

confidence: 99%

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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Dorsal raphe oxytocin receptors regulate the neurobehavioral consequences of social touch

Cited by 3 publications

References 71 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 receptor expression in the midbrain dorsal raphe is dynamic across female reproduction in rats

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

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