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Estrogen Withdrawal Increases Postpartum Anxiety via Oxytocin Plasticity in the Paraventricular Hypothalamus and Dorsal Raphe Nucleus
Abstract
Background
Estrogen 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. How estrogen withdrawal impacts oxytocin neurocircuitry has not been examined.
Methods
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 Ovariectomized females were given daily injections to approximate hormone levels during gestation and then withdrawn from estrogen to simulate postpartum estrogen withdrawal. 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Estrogen-withdrawn females had increased anxiety-like behaviors in the elevated plus and open field, but did not differ from controls in sucrose preference. Furthermore, estrogen-withdrawn females had more oxytocin-immunoreactive cells and oxytocin mRNA in the PVH, as well as an increase in oxytocin receptor density in the dorsal raphe nucleus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oxytocin receptors in the DRN during estrogen withdrawal prevented the high-anxiety behavioral phenotype in estrogen-withdrawn females.
Conclusions
Estrogen withdrawal induces oxytocin neuroplasticity 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.
... Specifically, estrogen withdrawal following a hormone-simulated pregnancy increases immobility in the forced swim test (Green et al., 2009;Schiller et al., 2013;Stoffel and Craft, 2004), decreases sucrose preference (Green et al., 2009;Navarre et al., 2010), decreases escape performance following inescapable shock (Baka et al., 2017;Suda et al., 2008), and decreases the time spent in the open arms of an elevated plus (Suda et al., 2008) in female rats. Many of these behavioral results have been replicated in mice (Yang et al., 2017;Zhang et al., 2016) and Syrian hamsters (Hedges et al., 2021), suggesting it is a highly reproducible way to model the impact of postpartum estrogen withdrawal on behavior across multiple species. When taken together with data from females that are either pregnant or treated with pregnancy-like hormones, these data suggest that high levels of estrogen during late pregnancy may confer resilience, whereas rapid withdrawal from estrogen may confer susceptibility to disruptions in mood/affect. ...
... Like in parturient female rats, estrogen withdrawal following treatment with pregnancy-like hormones increases OTR receptor density in the DRN. What's more, pharmacological blockade of OTRs during estrogen withdrawal prevents the characteristic increase in anxiety-like behaviors in the elevated plus and open field (Hedges et al., 2021), also matching the findings in parturient female rats. Interestingly, these changes are accompanied by an increase in oxytocin immunoreactivity in the PVN, suggesting that increased OTR binding in the DRN may be a postsynaptic consequence of increased oxytocin transmission from the PVH (Hedges et al., 2021). ...
... What's more, pharmacological blockade of OTRs during estrogen withdrawal prevents the characteristic increase in anxiety-like behaviors in the elevated plus and open field (Hedges et al., 2021), also matching the findings in parturient female rats. Interestingly, these changes are accompanied by an increase in oxytocin immunoreactivity in the PVN, suggesting that increased OTR binding in the DRN may be a postsynaptic consequence of increased oxytocin transmission from the PVH (Hedges et al., 2021). ...
Major life transitions often co-occur with significant fluctuations in hormones that modulate the central nervous system. These hormones enact neuroplastic mechanisms that prepare an organism to respond to novel environmental conditions and/or previously unencountered cognitive, emotional, and/or behavioral demands. In this review, we will explore several examples of how hormones mediate neuroplastic changes in order to produce adaptive responses, particularly during transitions in life stages. First, we will explore hormonal influences on social recognition in both males and females as they transition to sexual maturity. Next, we will probe the role of hormones in mediating the transitions to motherhood and fatherhood, respectively. Finally, we will survey the long-term impact of reproductive experience on neuroplasticity in females, including potential protective effects and risk factors associated with reproductive experience in mid-life and beyond. Ultimately, a more complete understanding of how hormones influence neuroplasticity throughout the lifespan, beyond development, is necessary for understanding how individuals respond to life changes in adaptive ways.
... No data were missing. The volume retention was 39% (20). Details are presented in Table 1. ...
... Estrogen decreases rapidly after pregnancy and childbirth and remains low in women who breastfeed, during and after lactation, until menstruation returns. 20 Many women lose breast firmness after childbirth and lactation and opt for breast augmentation. The quality of transplanted fat grafts may be lower because breast augmentation during that period occurs after a low-estrogen state. ...
Background
Regarding autologous fat grafting for breast augmentation, the factors influencing volume retention are unclear. Few studies have assessed which factors, particularly patient-related variables, could affect volume retention and to what extent, without performing multivariate analysis. In this study, we performed three-dimensional breast volume measurements before and after autologous fat grafting, calculated the volume and volume retention, and investigated factors that may affect volume retention.
Methods
A total of 204 breasts that underwent autologous fat grafting by the same surgeon at our hospital between May 25 and December 25, 2021 were included. Volumetric measurements were taken preoperatively and at 1, 3, and 6 months postoperatively using a three-dimensional camera; volume retention was calculated. Linear mixed model analysis was performed to examine the effects of age, body mass index, number of total autologous fat grafting procedures, pregnancy and lactation history, smoking status, fat processing techniques (sedimentation versus centrifugation), preoperative volume, and weight change at the 3- and 6-month postoperative volume retention analyses.
Results
Using multivariate analysis, the preoperative volume was found to be a significant factor at 3 and 6 months. The preoperative volume affected fat volume retention rate by 0.004 ( P = 0.001) and 0.008 ( P = 0.011) per 10 mL at 3 and 6 months, respectively.
Conclusions
The preoperative volume likely affected fat volume retention. Specifically, a 100-mL increase in the preoperative breast volume might increase the volume retention by 4%–8%. Preoperative volume is an important confounding factor for future studies.
... A deficiency in reelin levels has been shown to increase susceptibility to the impact of chronic CORT exposure on despair-like behavior measured with the forced swim test (FST), as evidenced by studies involving heterozygous reeler mice (Lussier et al., 2011). During the post-partum period, estrogen levels decrease significantly and might contribute to the development of PPD (Hedges et al., 2021) and while estrogen can influence the reelin system and vice versa (Bender et al., 2010;Meseke et al., 2018) whether alterations in reelin occur during the critical post-partum phase and could be a vulnerability factor remains unexplored. ...
... Additionally, while prior research has shown that estrogen can influence reelin and oxytocin levels (Shughrue et al., 2002;Hedges et al., 2021) and enhances HPA axis response to stress (Isgor et al., 2003;Figueiredo et al., 2007), alterations to estrogen did not significantly *Indicates a statistically significant value. *refers to the p value, with *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. ...
Introduction
Treatment with the synaptic plasticity protein reelin has rapid antidepressant-like effects in adult corticosterone (CORT)-induced depressed rats, whether administered repeatedly or acutely. However, these effects remain unexplored in the context of post-partum depression (PPD).
Methods
This study investigated the antidepressant-like effect of a single injection of reelin in a CORT-induced model of PPD. Long-Evans female dams received either daily subcutaneous CORT (40 mg/kg) or saline injections (controls) from the post-partum day (PD) 2 to 22, and on PD22 were treated with a single intravenous reelin (3 μg) or vehicle injection.
Results
Reelin treatment fully normalized to control levels the CORT-induced increase in Forced Swim Test (FST) immobility and the decrease in reelin-positive cells in the subgranular zone of the intermediate hippocampus. It also increased the number of oxytocin-positive cells in the paraventricular nucleus (PVN), the number of reelin-positive cells in the dorsal and ventral hippocampus, and the dendritic complexity of newborn neurons in the intermediate hippocampus, causing a partial recovery compared to controls. None of these changes were associated with fluctuations in estrogen levels measured peripherally.
Discussion
This study brings new insights into the putative antidepressant-like effect of peripherally administered reelin in an animal model of PPD. Future studies should be conducted to investigate these effects on a dose–response paradigm and to further elucidate the mechanisms underlying the antidepressant-like effects of reelin.
... To understand the neural circuitry mechanisms that underlie the depressive effects specifically caused by fluctuations in reproductive hormone levels, it is critical to identify which brain structures and associated circuits are susceptible to the hormonal fluctuations and how their abnormal activity can result in depressive-like behaviors. Previous studies suggested that the hippocampus and amygdala, two structures of the limbic system that express estrogen receptors, may play a role in responding to reproductive hormone fluctuations 6,7 and that oxytocin signaling in the paraventricular hypothalamus and dorsal well as reduced pup grooming and social preference (that is, reduced sociability), consistent with previous studies 7,8,23 . ...
... To examine the cell-intrinsic excitability, we injected a series of step currents (1-s duration) at different amplitudes into the recorded cell in current-clamp mode (Fig. 2f). We found that the evoked spike raphe (DR) may change after estrogen withdrawal 8 . Despite these studies, the neural circuit mechanisms for the induction and expression of distinct depression-related phenotypes associated with reproductive hormone fluctuations remain largely unclear. ...
Fluctuations in reproductive hormone levels are associated with mood disruptions in women, such as in postpartum and perimenopausal depression. However, the neural circuit mechanisms remain unclear. Here we report that medial preoptic area (MPOA) GABAergic neurons mediate multifaceted depressive-like behaviors in female mice after ovarian hormone withdrawal (HW), which can be attributed to downregulation of activity in Esr1 (estrogen receptor-1)-expressing GABAergic neurons. Enhancing activity of these neurons ameliorates depressive-like behaviors in HW-treated mice, whereas reducing their activity results in expression of these behaviors. Two separate subpopulations mediate different symptoms: a subpopulation projecting to the ventral tegmental area (VTA) mediates anhedonia and another projecting to the periaqueductal gray mediates immobility. These projections enhance activity of dopaminergic neurons in the VTA and serotonergic neurons in the dorsal raphe, respectively, with increased release of dopamine and serotonin, possibly through disinhibition mechanisms. Thus, the MPOA is a hub that mediates depressive-like behaviors resulting from transitions in reproductive hormone levels.
... Next, it is necessary to examine the HPA axis by measuring levels of corticosterone or other stress-responsive factors in RAGE KO mice. In contrast, estrogen withdrawal in Syrian hamsters is involved in postpartum anxiety increase, which is associated with activation of OT neurons in the paraventricular hypothalamus and subsequent activation of OT receptors in the dorsal raphe nucleus [59,60]. It has been suggested that this OT neuroplasticity leads to serotonergic and dopaminergic neurocircuit activation [59]. ...
... In contrast, estrogen withdrawal in Syrian hamsters is involved in postpartum anxiety increase, which is associated with activation of OT neurons in the paraventricular hypothalamus and subsequent activation of OT receptors in the dorsal raphe nucleus [59,60]. It has been suggested that this OT neuroplasticity leads to serotonergic and dopaminergic neurocircuit activation [59]. Therefore, it will be necessary to examine brain region-or circuit-specific mechanisms for induction of postpartum depression via modulation of OT, such as the hypothalamus-raphe circuit. ...
The receptor for advanced glycation end-products (RAGE), a pattern recognition molecule, has a role in the remodeling of vascular endothelial cells mainly in lungs, kidney and brain under pathological conditions. We recently discovered that RAGE binds oxytocin (OT) and transports it to the brain from circulation on neurovascular endothelial cells. We produced knockout mice of the mouse homologue of the human RAGE gene, Ager, designated RAGE KO mice. In RAGE KO mice, while hyperactivity has been reported in male mice, maternal behavior was impaired in female mice. After an additional stress, deficits in pup care were observed in RAGE KO mother mice. This resulted in pup death within 1–2 days, suggesting that RAGE plays a critical role during the postpartum period. Thus, RAGE seems to be important in the manifestation of normal maternal behavior in dams. In this review, we summarize the significance of brain OT transport by RAGE and propose that RAGE-dependent OT can dampen stress signals during pregnancy, delivery and early postpartum periods. To the best of our knowledge, there have been no previous articles on these RAGE-dependent results. Based on these results in mice, we discuss a potential critical role of RAGE in emotion swings at the puerperium (peripartum) and postpartum periods in women.
... When examining factors that influence women's sexuality, it is essential to consider the hormonal fluctuations that occur during the postpartum period. During this time, there is a decrease in estrogen and progesterone levels, while prolactin levels rise in breastfeeding mothers [52,53]. Additionally, changes in cortisol, oxytocin, and androgens, such as DHEAS, may also play a role in altering sexual function, often contributing to a reduction in sexual desire and activity [53]. ...
Background: The postpartum period can carry strong stress related to the sudden changes in a woman’s life, which may contribute to changes in the female sexual sphere. The aim of this study was to determine the impact of stress on women’s sexuality in the early motherhood period. Methods: A total of 111 women were studied, including 65 in the puerperal period and 46 women who constituted the control group. We used the author’s questionnaire and five standardized psychological questionnaires (CISS-21,STAI, PSS-10, SSS-W, and the Mell–Krat Scale for women). Results: Perceived stress (PSS-10 scores) was significantly lower (p < 0.001) and sexual satisfaction (SSS-W scores) was significantly higher both regarding the summary scores (p < 0.001) and in all subscales (contentment, communication, and compatibility). In the study group, the intensity of stress was negatively correlated with the level of sexual satisfaction (p = 0.014). Women with an emotional way of coping with stress (CISS-21 inventory) in both groups achieved higher scores of sexual satisfaction in terms of communication, but a lower level in terms of interpersonal contact (p = 0.007), but higher stress intensity scores in the PSS-10 scale and in both STAI questionnaire stems. Conclusions: The early period of motherhood does not increase stress levels or decrease sexual satisfaction. It is likely that the sense of stability promotes a reduction in stress levels, which contributes to better sexual satisfaction.
... Additionally, Escherichia coli and other bacteria can metabolize and produce β-glucuronidase (GUS), enzymes that influence estrogen levels by promoting the dissociation and hydroxylation of estrogen in the gut (Hu et al., 2023). Fluctuations in estrogen levels are also closely linked to anxiety, as estrogen withdrawal can induce neural plasticity in hypothalamic and dorsal raphe nucleus neurons, increasing anxiety-like behaviors (Hedges et al., 2021). Another study demonstrated that middle-aged female rats displayed anxiety-like states post-ovariectomy, which significantly improved following estradiol supplementation (Renczés et al., 2020). ...
Anxiety disorders, prevalent mental health conditions, receive significant attention globally due to their intricate etiology and the suboptimal effectiveness of existing therapies. Research is increasingly recognizing that the genesis of anxiety involves not only neurochemical brain alterations but also changes in gut microbiota. The microbiota-gut-brain axis (MGBA), serving as a bidirectional communication pathway between the gut microbiota and the central nervous system (CNS), is at the forefront of novel approaches to deciphering the complex pathophysiology of anxiety disorders. This review scrutinizes the role and recent advancements in the MGBA concerning anxiety disorders through a review of the literature, emphasizing mechanisms via neural signals, endocrine pathways, and immune responses. The evidence robustly supports the critical influence of MGBA in both the development and progression of these disorders. Furthermore, this discussion explores potential therapeutic avenues stemming from these insights, alongside the challenges and issues present in this realm. Collectively, our findings aim to enhance understanding of the pathological mechanisms and foster improved preventative and therapeutic strategies for anxiety disorders.
... In PPD-A patients, this attentionmediated inhibition of visual areas is diminished suggesting that patients have deficits in filtering out task-irrelevant visual stimuli, which allows PPD-A patients to be overly attentive and "hypervigilant" and thus experience anxiety symptoms. We found that enhanced functional connectivity between DMN and FPN in PPD-A patients is associated with reduced blood E2 levels, which is consistent with a previous finding that the decrease in estrogen is associated with increased postnatal anxiety-like behavior in mice (Hedges et al. 2021). Maternal-specific activation of motor-sensory-auditory regions is significantly altered during the processing of infant emotional cues (Swain 2008). ...
Postpartum depression and postpartum depression with anxiety, which are highly prevalent and debilitating disorders, become a growing public concern. The high overlap on the symptomatic and neurobiological levels led to ongoing debates about their diagnostic and neurobiological uniqueness. Delineating the shared and disorder-specific intrinsic functional connectivities and their causal interactions is fundamental to precision diagnosis and treatment. In this study, we recruited 138 participants including 45 postpartum depression, 31 postpartum depression comorbid with anxiety patients, and 62 healthy postnatal women with age ranging from 23 to 40 years. We combined independent component analysis, resting-state functional connectivity, and Granger causality analysis to reveal the abnormal intrinsic functional couplings and their causal interactions in postpartum depression and postpartum depression comorbid with anxiety from a large-scale brain network perspective. We found that they exhibited widespread abnormalities in intrinsic and effective functional network connectivities. Importantly, the intrinsic and effective functional network connectivities within or between the fronto-parietal network, default model network, ventral and dorsal attention network, sensorimotor network, and visual network, especially the functional imbalances between primary and association cortices could serve as effective neural markers to differentiate postpartum depression, postpartum depression comorbid with anxiety, and healthy controls. Our findings provide the initial evidence for shared and disorder-specific intrinsic and effective functional network connectivities for postpartum depression and postpartum depression comorbid with anxiety, which provide an underlying neuropathological basis for postpartum depression or postpartum depression comorbid with anxiety to facilitate precision diagnosis and therapy in future studies.
... En el caso de ratones se ha demostrado que la expresión de receptores para la hormona liberadora de corticotropina disminuye en el NPV cuando hembras son expuestas a estrés psicosocial durante la gestación (Zoubovsky et al., 2020). La participación del NPV en el comportamiento materna también se asocia a la supresión de estrógenos durante el periodo postparto, y aunque propicia el comportamiento materno también se ha asociado a comportamientos de ansiedad en las madres (Hedges et al., 2021). Figura 11. ...
... In humans, withdrawal of ovarian hormones through the use of gonadotropin-releasing hormone agonists increases negative mood scores, along with reducing hippocampal volume and hippocampal functional connectivity 117,[125][126][127] . In rodents, withdrawal of high oestradiol and progesterone levels increases depressive-like endophenotypes, including reduced neurogenesis in the dentate gyrus, highlighting a potential mechanism linking steroid hormones and depression 93,118,119,128 . Thus, several lines of evidence in humans and ...
Sex differences, driven in part by steroid hormones, shape the structure and function of the brain throughout the lifespan and manifest across brain health and disease. The influence of steroid hormones on neuroplasticity, particularly in the adult hippocampus, differs between the sexes, which has important implications for disorders and diseases that compromise hippocampus integrity, such as depression and Alzheimer disease. This Review outlines the intricate relationship between steroid hormones and hippocampal neuroplasticity across the adult lifespan and explores how the unique physiology of male and female individuals can affect health and disease. Despite calls to include sex and gender in research, only 5% of neuroscience studies published in 2019 directly investigated the influence of sex. Drawing on insights from depression, Alzheimer disease and relevant hippocampal plasticity, this Review underscores the importance of considering sex and steroid hormones to achieve a comprehensive understanding of disease susceptibility and mechanisms. Such consideration will enable the discovery of personalized treatments, ultimately leading to improved health outcomes for all.
... These psychological problems negatively affect postpartum women's mental state and physical rehabilitation, even resulting in selfharm and suicide (3)(4)(5). The occurrence of anxiety and depression in postpartum women is associated with many factors, which mainly include postpartum complications, hormonal imbalances, and immune-inflammatory abnormalities (6)(7)(8)(9). Notably, current evidence suggests that T cells may play an important role in immune-inflammatory processes and are involved in the development of anxiety and depression (10,11). Specifically, human T helper 17 (Th17) cells secrete the proinflammatory cytokines interleukin (IL)-17 and IL-22, which impair the blood-brain barrier and kill human neurons in vivo and in vitro, thereby recruiting cluster of differentiation 4 + (CD4 + ) lymphocytes and promoting central nervous system inflammation (12). ...
Jun N-terminal kinase pathway-associated phosphatase (JKAP) regulates CD4+ T-cell differentiation and immunity, which are linked to mental disorders. This study aimed to explore the relationships between JKAP and T helper 17 (Th17)/regulatory T (Treg) ratio, as well as their associations with anxiety and depression in postpartum women. Serum JKAP were measured by enzyme-linked immunosorbent assay and blood Th17 and Treg cells were measured by flow cytometry in 250 postpartum women. Anxiety and depression were evaluated by the 6-item State-Trait Anxiety Inventory (STAI6) and Edinburgh Postnatal Depression Scale (EPDS). Anxiety and depression rates were 22.0 and 28.4%, respectively, among postpartum women. Notably, JKAP was negatively associated with the STAI6 (P=0.002) and EPDS scores (P<0.001) in postpartum women and was lower in postpartum women with anxiety (P=0.023) or depression (P=0.002) than in those without. Moreover, JKAP was inversely related to Th17 cells and Th17/Treg ratio but positively correlated with Treg cells in postpartum women (all P<0.001). Interestingly, Th17 cells and Th17/Treg ratio were both positively associated with STAI6 and EPDS scores in postpartum women (all P<0.001). Furthermore, Th17 cells and Th17/Treg ratio were lower in postpartum women with anxiety or depression than in those without (all P<0.01). Nevertheless, Treg cells were not linked to anxiety or depression in postpartum women. JKAP was negatively associated with Th17 cells and Th17/Treg ratio; moreover, they all related to anxiety and depression in postpartum women, indicating that JKAP may be involved in postpartum anxiety and depression via interactions with Th17 cells.
... This disparity is especially pronounced in women over the age of 40 (4). A separate study found that PPD can last up to three years, which is far longer than previously thought (5). PPD has a long duration and a significant impact, hurting relationships, families, society, and maternal health and placing mothers and newborns at risk. ...
Background
To explore the potential causal associations between coeliac disease(CD) and postpartum depression(PPD) by using two-sample Mendelian randomization(MR) analysis.
Methods
The IEU OPEN GWAS project was utilized to identify genetic loci strongly associated with CD as instrumental variables (IVs), and MR analysis was performed using inverse variance weighting(IVW), weighted median, weighted model, and MR-Egger. MR analyses were used to examine whether there was a link between CD and PPD, with an OR and 95% CI. Meanwhile, the relationship between CD and depression(DP) was analyzed using MR. The sensitivity analysis was conducted using MR-Egger intercept analysis, Cochran’s Q test, and leave-one-out analysis.
Results
From the GWAS online database, 13 single-nucleotide polymorphisms (SNPs) were chosen as IVs. The IVW results showed a relationship between PPD and a genetically predicted risk of developing CD (OR = 1.022, 95% CI: 1.001–1.044, P = 0.043). However, the presence of DP was not linked with CD (OR=0.991, 95% CI: 0.978–1.003, P=0.151). Potential horizontal pleiotropy was not discovered using MR-Egger intercept analysis (PPD: P=0.725; DP: P=0.785), and Cochran’s Q test for heterogeneity revealed no significant heterogeneity (PPD: P=0.486; DP: P=0.909). A leave-one-out analysis found that individual SNPs had minimal effect on overall causal estimations.
Conclusion
MR research discovered a link between CD and PPD.
... Ovariectomy in rodents induces anxiety and depressive-like behaviors [181]. The withdrawal of estrogen during the postpartum period increased anxiety-like behavior by changing the oxytocin neurocircuitry in the paraventricular nucleus of the hypothalamus and dorsal raphe nucleus [182]. Estrogen administration mitigates the OVX-induced anxiety-like behavior by activating genomic and non-genomic ERs mechanisms. ...
Estrogen regulates a wide range of neuronal functions in the brain, such as dendritic spine formation, remodeling of synaptic plasticity, cognition, neurotransmission, and neurodevelopment. Estrogen interacts with intracellular estrogen receptors (ERs) and membrane-bound ERs to produce its effect via genomic and non-genomic pathways. Any alterations in these pathways affect the number, size, and shape of dendritic spines in neurons associated with psychiatric diseases. Increasing evidence suggests that estrogen fluctuation causes changes in dendritic spine density, morphology, and synapse numbers of excitatory and inhibitory neurons differently in males and females. In this review, we discuss the role of estrogen hormone in rodents and humans based on sex differences. First, we explain estrogen role in learning and memory and show that a high estrogen level alleviates the deficits in learning and memory. Secondly, we point out that estrogen produces a striking difference in emotional memories in men and women, which leads them to display sex-specific differences in underlying neuronal signaling. Lastly, we discuss that fluctuations in estrogen levels in men and women are related to neuropsychiatric disorders, including schizophrenia, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BPD), major depressive disorder (MDD), substance use disorder (SUD), and anxiety disorders.
... The open-field assay has been extensively applied in assessing locomotor activity. It was performed in this study based on previous descriptions after slight modifications 53 . In summary, the mice engaged with the open arena (50 × 50 × 50 cm, L × W × H) for a duration of 5 min. ...
Spinal cord injury (SCI) can reshape gut microbial composition, significantly affecting clinical outcomes in SCI patients. However, mechanisms regarding gut–brain interactions and their clinical implications have not been elucidated. We hypothesized that short-chain fatty acids (SCFAs), intestinal microbial bioactive metabolites, may significantly affect the gut–brain axis and enhance functional recovery in a mouse model of SCI. We enrolled 59 SCI patients and 27 healthy control subjects and collected samples. Thereafter, gut microbiota and SCFAs were analyzed using 16 S rDNA sequencing and gas chromatography–mass spectrometry, respectively. We observed an increase in Actinobacteriota abundance and a decrease in Firmicute s abundance. Particularly, the SCFA-producing genera, such as Faecalibacterium , Megamonas , and Agathobacte r were significantly downregulated among SCI patients compared to healthy controls. Moreover, SCI induced downregulation of acetic acid (AA), propionic acid (PA), and butyric acid (BA) in the SCI group. Fecal SCFA contents were altered in SCI patients with different injury course and injury segments. Main SCFAs (AA, BA, and PA) were administered in combination to treat SCI mice. SCFA supplementation significantly improved locomotor recovery in SCI mice, enhanced neuronal survival, promoted axonal formation, reduced astrogliosis, and suppressed microglial activation. Furthermore, SCFA supplementation downregulated NF-κB signaling while upregulating neurotrophin-3 expression following SCI. Microbial sequencing and metabolomics analysis showed that SCI patients exhibited a lower level of certain SCFAs and related bacterial strains than healthy controls. SCFA supplementation can reduce inflammation and enhance nourishing elements, facilitating the restoration of neurological tissues and the improvement of functional recuperation. Trial registration: This study was registered in the China Clinical Trial Registry ( www.chictr.org.cn ) on February 13, 2017 (ChiCTR-RPC-17010621).
... And treatment with ERβ ligand agonist, 5α-androstane, 3β,17β-diol (3β-diol), upregulates the expression of OXT mRNA and promotes OXT transcription via CREB and steroid receptor coactivator-1 [25]. In particular, estrogen withdrawal induces hypothalamic oxytocin neuronal plasticity and increases anxiety behaviors via enhancing OXT transmission between the PVN and dorsal raphe nucleus [26]. In addition, androgen receptors have been found to co-localize with hypothalamic OXT by immunocytochemistry in the postmortem brain of patients with mood disorders [27]. ...
Oxytocin (OXT), produced and secreted in the paraventricular nucleus and supraoptic nucleus of magnocellular and parvocellular neurons. The diverse presence and activity of oxytocin suggests a potential for this neuropeptide in the pathogenesis and treatment of stress-related neuropsychiatric disorders (anxiety, depression and post-traumatic stress disorder (PTSD)). For a more comprehensive understanding of the mechanism of OXT's anti-stress action, the signaling cascade of OXT binding to targeting stress were summarized. Then the advance of OXT treatment in depression, anxiety, PTSD and the major projection region of OXT neuron were discussed. Further, the efficacy of endogenous and exogenous OXT in stress responses were highlighted in this review. To augment the level of OXT in stress-related neuropsychiatric disorders, current biological strategies were summarized to shed a light on the treatment of stress-induced psychiatric disorders. We also conclude some of the major puzzles in the therapeutic uses of OXT in stress-related neuropsychiatric disorders. Although some questions remain to be resolved, OXT has an enormous potential therapeutic use as a hormone that regulates stress responses.
... In addition, a previous study found that ovarian hormone itself affected women's fat metabolism. Estrogen increases dramatically during pregnancy but quickly drops below pre-pregnancy levels at birth and remains suppressed during the postpartum period, so changes in hormone levels may partly affect postpartum weight [41,42] . ...
Objective
Postpartum weight retention (PPWR) is a common problem among women after childbirth. The main objectives of this study are to understand the changes in body weight of breastfeeding mothers during long-term follow-up and preliminarily explore the relationship between maternal body weight and human milk composition, including macronutrients, leptin, and adiponectin.
Methods
The study included a longitudinal cohort (122 mothers), and a cross-sectional cohort (37 mothers). The human milk, maternal weight, and dietary surveys were collected in the longitudinal cohort at different follow-up time points (1−14 days postpartum, 2−4 months postpartum, 5−7 months postpartum, and 12−17 months postpartum). The maternal body weight was analyzed using the responses in the survey questionnaires. A milk analyzer based on the mid-infrared spectroscopy (MIRS) was used to determine milk composition, and nutrition analysis software evaluated dietary intakes. In the cross-sectional cohort, participating mothers were asked to provide blood and human milk samples and pertinent information related to maternal body composition. Maternal body composition was measured by bioelectrical impedance analysis (BIA), while ELISA analyzed leptin and adiponectin in milk and serum.
Results
At 5−7 months postpartum, the PPWR of breastfeeding mothers was (2.46 ± 3.59) kg. At 12−17 months postpartum, the PPWR was (0.98 ± 4.06) kg. PPWR was found to be negatively correlated with milk fat content within 14 days postpartum and positively correlated at 2−4 months postpartum. In addition, the maternal weight and body muscle mass were positively correlated with leptin and adiponectin in milk. Plasma leptin was positively correlated with the mother’s body weight, body mass index (BMI), FAT percentage, and body fat mass, while plasma adiponectin did not correlate with any parameter. The results also indicate that the PPWR did not correlate with leptin and adiponectin in plasma or milk.
Conclusions
Breastfeeding mothers may retain considerable weight gain one year after delivery. Human milk composition may be related to changes in maternal body weight. Leptin and adiponectin in breast milk and leptin in plasma are associated with the maternal body composition. This study supports the notion that maternal nutritional status may affect offspring health through lactation, and future research should focus on exploring weight management of postpartum mothers.
... En el caso de ratones se ha demostrado que la expresión de receptores para la hormona liberadora de corticotropina disminuye en el NPV cuando hembras son expuestas a estrés psicosocial durante la gestación (Zoubovsky et al., 2020). La participación del NPV en el comportamiento materna también se asocia a la supresión de estrógenos durante el periodo postparto, y aunque propicia el comportamiento materno también se ha asociado a comportamientos de ansiedad en las madres (Hedges et al., 2021). ...
... The changes above were considered to be associated with reduced estrogen and glycogen expression in the vaginal epithelium of postpartum women (Hedges et al., 2021). In addition, amniotic fluid and lochia entering the vagina will affect the acidic environment. ...
The impairment of pelvic floor muscle functions and Lactobacillus -deficient vaginal microbiota is common in postpartum women. However, few studies have explored the correlation between pelvic floor muscle functions and vaginal microbiota. Given this research gap, our study aims to investigate any potential association between these two conditions of postpartum women (6–8 weeks after childbirth). A total of 230 women who required postpartum pelvic floor function examination at Peking University International Hospital from December 2021 to April 2022 were enrolled in this study. The collected questionnaire information included progestational weight, body mass index (BMI), weight gain during pregnancy, neonatal weight, delivery type, multiparity, postpartum time, and urinary incontinence (UI). A total of 187 samples of vaginal secretions were collected, and the vaginal microbiota was detected by 16S rRNA sequence analysis. Finally, 183 samples were analyzed in the trial. All individuals were divided into two groups according to the results of pelvic floor muscle assessment to explore the difference between the incidence of postpartum urinary incontinence and vaginal microbiota. We found that the prevalence of UI was higher in the group with weakened pelvic floor muscles. Vaginal delivery, overweight, age, neonatal weight, and weight gain during pregnancy were all risk factors for postpartum urinary incontinence. The vaginal microbiome was no longer Lactobacillus dominant of most postpartum women (91.8%), while the diversity of microbiota increased. The Lactobacillus -deficient community, commonly labeled as community state type (CST) IV, was sub-divided into four communities. The abundance of vaginal Lactobacillus decreased in the group with compromised pelvic muscle functions, while the species richness and diversity increased significantly. In conclusion, the decreased pelvic floor muscle functions of postpartum women 6–8 weeks after delivery may disrupt the balance of vaginal microbiota, and the restoration of pelvic floor functions may contribute to a healthy and balanced vaginal microbiota.
... ; https://doi.org/10.1101/2022.10.27.514063 doi: bioRxiv preprint increased locomotion in "early pregnancy" (estradiol plus progesterone) is lower than in "late pregnancy" (estradiol alone). During pregnancy, voluntary wheel running is dramatically lowered in rats in mice 73,74 54 . In the future, more comprehensive brain region sampling, as well as identifying the neurochemical phenotype and connection patterns of cFos-ir cells, is needed to fully elucidate the impact of peripartum estradiol fluctuations on sleep-associated neural circuitry and behavioral outcomes. ...
Sleep disruptions are a common occurrence during the peripartum period. While physical and environmental factors associated with pregnancy and newborn care account for some sleep disruptions, there is evidence that peripartum fluctuations in estrogens may independently impact sleep. We therefore used a hormone-simulated pseudopregnancy in female Syrian hamsters to test the hypothesis that pregnancy-like increases in estradiol decrease sleep in the absence of other factors. Adult female Syrian hamsters were ovariectomized and given daily hormone injections that simulate estradiol levels during early pregnancy, late pregnancy, and the postpartum period. Home cage video recordings were captured at seven timepoints and videos were analyzed for actigraphy. During “late pregnancy,” total sleep time and sleep efficiency were decreased in hormone-treated animals during the white light period compared to vehicle controls. During both “early pregnancy” and “late pregnancy,” locomotion was increased in the white light period for hormone-treated animals; this change continued into the “postpartum period” for animals who continued to receive estradiol treatment, but not for animals who were withdrawn from estradiol. At the conclusion of the experiment, animals were euthanized and cFos expression was quantified in the ventral lateral preoptic area (VLPO) and lateral hypothalamus (LH). Animals who continued to receive high levels of estradiol during the “postpartum” period had significantly more cFos in the VLPO and LH than animals who were withdrawn from hormones or vehicle controls. Together, these data suggest that increased levels of estradiol during pregnancy are associated with sleep suppression which may be mediated by increased activation of hypothalamic nuclei.
... The fetus' expulsion stimulates sympathetic fibers in the vaginocervical region [21], activating hypothalamic oxytocin secretion [83]. Cytologic studies have shown that in the postpartum period, oxytocin immunoreactive cells and oxytocinergic cells increase in the dorsal raphe [84]. In addition to oxytocin, estrogen and dopamine concentrations are known to participate in the bonding process in ruminants [19,85]. ...
Maternal behavior, in water buffalo and other ruminants, is a set of patterns of a determined species, including calving, imprinting, and suckling. This behavior is mainly triggered by hormone concentration changes and their interactions with their respective receptors in the brain, particularly oxytocin. These chemical signals also influence mother–young bonding, a critical process for neonatal survival that develops during the first postpartum hours. Currently, dairy buffalo behavior during parturition has rarely been studied. For this reason, this review aims to analyze the existing scientific evidence regarding maternal behavior in water buffalo during calving. It will address the mechanisms of imprinting, maternal care, and allosuckling strategies that may influence the survival and health of calves.
... Our studies also showed that consistent with a generally anxiogenic role of serotonin [104][105][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]). ...
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’.
... Studies have also shown changes in the hypothalamic-pituitary-adrenal (HPA) axis, where cortisol levels rise significantly during pregnancy, peak at delivery and then tend to decline (Hedges et al., 2021;Yang et al., 2017). There are still several doubts regarding the physiological mechanisms and changes in the brain structures that recur in the disease. ...
Obesity is currently one of the most serious health problems, affecting 13% of the world's adult population. Obesity is characterized by persistent low‐grade chronic inflammation that assumes systemic proportions and triggers several associated metabolic diseases. Furthermore, obesity has been associated with an increased occurrence of central disorders such as impaired cognitive function, reward system dysfunction, and depression. In summary, there is a quantitative reduction in the release of neurotransmitters in depression. Postsynaptic cells capture lower concentrations of neurotransmitters, which leads to a functional reduction in the central nervous system (CNS). Globally, approximately 15–65% of women experience depressive symptoms during pregnancy, depending on their location. Depressive symptoms persist in some women, leading to postpartum depression (PPD). Thus, obesity may be considered a risk factor for PPD development. This study aimed to synthesize studies on the impact of obesity‐related neuroinflammation and PPD. We conducted a narrative review of the relevant literature. The search was performed in electronic databases, specifically PubMed, selecting articles in English published from 2014 to 2021 using the narrative review methodology.
... Furthermore, the translocator protein (18 kDa) (TSPO) and related neurosteroids in the hippocampus have also received attention as a potential target for treating PPD in rats (Ren et al., 2020) and mice . In addition to rats and mice, recent studies in Syrian hamsters reported increased anxiety-like behavior but not anhedonia in a model of estrogen withdrawal following HSP, concordant with increased plasticity in the oxytocinergic neural system (Hedges et al., 2021). Since these are models that simulate a hormonal situation and not a physiological pregnancy (with all the physiological, metabolic, and psychological changes), there are no increases in oxytocin and prolactin, nor does the normal peak of postpartum estrogen (postpartum estrus) occur in the rodents. ...
Postpartum depression (PPD) is a heterogeneous mood disorder and the most frequent psychiatric complication of the postnatal period. Given its potential long-lasting repercussions on the well-being of the mother and the infants, it should be a priority in public health. In spite of efforts devoted to clinical investigation and preclinical studies, the underlying neurobiological mechanisms of this disorder remain unknown in detail. Much of the progress in the area has been made from animal models, especially rodent models. The aim of this mini-review is to update the current rodent models in PPD research and their main contributions to the field. Animal models are critical tools to advance understanding of the pathophysiological basis of this disorder and to help the development of new therapeutic strategies. Here, we group PPD models into 2 main categories (Models based on hormone manipulations, Models based on stress exposure), each of which includes different paradigms that reflect risk factors or physiological conditions associated with this disease. Finally, we provide an overview of emerging models that provide new perspectives on the study of possible pathophysiological factors related to PPD, to contribute to tackling potential therapeutic targets.
... These sex hormones radically decrease after delivery. In animal models, such rapid estrogen withdrawal has been linked to anxiety and depressive like behaviors and, notably, causing alterations of brain neurogenesis (Hedges et al., 2021;Zhang et al., 2016). Women with a previous history of premenstrual syndrome are shown to have increased risk of perinatal depression (Wikman et al., 2019), indicating that individual vulnerability to changes in hormonal levels might be an important factor in perinatal mood symptoms (Bloch et al., 2000;de Rezende, Garcia-Leal, Silva de S a, Cavalli and Del-Ben, 2019). ...
Maternal mental health spans in a temporary manner from pre-conception through the phases of pregnancy, childbirth, and the postpartum period (i.e., perinatal). The psychoneuroimmunology (PNI) field has made important contributions to the knowledge of the pathophysiology of poor perinatal mental health, but the PNI lens could be used more broadly to inform clinical practice. This review argues that PNI holds the key to several important aspects of variations in mental health for pregnant and postpartum women. This review describes existing knowledge from studies on immune activation in maternal depression during pregnancy and postpartum, and other important features such as stress reactivity, the microbiome, and its metabolites. The importance of objective measures for screening and prediction is discussed as well as the need for novel therapeutics to treat poor mental health in the perinatal period. The PNI framework could thus be further applied to inform research about the mechanisms of perinatal psychiatric morbidity, which could pave the way for future precision medicine for perinatal mental health issues.
... 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. ...
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.
... Because central OT is anxiolytic in non-parous rodents (Jurek and Neumann, 2018), including after infusion into the ventral periaqueductal gray or mPFC of postpartum females (Figueira et al., 2008;Sabihi et al., 2014), this reduction of anxiety was unexpected. Consistent with our results, though, increased OTR expression in the DR of female hamsters following hormone-simulated pseudopregnancy was very recently shown to be anxiogenic (Hedges et al., 2020). These results collectively suggest that oxytocin's effects on anxiety are brain-site specific, with OTR activity in the DR normally having anxiogenic effects. ...
Oxytocin receptors (OTRs) in the midbrain dorsal raphe (DR; the source of most forebrain serotonin) have recently been identified as a potential pharmacological target for treating numerous psychiatric disorders. However, almost all research on this topic has been conducted with males and the role of DR OTRs in female social and affective behaviors is mostly unknown. This may be particularly relevant during early motherhood, a time of high endogenous oxytocin signaling, but also a time of elevated risk for psychiatric dysfunction. To investigate whether OTRs in the DR are necessary for postpartum female social and affective behaviors, we constructed and then injected an adeno-associated virus permanently expressing an shRNA targeting OTR mRNA into the DR. We then observed a suite of social and affective behaviors postpartum. OTR knockdown in the maternal DR led to pup loss after parturition, decreased nursing, increased aggression, and increased behavioral despair. These effects of OTR knockdown in the DR may be due to disrupted plasticity in the primary somatosensory cortex (S1), which mediates maternal sensitivity to tactile cues from young, as we also found significantly more plasticity-restricting perineuronal nets (PNNs) in the S1 rostral barrel field and a trend for fewer PNNs in the caudal barrel field of OTR-knockdown mothers. These results demonstrate that OTRs in the midbrain DR are essential for postpartum maternal social and affective behaviors, involved in postpartum cortical plasticity, and suggest that pharmacotherapies targeting OTRs in the DR might be effective treatments for some peripartum affective disorders.
... In postpartum depression hypersecretion of cortisol has been observed 14,15 . Besides steroid hormones, the peptide hormone oxytocin (OXT) has recently gained attention for potential involvement in depression [16][17][18][19] . For instance, oxytocin was shown to be associated with the HPA axis function and depression in postpartum women, suggesting an interaction between oxytocin and glucocorticoids during the postpartum period on depressive behavior 20,21 . ...
Gestational stress can increase postpartum depression in women. To treat maternal depression, fluoxetine (FLX) is most commonly prescribed. While FLX may be effective for the mother, at high doses it may have adverse effects on the fetus. As environmental enrichment (EE) can reduce maternal stress effects, we hypothesized that a subthreshold dose of FLX increases the impact of EE to reduce anxiety and depression-like behavior in postpartum dams exposed to gestational stress. We evaluated this hypothesis in mice and to assess underlying mechanisms we additionally measured hypothalamic–pituitary–adrenal (HPA) axis function and brain levels of the hormone oxytocin, which are thought to be implicated in postpartum depression. Gestational stress increased anxiety- and depression-like behavior in postpartum dams. This was accompanied by an increase in HPA axis function and a decrease in whole-brain oxytocin levels in dams. A combination of FLX and EE remediated the behavioral, HPA axis and oxytocin changes induced by gestational stress. Central administration of an oxytocin receptor antagonist prevented the remediating effect of FLX + EE, indicating that brain oxytocin contributes to the effect of FLX + EE. These findings suggest that oxytocin is causally involved in FLX + EE mediated remediation of postpartum stress-related behaviors, and HPA axis function in postpartum dams.
... 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 It should be noted that, in a previous study conducted in laboratory mice, knocking out OTRs specifically on serotonergic cells did not affect maternal behaviours. 77 82 Alternatively, some rostral DR TH-IR neurones in recently parturient females may be newly born, because our group has previously shown that the female rat DR is a neurogenic niche and that the survival of newborn DR cells is highest during the peripartum period. ...
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 drive successful motherhood.
Background
Depression and anxiety may significantly affect women in the menopausal transition and menopause. In addition to traditional treatment strategies such as hormone therapy, antidepressants, and psychotherapy, physical activity (PA) have been increasingly studied, but there is no consensus about their role in menopausal women with depression and anxiety.
Objective
The current study aimed to evaluate the effect of PA on the severity of depressive (DS) and anxiety (AS) symptoms in women during the menopausal transition and menopause.
Methods
We searched for relevant published studies in PubMed, Embase, Web of Science, Cochrane Library, and CINAHL prior to 8 April 2024, focusing on randomized controlled trials documenting the effect of physical activity on DS and AS, and assessed study quality using the Newcastle–Ottawa Scale.
Results
The data used for meta-analysis were derived from 21 studies (DS, n = 9; AS, n = 1; DS and AS combined, n = 11) involving 2020 participants. The results showed that PA groups demonstrated a statistically significant effect of depressive symptoms versus controls (DS [SMD: -0.66, 95% CI: -0.99 to -0.33; P < 0.001]; AS [SMD: -0.55, 95% CI: -0.82 to -0.27; P < 0.001]). As subgroup analyses demonstrated, physical exercise also reduced depressive symptom of women in menopausal status (SMD =-0.56, 95% CI: −0.96 to − 0.17, p = 0.006, I² = 69%), postmenopausal status (SMD =-0.94, 95% CI: −1.46 to − 0.42, p = 0.0004, I² = 94%), and both in menopausal transition and postmenopausal status (SMD =-0.30, 95% CI: −0.49 to − 0.12, p = 0.001, I² = 0%), while it only reduced anxiety symptom of postmenopausal women (SMD =-0.96, 95% CI: −1.49 to − 0.43, p = 0.0004, I² = 89%). Low-intensity and moderate-intensity exercise both produced increasingly benefits over depressive and anxiety symptoms. However, there is no statistically significant effect of exercise intensity on both depressive symptom and anxiety symptom.
Conclusion
Physical activities with low to moderate intensity can impart remarkable improvements for managing menopausal women with depression and anxiety.
Peripheral inflammation is closely related to the pathogenesis of sickness behaviors and psychiatric disorders such as anxiety and depression. The circumventricular organs (CVOs) are important brain sites to perceive peripheral inflammatory signals, but few studies have reported their role in inflammation-induced anxiety or depression. Using a mouse model of lipopolysaccharide (LPS)–induced inflammation, we identified a previously unreported role of the subfornical organ (SFO), one of the CVOs, in combating inflammation-induced anxiety. LPS treatment induced anxiety-like and sickness behaviors in mice. Although both the SFO and the organum vasculosum of the lamina terminalis (a CVO) neurons were activated after LPS treatment, only manipulating SFO neurons modulated LPS-induced anxiety-like behaviors. Activating or inhibiting SFO neurons alleviated or aggravated LPS-induced anxiety-like behaviors. In addition, SFO exerted this effect through glutamatergic projections to the bed nucleus of the stria terminalis. Manipulating SFO neurons did not affect LPS-induced sickness behaviors. Thus, we uncovered an active role of SFO neurons in counteracting peripheral inflammation-induced anxiety.
Female hormones, functioning as neuroactive steroids, are utilized beyond menopausal hormone therapy. The rapid onset of allopregnanolone analogs, such as brexanolone and zuranolone, in treating depression, and the effectiveness of megestrol acetate in addressing appetite and weight gain, prompted the Food and Drug Administration to authorize the use of progesterone for treating postpartum depression and cancer-related cachexia. Progesterone has also been found to alleviate neuropathic pain in animal studies. These off-label applications offer a promising option for patients with advanced cancer who often experience various mood disorders such as depression, persistent pain, social isolation, and physical complications like cachexia. These patients have shown low tolerance to opioids and mood-regulating medications. However, the potential risks and uncertainties associated with hormone therapy treatment modalities can be daunting for both patients and medical professionals. This review aims to offer a comprehensive understanding of the non-reproductive functions and mechanisms of female hormones in brain health.
Mental illness during pregnancy and the postpartum period is a growing health crisis. We know that at least 1 in 7 women during the perinatal period will experience a mood or anxiety disorder such as perinatal depression (PND) or general anxiety disorder. These mental illnesses significantly impact the well-being of the mother, as well as how she interacts with her infant and family. Over the past 10 years there has been a growing need to understand the neuroendocrine mechanisms mediating perinatal mental illness. Much of this research has focused on aspects of the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes and thus this chapter will focus on these two systems in perinatal mental illness. This chapter will review our current understanding of the neuroendocrinology of perinatal mental illness from research in women and animal models, with a focus on PND and anxiety, but will also consider the limited data we have for other perinatal mental illnesses such as postpartum psychosis and childbirth-related post-traumatic stress disorder. We have much research to do to fully understand the mechanisms behind these disorders and will discuss options for future research. Increased understanding of the unique neuroendocrine profiles associated with perinatal mental illness will allow us to predict risk, develop effective treatments and, ultimately, prevent suffering for millions of mothers during this critical time in life.
Pregnancy and the post-partum period are associated with substantial fluctuations in hormone levels and are frequently associated with significant stress. Many individuals also experience affective disturbances during the peri-partum period, including anxiety, the 'baby blues,' and post-partum depression. However, the extent to which these affective changes result from rapidly altering hormone levels, increased stress, or the combination of both remains largely unknown. The current study sought to evaluate the consequences of pregnancy-like hormonal changes on behavior and gene expression in c57BL6 mice in the absence of stress using a hormone-simulated pregnancy model. Our results reveal that animals receiving hormone injections to simulate the high levels of estrogen observed in late pregnancy and animals withdrawn from estrogen to mimic the rapid decline in this hormone following parturition both exhibit increased anxiety-like behavior compared to ovariectomized controls in the novel open field test. However, no other significant anxiety- or depression-like alterations were observed in either hormone-treated group compared to ovariectomized controls. Both hormone administration and estrogen withdrawal were shown to induce several significant alterations in gene expression in the bed nucleus of the stria terminalis and the periventricular nucleus of the hypothalamus. In contrast to the estrogen withdrawal hypothesis of post-partum depression, our results suggest that this method estrogen withdrawal following hormone-simulated pregnancy in the absence of stress does not induce phenotypes consistent with postpartum depression in c57BL/6 mice. However, given that estrogen withdrawal does lead to significant gene expression changes in two stress-sensitive brain regions, it remains possible that estrogen withdrawal could still contribute to affective dysregulation in the peripartum period by influencing susceptibility to stress. Future research is required to evaluate this possibility.
Sleep disruptions are a common occurrence during the peripartum period. While physical and environmental factors associated with pregnancy and newborn care account for some sleep disruptions, there is evidence that peripartum fluctuations in estrogens may independently impact sleep. However, the impact of these large fluctuations in estrogens on peripartum sleep is unclear because it is difficult to tease apart the effects of estrogens on sleep from effects associated with the growth and development of the fetus or parental care. We therefore used a hormone-simulated pseudopregnancy (HSP) in female Syrian hamsters to test the hypothesis that pregnancy-like increases in estradiol decrease sleep in the absence of other factors. Adult female Syrian hamsters were ovariectomized and given daily hormone injections that simulate estradiol levels during early pregnancy, late pregnancy, and the postpartum period. Home cage video recordings were captured at seven timepoints and videos were analyzed for actigraphy. During "late pregnancy," total sleep time and sleep efficiency were decreased in hormone-treated animals during the white light period compared to pretest levels. Likewise, during "late pregnancy," locomotion was increased in the white light period for hormone-treated animals compared to pretest levels. These changes continued into the "postpartum period" for animals who continued to receive estradiol treatment, but not for animals who were withdrawn from estradiol. At the conclusion of the experiment, animals were euthanized and cFos expression was quantified in the ventral lateral preoptic area (VLPO) and lateral hypothalamus (LH). Animals who continued to receive high levels of estradiol during the "postpartum" period had significantly more cFos in the VLPO and LH than animals who were withdrawn from hormones or vehicle controls. Together, these data suggest that increased levels of estradiol during pregnancy are associated with sleep suppression, which may be mediated by increased activation of hypothalamic nuclei.
In placental mammals, estradiol levels are chronically elevated during pregnancy, but quickly drop to prepartum levels following birth. This may produce an "estrogen withdrawal" state that has been linked to changes in affective states in humans and rodents during the postpartum period. The neural mechanisms underlying these affective changes, however, are understudied. We used a hormone-simulated pseudopregnancy (HSP), a model of postpartum estrogen withdrawal, in adult female C57BL/6 mice to test the impact of postpartum estradiol withdrawal on several behavioral measures of anxiety and motivation. We found that estradiol withdrawal following HSP increased anxiety-like behavior in the elevated plus maze, but not in the open field or marble burying tests. Although hormone treatment during HSP consistently increased sucrose consumption, sucrose preference was generally not impacted by hormone treatment or subsequent estradiol withdrawal. In the social motivation test, estradiol withdrawal decreased the amount of time spent in proximity to a social stimulus animal. These behavioral changes were accompanied by changes in the expression of ∆FosB, a transcription factor correlated with stable long-term plasticity, in the nucleus accumbens (NAc). Specifically, estrogen-withdrawn females had higher ∆FosB expression in the nucleus accumbens core, but ∆FosB expression did not vary across hormone conditions in the nucleus accumbens shell. Using transgenic reporter mice, we found that this increase in ∆FosB occurred in both D1- and D2-expressing cells in the NAc core. Together, these results suggest that postpartum estrogen withdrawal impacts anxiety and motivation and increases ∆FosB in the NAc core.
Repeated exposure to the stress hormone corticosterone results in depressive-like behaviours paralleled by the downregulation of hippocampal reelin expression. Reelin is expressed in key neural populations involved in the stress response, but whether its hypothalamic expression is sex-specific or involved in sex-specific vulnerability to stress is unknown. Female and male rats were treated with either daily vehicle or corticosterone injections (40 mg/kg) for 21 days. Thereafter, they were subjected to several behavioural tasks before being sacrificed to allow the analysis of reelin expression in hypothalamic nuclei. The basal density of reelin-positive cells in males was significantly higher in the paraventricular nucleus (19 %) and in the medial preoptic area (51 %) compared to females. Chronic corticosterone injections increased the immobility time in the forced swim test in males (107 %) and females (108 %) and decreased the exploration of the elevated plus maze in males (34 %). Corticosterone also caused a significant decrease in the density of reelin-positive cells in males, in both ventrodorsal (37 %) and ventrolateral (32 %) subdivisions of the paraventricular nucleus, while not affecting females. Moreover, in the paraventricular nucleus of males, 30 % of the basal reelin-positive cells co-expressed oxytocin while only 17.5 % did in females, showing a positive correlation between reelin and oxytocin levels. Chronic corticosterone did not significantly affect co-localization levels. For the first time, this study shows that there is a sexually dimorphic subpopulation of reelin-positive neurons in the paraventricular nucleus that can be differentially affected by chronic stress.
Depression and anxiety are common neuropsychiatric symptom of Parkinson's disease (PD), reflecting reduced quality of life in patients with PD. Silibinin (silybin), a flavonoid extracted and isolated from the fruit of Silybum marianum (L.) Gaertn, is widely used for the treatment of hepatic diseases. We report here that silibinin shows anti-depressant and anti-anxiety effects on 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model mice with PD. All the results of open field test, elevated plus test, tail suspension test and forced swimming test demonstrated that silibinin administration significantly attenuated MPTP-induced depression/anxiety. Hematoxylin-eosin (HE) staining and Nissl staining results showed that MPTP injection caused the damage of hippocampal neurons, but this was ameliorated by oral administration of silibinin. Silibinin significantly restored hippocampal levels of 5-hydroxyptramine (5-HT) and noradrenaline (NA), two important neurotransmitters for regulating mood, which decreased in MPTP-injected mice. Neuroinflammation, as reflected by the increased expressions of IL-1β, TNFα and IFN-β, was marked in the hippocampus of MPTP-treated mice, accompanying increased stimulator of interferon genes (STING) and interferon regulatory factor-3 (IRF3). Silibinin administration, however, down-regulated the levels of IL-1β, TNFα and IFN-β, as well as STING and IRF3, protecting MPTP-induced PD model mice. These findings indicate that silibinin has a potential of being further developed as a therapeutic for depression and anxiety in PD.
Prosocial interactions are essential for group-living animals and are regulated by tactile cues shared among the group members. Neurobiological mechanisms through which social touch influences prosociality and related affective behaviors are relatively unknown. Using the evolutionarily ancient mother-young dyad as a model, we hypothesized that neurobehavioral consequences of social touch involves an interaction between central oxytocin (released during social touch) and serotonin (regulating affect and neuroplasticity). New mother rats showed upregulation of numerous aspects of the oxytocin system in the midbrain dorsal raphe (DR; source of forebrain serotonin) compared to non-maternal females. Preventing this upregulation by OTR knockdown in the maternal DR elicited infanticide, reduced nursing, increased aggression, and decreased active coping behavior. OTR knockdown also decreased serotonin-immunoreactive fibers, and increased neuroplasticity-restricting perineuronal nets, in the primary somatosensory cortex. Thus, oxytocin signaling in the DR regulates mechanisms involved in serotonin-induced cortical plasticity, which refines the tactile processing underlying prosocial behaviors.
Altered physiological states require neuronal adaptation. In late pregnancy and lactation, a sub-population of the mouse hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons alters their behavior to synthesize and release met-enkephalin rather than dopamine. These neurons normally release dopamine to inhibit prolactin secretion and are activated by prolactin in a short-loop feedback manner. In lactation, dopamine synthesis is suppressed in an opioid-dependent (naloxone-reversible) manner, meaning that prolactin secretion is disinhibited. Conditional deletion of the prolactin receptor in neurons reveals that this change in phenotype appears to be driven by prolactin itself, apparently through an alteration in intracellular signaling downstream of the prolactin receptor that favors enkephalin production instead of dopamine. Thus, prolactin effectively facilitates its own secretion, which is essential for lactation and maternal behavior. These studies provide evidence of a physiologically important, reversible alteration in the behavior of a specific population of hypothalamic neurons in the adult brain.
Oxytocin (OT) is widely known for promoting social interactions, but there is growing appreciation that it can sometimes induce avoidance of social contexts. The social salience hypothesis posed an innovative solution to these apparently opposing actions by proposing that OT enhances the salience of both positive and negative social interactions. The mesolimbic dopamine system was put forth as a likely system to evaluate social salience owing to its well-described role in motivation. Evidence from several sources supports the premise that OT acting within the nucleus accumbens and ventral tegmental area facilitates social reward and approach behavior. However, in aversive social contexts, additional pathways play critical roles in mediating the effects of OT. Recent data indicate that OT acts in the bed nucleus of the stria terminalis to induce avoidance of potentially dangerous social contexts. Here, we review evidence for neural circuits mediating the effects of OT in appetitive and aversive social contexts. Specifically, we propose that distinct but potentially overlapping circuits mediate OT-dependent social approach or social avoidance. We conclude that a broader and more inclusive consideration of neural circuits of social approach and avoidance is needed as the field continues to evaluate the potential of OT-based therapeutics.
The paraventricular nucleus of the hypothalamus (PVH), located in the ventral diencephalon adjacent to the third ventricle, is a highly conserved brain region present in species from zebrafish to humans. The PVH is composed of three main types of neurons, including magnocellular, parvocellular, and long-projecting neurons, which play imperative roles in the regulation of energy balance and various endocrinological activities. In this review, we mainly focus on recent findings about the early development of the hypothalamus and the PVH, the functions of the PVH in the modulation of energy homeostasis and in the hypothalamus-pituitary system, and human diseases associated with the PVH such as obesity, short stature, hypertension, and diabetes insipidus. Thus, the investigations of the PVH will benefit not only the understanding of the development of the central nervous system but also the etiology and therapy of human diseases.
The many facets of the oxytocin (OXT) system of the brain and periphery elicited nearly 25,000 publications since 1930 (see FIGURE 1, as listed in PubMed), which revealed central roles for OXT and its receptor (OXTR) in reproduction, and social and emotional behaviors in animal and human studies focusing on mental and physical health and disease. In this review, we discuss the mechanisms of OXT expression and release, expression and binding of the OXTR in brain and periphery, OXTR-coupled signaling cascades, and their involvement in behavioral outcomes to assemble a comprehensive picture of the central and peripheral OXT system. Traditionally known for its role in milk let-down and uterine contraction during labor, OXT also has implications in physiological, and also behavioral, aspects of reproduction, such as sexual and maternal behaviors and pair bonding, but also anxiety, trust, sociability, food intake, or even drug abuse. The many facets of OXT are, on a molecular basis, brought about by a single receptor. The OXTR, a 7-transmembrane G protein-coupled receptor capable of binding to either Gαi or Gαq proteins, activates a set of signaling cascades, such as the MAPK, PKC, PLC, or CaMK pathways, which converge on transcription factors like CREB or MEF-2. The cellular response to OXT includes regulation of neurite outgrowth, cellular viability, and increased survival. OXTergic projections in the brain represent anxiety and stress-regulating circuits connecting the paraventricular nucleus of the hypothalamus, amygdala, bed nucleus of the stria terminalis, or the medial prefrontal cortex. Which OXT-induced patterns finally alter the behavior of an animal or a human being is still poorly understood, and studying those OXTR-coupled signaling cascades is one initial step toward a better understanding of the molecular background of those behavioral effects.
Stress and withdrawal of female reproductive hormones are known risk factors of postpartum depression. Although both of these factors are capable of powerfully modulating neuronal plasticity, there is no direct electron microscopic evidence of hippocampal spine synapse remodeling in postpartum depression. To address this issue, hormonal conditions of pregnancy and postpartum period were simulated in ovariectomized adult female Sprague-Dawley rats (n=76). The number of hippocampal spine synapses and the depressive behavior of rats in an active escape task were investigated in untreated control, hormone-withdrawn 'postpartum', simulated proestrus, and hormone-treated 'postpartum' animals. After 'postpartum' withdrawal of gonadal steroids, inescapable stress caused a loss of hippocampal spine synapses, which was related to poor escape performance in hormone-withdrawn 'postpartum' females. These responses were equivalent with the changes observed in untreated controls that is an established animal model of major depression. Maintaining proestrus levels of ovarian hormones during 'postpartum' stress exposure did not affect synaptic and behavioral responses to inescapable stress in simulated proestrus animals. By contrast, maintaining pregnancy levels of estradiol and progesterone during 'postpartum' stress exposure completely prevented the stress-induced loss of hippocampal spine synapses, which was associated with improved escape performance in hormone-treated 'postpartum' females. This protective effect appears to be mediated by a muted stress response as measured by serum corticosterone concentrations. In line with our emerging 'synaptogenic hypothesis' of depression, the loss of hippocampal spine synapses may be a novel perspective both in the pathomechanism and in the clinical management of postpartum affective illness.
The mammalian hypothalamic magnocellular neurons of the supraoptic and paraventricular nuclei are among the best understood of all peptidergic neurons. Through their anatomical features, vasopressin- and oxytocin-containing neurons have revealed many important aspects of dendritic functions. Here, we review our understanding of the mechanisms of somato-dendritic peptide release, and the effects of autocrine, paracrine and hormone-like signalling on neuronal networks and behaviour.
© 2015 The Author(s) Published by the Royal Society. All rights reserved.
Mother rabbits construct an elaborate maternal nest before parturition and display a single, brief, daily nursing bout throughout lactation. These features present a unique model for investigating the relevance of changes in neuroendocrine secretion associated with pregnancy and parturition for the regulation of maternal behavior. In the present study we analyzed changes in the location, somal size, and number of oxytocin (OT)and arginine vasopressin (AVP)-immunoreactive (IR) neurons in the hypothalamus of rabbits in estrus, late pregnancy (day 29), and postpartum day 1. From estrus to late pregnancy, the number of OT-IR neurons increased in the scattered cell groups located in the lateral hypothalamic area (LHA), but not in the magnocellular nuclei, i.e., paraventricular nucleus (PVN) and supraoptic nucleus (SON). On postpartum day 1 the increase in the number of OT-IR neurons was sustained in the LHA and became apparent also in the main body of the PVN, in which the number of OT-IR neurons doubled. Increases in the somal size of OT-IR cells were seen in all three nuclei only on postpartum day 1. No OT-IR cells were found in the suprachiasmatic nucleus (SCN). From late pregnancy and into postpartum day 1 increases in the somal size of AVP-IR neurons were detected in the PVN, SON, and LHA but not in the SCN. The number of AVP-IR neurons increased between late pregnancy and postpartum day 1 in the SON only. The changes observed in OT and AVP expression in specific hypothalamic nuclei may be related to specific somatic and behavioral events occurring around the time of parturition, e.g., nest-building, maintenance of homeothermy, elevation of blood volume, and nursing in mother rabbits.
We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V(1a), V(1b) and V(2) receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V(1b) receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V(1a) agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V(2) /V(1a) antagonist, conivaptan and the V(2) antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V(1a), V(1b) and V(2) antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences.
The oxytocin receptor has been implicated in the regulation of reproductive physiology as well as social and emotional behaviors. The neurochemical mechanisms by which oxytocin receptor modulates social and emotional behavior remains elusive, in part because of a lack of sensitive and selective antibodies for cellular localization. To more precisely characterize oxytocin receptor-expressing neurons within the brain, we generated an oxytocin receptor-reporter mouse in which part of the oxytocin receptor gene was replaced with Venus cDNA (a variant of yellow fluorescent protein). Examination of the Venus expression revealed that, in the raphe nuclei, about one-half of tryptophan hydroxylase-immunoreactive neurons were positive for Venus, suggesting a potential role for oxytocin in the modulation of serotonin release. Oxytocin infusion facilitated serotonin release within the median raphe nucleus and reduced anxiety-related behavior. Infusion of a 5-HT(2A/2C) receptor antagonist blocked the anxiolytic effect of oxytocin, suggesting that oxytocin receptor activation in serotonergic neurons mediates the anxiolytic effects of oxytocin. This is the first demonstration that oxytocin may regulate serotonin release and exert anxiolytic effects via direct activation of oxytocin receptor expressed in serotonergic neurons of the raphe nuclei. These results also have important implications for psychiatric disorders such as autism and depression in which both the oxytocin and serotonin systems have been implicated.
The regulation of the onset of maternal behavior in the rat is under hormonal control. This study reports a new endocrine model for the study of the hormonal regulation of maternal responsiveness. The model employs the administration of physiological amounts of the steroids estradiol (E2) and progesterone (P) via Silastic implants to inexperienced nulliparous rats and measurement of the effects of these implants on maternal behavior. In the first two experiments, the levels of E2 and P in the sera of pregnant and hormone-treated rats were measured by RIA. Using known physiological treatments of E2 given in combination with P, the effects of E2 and P on maternal behavior were measured. Treatment with a combination of E2 at all dosages plus P for 2 weeks before P removal and behavioral testing stimulated a fast onset of maternal behavior in ovariectomized nulliparous rats. Exposure for 2 weeks to small E2 implants (1 or 2 mm; approximately 20-30 pg/ml serum) did not affect maternal responsiveness, whereas large E2 implants (10 mm; approximately 110 pg/ml serum) stimulated maternal behavior. P treatment alone had no behavioral effect. Simultaneous removal of E2 plus P before exposure to foster young also resulted in a stimulation of behavioral responsiveness, indicating that the presence of elevated titers of circulating E2 is not a requirement for stimulation to occur. In addition to facilitating a rapid onset of behavior, the quality of the response in steroid-primed rats was similar to that measured in lactating rats in a T-maze test. In another experiment, when female rats were treated with P before E2 administration, maternal behavior was rapidly induced. Thus, P itself can sensitize the female to the behavioral effects of E2. Finally, the duration of steroid-exposure before testing was found to influence maternal behavior. Increased durations of E2 plus P exposure before testing were accompanied by decreased latencies to respond maternally to foster young. These data indicate that during pregnancy, E2 and P prime the female to respond to her young at birth. The intensity of the steroidal priming increases as pregnancy progresses, and this primed potential is subsequently unmasked by the decline in P and the maintenance of E2 secretion around parturition. These findings demonstrate that behavioral processes can be modified in the adult animal as a result of long term changes in endocrine state, i.e. pregnancy.
The hypothalamo-neurohypophysial system (HNS) is the major peptidergic neurosecretory system through which the brain controls peripheral physiology. The hormones vasopressin and oxytocin released from the HNS at the neurohypophysis serve homeostatic functions of water balance and reproduction. From a physiological viewpoint, the core question on the HNS has always been, "How is the rate of hormone production controlled?" Despite a clear description of the physiology, anatomy, cell biology, and biochemistry of the HNS gained over the last 100 years, this question has remained largely unanswered. However, recently, significant progress has been made through studies of gene identity and gene expression in the magnocellular neurons (MCNs) that constitute the HNS. These are keys to mechanisms and events that exist in the HNS. This review is an inventory of what we know about genes expressed in the HNS, about the regulation of their expression in response to physiological stimuli, and about their function. Genes relevant to the central question include receptors and signal transduction components that receive and process the message that the organism is in demand of a neurohypophysial hormone. The key players in gene regulatory events, the transcription factors, deserve special attention. They do not only control rates of hormone production at the level of the gene, but also determine the molecular make-up of the cell essential for appropriate development and physiological functioning. Finally, the HNS neurons are equipped with a machinery to produce and secrete hormones in a regulated manner. With the availability of several gene transfer approaches applicable to the HNS, it is anticipated that new insights will be obtained on how the HNS is able to respond to the physiological demands for its hormones.
In most mammalian species lactation suppresses fertility. There is no doubt that it is the suckling stimulus that provides the controlling signal, and, in human reproduction, this is the only truly physiological signal that suppresses fertility in normally nourished, healthy women. In breastfeeding women, the return of normal fertility follows a relatively well-defined path progressing through: an almost complete inhibition of gonadotrophin-releasing hormone/luteinizing hormone (GnRH/LH) pulsatile secretion in the early stages of lactation; return of erratic pulsatile secretion with some ovarian follicle development associated with increases in inhibin B and oestradiol; a resumption of apparently normal follicle growth associated with a normal increase in oestradiol, but often an absence of ovulation, or formation of an inadequate corpus luteum; and a return to normal ovulatory menstrual cycles. A key element in controlling the rate of this progression is the impact of the suckling stimulus on the GnRH pulse generator, a common feature of lactation in those species for which there is information. The variability in the duration of lactational amenorrhoea between women is related to the variation in the strength of the suckling stimulus, a unique situation between each mother and baby. Full breastfeeding can provide a reliable contraceptive effect in the first 6 to 9 months, but the precise mechanisms whereby the suckling stimulus affects GnRH pulsatile secretion remain unknown. Many studies on the hypothalamic pathways that might be involved in the translation of the neural suckling stimulus to suppression of hypothalamic GnRH secretion have been undertaken, principally in rats. In women, suckling increases the sensitivity of the hypothalamus to the negative feedback effect of oestradiol on suppressing the GnRH/LH pulse generator, a mechanism that appears to be common across species. In contrast, the role of prolactin in the control of GnRH appears to be species-dependent, with the importance varying from none to an important role in late or throughout lactation. In women, there is little evidence for a role of leptin, opioids or dopamine, although this may merely reflect the ethical dilemma of being able to give sufficient drug to test the system in the mother since these drugs will pass through the breast milk to the baby. Regardless of mechanism, practical guidelines for using breastfeeding as a natural contraceptive have been developed, which allows mothers to utilize the only natural suppressor of fertility in women as an effective means of spacing births.
Serotonergic systems play an important and generalized role in regulation of sleep-wake states and behavioral arousal. Recent in vivo electrophysiologic recording studies in animals suggest that several different subtypes of serotonergic neurons with unique behavioral correlates exist within the brainstem raphe nuclei, raising the possibility that topographically organized subpopulations of serotonergic neurons may have unique behavioral or physiologic correlates and unique functional properties. We have shown that the stress-related and anxiogenic neuropeptide corticotropin-releasing factor can stimulate the in vitro neuronal firing rates of topographically organized subpopulations of serotonergic neurons within the dorsal raphe nucleus (DR). These findings are consistent with a wealth of behavioral studies suggesting that serotonergic systems within the DR are involved in the modulation of ongoing anxiety-related behavior and in behavioral sensitization, a process whereby anxiety- and fear-related behavioral responses are sensitized for a period of up to 24 to 48 h. The dorsomedial subdivision of the DR, particularly its middle and caudal aspects, has attracted considerable attention as a region that may play a critical role in the regulation of acute and chronic anxiety states. Future studies aimed at characterization of the molecular and cellular properties of topographically organized subpopulations of serotonergic neurons are likely to lead to major advances in our understanding of the role of serotonergic systems in stress-related physiology and behavior.
Oxytocin (OT) and arginine vasopressin (AVP), as well as synthetic ligands targeting their receptors (OTR, V1aR), are used in a wide variety of research contexts, but their pharmacological properties are determined in only a few species. Syrian hamsters (Mesocricetus auratus) have a long history of use as a behavioral and biomedical model for the study of OT and AVP, and more recently, hamsters have been used to investigate behavioral consequences of OT‐mediated activation of V1aR. We sought to determine the binding affinities of OT, AVP, and the selective V1aR antagonist, Manning compound, for OTR and V1aR in hamster brains. We performed saturation binding assays to determine the Kd values for the selective OTR and V1aR radioligands, [125I]ornithine vasotocin analog and [125I]linear vasopressin antagonist. We then performed competition binding assays to determine Ki values for OT, AVP, and Manning Compound at both the OTR and V1aR. We found that OT and AVP each had the highest affinity for their canonical receptors (OT‐OTR Ki=4.28(95% CI=2.9‐6.3) nM; AVP‐V1ar Ki=4.70(95% CI=1.5‐14.1) nM), and had the lowest affinity for their non‐canonical ligands (OT‐V1aR=495.2 (95% CI=198.5‐1276) nM; AVP‐OTR Ki=36.1(95% CI=12.4‐97.0) nM). Manning compound had the highest affinity for the V1aR (MC‐V1aR Ki=6.87(95% CI=4.0‐11.9) nM; MC‐OTR Ki=213.8(95% CI=117.3‐392.7) nM), but Manning Compound was not as selective for the V1aR in hamsters as has been reported for the receptor in rats. When comparing these data to previously published work, we found that the promiscuity of the V1aR in hamsters with respect to OT and AVP binding is more similar to the promiscuity of the human V1aR than to the rat V1aR receptor. Moreover, the selectivity of OT at hamster receptors is more similar to the selectivity of OT at human receptors than the selectivity of OT at rat receptors. These data highlight the importance of determining the pharmacological properties of behaviorally relevant compounds in diverse model species.
It is widely held that social isolation produces higher rates of mortality and morbidity and has deleterious effects on an individual's sociality. Relatedly, it is widely observed that socially isolated adult rodents display significantly higher levels of aggression when placed in a social situation than do their conspecifics living in social groups. In the following study, we investigated the effects of social isolation on several neurochemical signals that play key roles in the regulation of social behavior in adults. More specifically, we examined the effects of social isolation on vasopressin (AVP) V1a, oxytocin (OT) and serotonin (5-HT)1a receptor binding within the neural circuit controlling social behavior. Male and female Syrian hamsters were housed individually or with two other hamsters for four weeks and were then tested with a same-sex nonaggressive intruder in a neutral arena for 5 min. Social isolation significantly increased aggression in both males and females and altered receptor binding in several brain regions in a sex-dependent manner. For example, V1a receptor binding was greater in socially isolated males in the anterior hypothalamus than it was in any other group. Taken together, these data provide substantial new support for the proposition that the social environment can have a significant impact on the structural and neurochemical mechanisms regulating social behavior and that the amount and type of social interactions can produce differential effects on the circuit regulating social behavior in a sex-dependent manner.
Postpartum estrogen (E2) withdrawal is known to be a particularly vulnerable time for depressive symptoms. In this study, ovariectomized (OVX) mice were treated with co-administration of estradiol benzoate and progesterone (E2/P4) followed by administration of E2 alone (E2) and a subsequent E2 withdrawal (EW) to mimic the hormonal changes during pregnancy and postpartum. The objective of this study was to investigate the influence of E2 withdrawal after hormone-simulated pregnancy on synaptic function and plasticity in basolateral amygdala complex (BLA). In comparison to control mice, EW mice spent less time in the central portion of open-field test and open arms of elevated plus-maze. Excitatory postsynaptic potentials (EPSPs) slopes at external capsule BLA synapse were reduced in E2/P4-mice, recovered in E2-mice, and increased in EW-mice. EW-mice showed a significant increase in duration of EPSPs and paired-pulse inhibition (PPI) with multi-spike responses of EPSPs and impairment of long-term depression (LTD) induction, which were corrected by GABAAR agonist muscimol. Levels of estrogen receptor (ER) GPR30, ERα and ERβ expression in BLA of EW-mice were lower than those in control mice. The bath-application of GPR30 agonist G-1 in BLA of EW-mice recovered the GABAAR-mediated inhibition and LTD indication, but ERβ agonist DPN or ERα agonist PPT could not. A single BLA-injection of G-1 rather than DPN or PPT in EW-mice could partially relieve the anxiety-like behaviors. The results indicate that postpartum E2 withdrawal causes dysfunction of GABAAR-mediated inhibition in the BLA through reducing GPR30 expression, which impairs LTD induction and causes anxiety-like behaviors.
Although Syrian hamsters are thought to be naturally solitary, recent evidence from our laboratory demonstrates that hamsters may actually prefer social contact. Hamsters increase their preference for a location associated with an agonistic encounter regardless of whether they have “won” or “lost”. It has also been reported that social housing as well as exposure to intermittent social defeat or a brief footshock stressor increase food intake and body mass in hamsters. By contrast, it has also been suggested that housing hamsters in social isolation causes anxiety-induced anorexia and reductions in body mass selectively in females. The purpose of this study was to determine the physiological consequences of housing hamsters in social isolation versus in social groups. Male and female hamsters were housed singly or in stable groups of 5 for 4 weeks after which they were weighed and trunk blood was collected. In addition, fat pads and thymus and adrenal glands were extracted and weighed. Serum and fecal cortisol were measured using an enzyme-linked immunoassay. Housing condition had no effect on serum or fecal cortisol, but socially housed hamsters displayed modest thymus gland involution. Socially housed females weighed more than did any other group, and socially housed females and males had more fat than did socially isolated hamsters. No wounding or tissue damage occurred in grouped hamsters. Overall, these data suggest that Syrian hamsters tolerate both stable social housing and social isolation in the laboratory although social housing is associated with some alteration in stress-related and bioenergetic measures.
Postpartum estrogen withdrawal is known to be a particularly vulnerable time for depressive symptoms. Ovariectomized adult mice (OVX-mice) treated with hormone-simulated pregnancy (HSP mice) followed by a subsequent estradiol benzoate (EB) withdrawal (EW mice) exhibited depression- and anxiety-like behaviors, as assessed by forced swim, tail suspension and elevated plus-maze, while HSP mice, OVX mice or EB-treated OVX mice (OVX/EB mice) did not. The survival and neurite growth of newborn neurons in hippocampal dentate gyrus were examined on day 5 after EW. Compared with controls, the numbers of 28-day-old BrdU+ and BrdU+/NeuN+ cells were increased in HSP mice but significantly decreased in EW mice; the numbers of 10-day-old BrdU+ cells were increased in HSP mice and OVX/EB mice; and the density of DCX+ fibers was reduced in EW mice and OVX mice. The phosphorylation of hippocampal NMDA receptor (NMDAr) NR2B subunit or Src was increased in HSP mice but decreased in EW mice. NMDAr agonist NMDA prevented the loss of 28-day-old BrdU+ cells and the depression- and anxiety-like behaviors in EW mice. NR2B inhibitor Ro25-6981 or Src inhibitor dasatinib caused depression- and anxiety-like behaviors in HSP mice with the reduction of 28-day-old BrdU+ cells. The hippocampal BDNF levels were reduced in EW mice and OVX mice. TrkB receptor inhibitor K252a reduced the density of DCX+ fibers in HSP mice without the reduction of 28-day-old BrdU+ cells, or the production of affective disorder. Collectively, these results indicate that postpartum estrogen withdrawal impairs hippocampal neurogenesis in mice that show depression- and anxiety-like behaviors.
In an effort to address inconsistencies in the literature, we tested a cross-species estrogen withdrawal model of postpartum depression (PPD) with a series of rodent experiments and a prospective, naturalistic human study. All rats were ovariectomized prior to experimentation. The first rat experiment examined the effects of low- and high-dose estradiol administration and withdrawal on lateral-hypothalamic self-stimulation, a behavioral index of anhedonia, in experimental (n=7) and vehicle-only control animals (n=7). The second rat experiment examined the effects of high-dose estradiol withdrawal on activity and immobility during the forced swim test, an index of behavioral despair, in a separate group of experimental (n=8) and vehicle-only control animals (n=8). In the human study, women with (n=8) and without (n=12) a history of PPD completed mood ratings and collected saliva samples (to assess estradiol levels) daily during the third trimester of pregnancy through 10 days postpartum. The presence of PPD was assessed at one month postpartum. In the animal studies, rats in the estradiol withdrawal group demonstrated significantly greater immobility and less swimming than controls. Estradiol withdrawal resulted in reduced responding for electrical stimulation (multiple intensities) relative to estradiol administration. In the human study, there was no significant association between estradiol and negative affect among women with or without a history of PPD. However, there was a correlation between daily estradiol levels and negative affect in the women with incident PPD at one month postpartum. Despite important cross-species differences, both the rat and human studies provided evidence of the effects of estradiol on perinatal depressive symptoms.
Postpartum depression (PPD) is a debilitating illness, yet little is known about its causes. The purpose of this study was to examine a major symptom of depression during the postpartum period, anhedonia, by comparing sucrose preference in female rats that had undergone actual pregnancy or hormone-simulated pregnancy (HSP) to their respective controls. Whereas HSP rats showed significantly less preference than vehicle control rats for 1% sucrose solution during the first three weeks of the “postpartum” period, previously pregnant females showed only slightly depressed sucrose preference for the first 1–2 days postpartum, compared to non-pregnant controls. Habituation to 1% sucrose during the pregnancy period, which increased preference upon later testing in previously pregnant rats tested on postpartum day 2, did not significantly increase preference in HSP rats, suggesting that depressed preference in the latter group was not due to neophobia. Pre-treatment with desipramine did not prevent suppressed sucrose preference in HSP rats, and preference was even further suppressed following chronic sertraline treatment. These results suggest that estradiol withdrawal following HSP may cause anhedonia during the early “postpartum” period. In contrast, females that have undergone actual pregnancy are less likely to show this effect, suggesting that postpartum hormonal changes other than the dramatic decline in estradiol may buffer its negative mood effects.
Activation of corticotrophin releasing factor (CRF) neurons in the paraventricular nucleus of the hypothalamus (PVN) is necessary for establishing the classic endocrine response to stress, while activation of forebrain CRF neurons mediates affective components of the stress response. Previous studies have reported that mRNA for CRF2 receptor (CRFR2) is expressed in the bed nucleus of the stria terminalis (BNST) as well as hypothalamic nuclei, but little is known about the localization and cellular distribution of CRFR2 in these regions. Using immunofluorescence with confocal microscopy, as well as electron microscopy, we demonstrate that in the BNST CRFR2-immunoreactive fibers represent moderate to strong labeling on axons terminals. Dual-immunofluorescence demonstrated that CRFR2-fibers co-localize oxytocin (OT), but not arginine-vasopressin (AVP), and make perisomatic contacts with CRF neurons. Dual-immunofluorescence and single cell RT-PCR demonstrate that in the hypothalamus, CRFR2 immunoreactivity and mRNA are found in OT, but not in CRF or AVP-neurons. Furthermore, CRF neurons of the PVN and BNST express mRNA for the oxytocin receptor, while the majority of OT/CRFR2 neurons in the hypothalamus do not. Finally, using adenoviral-based anterograde tracing of PVN neurons, we show that OT/CRFR2-immunoreactive fibers observed in the BNST originate in the PVN. Our results strongly suggest that CRFR2 located on oxytocinergic neurons and axon terminals might regulate the release of this neuropeptide and hence might be a crucial part of potential feedback loop between the hypothalamic oxytocin system and the forebrain CRF system that could significantly impact affective and social behaviors, in particular during times of stress.
Clinical evidence in humans suggests that there is some linkage between dysfunction in the timing of circadian rhythms and certain types of depression. In animal models, Syrian hamsters have been used extensively to study the pharmacology of circadian rhythms, while rats and mice are used to screen putative anxiolytics/antidepressant compounds. It would be beneficial to be able to test anxiolytic/antidepressant compounds in hamsters in conjunction with circadian rhythm studies. Therefore, in this study, Syrian hamsters were used in three experimental paradigms to evaluate anxiety: the elevated plus maze, the t-tube, and the open field Thatcher-Britton conflict test. Diazepam, tested with 2mg/kg and 5mg/kg intraperitoneal injections, was found to induce anxiolytic activity in each of the three tests. Hamsters were more likely to spend time in the open arms in the plus maze, displayed more exploratory behavior in the t-tube, and were quicker to enter a brightly lit exposed field in the Thatcher-Britton conflict test following injections of diazepam. Diazepam (2mg/kg) was also tested at three times during the 24-h day in the elevated plus maze: at the beginning and end of the lights-on period (Zeitgeber times 23 and 11, respectively) and once in the dark just before the room lights came on (Zeitgeber time 20). Diazepam induced anxiolytic activity only at Zeitgeber 23. Therefore, the following known and putative anxiolytic compounds were also evaluated in each of the three tests at Zeitgeber 23: citalopram, the neurokinin(1) receptor antagonists GR205171 and vestipitant, the corticotropin releasing factor(1) receptor antagonist CP154526, the cannabinoid receptor(1) agonist CP55940, the serotonin(6) receptor antagonist SB399885, and the metabotropic glutamate receptor(5) antagonists fenobam and MTEP. Vestipitant displayed some anxiolytic activity in the elevated plus maze, but this effect was not confirmed with GR205171. None of the other compounds displayed any anxiolytic activity in the tests. Nevertheless, the present results with diazepam - together with a few reports from other laboratories, indicate that the elevated plus maze may be a suitable procedure for evaluating the actions of anxiolytic compounds in Syrian hamsters. In view of current interest in novel classes of psychotropic agent interacting with diverse GABA(A) receptor recognition sites, further characterization appears justified.
The female sex steroid hormones, estrogens and progesterone, are produced in large amounts in pregnancy, increasing as pregnancy progresses. These hormones have essential peripheral actions to maintain pregnancy, and to secure safe delivery at term. They also have important actions on the brain in pregnancy, generally through interactions with neuropeptide systems in the brain, or through modulating the actions of circulating peptide hormones on the brain. Together, these steroid-peptide links form short chains that evoke changes in central physiological systems that favour the pregnancy, including altered control of water and electrolyte balance, appetite and energy partitioning and stress responses. In parallel such links prepare the brain, through inhibition of oxytocin secretion until it is needed to support parturition and for immediate expression of maternal behaviour postpartum. We focus here on recent advances in understanding some of these steroid-peptide links, especially on non-classical progesterone actions through allopregnanolone, its neuroactive steroid metabolite, and opioid peptide mechanisms.
In Syrian hamsters (Mesocricetus auratus), precopulatory behaviors such as vaginal scent marking are essential for attracting a suitable mate. Vaginal marking is dependent on forebrain areas implicated in the neural regulation of reproductive behaviors in rodents, including the medial preoptic/anterior hypothalamus (MPOA-AH). Within MPOA-AH, the neuropeptide oxytocin (OT) acts to facilitate copulation (lordosis), as well as ultrasonic vocalizations towards males. It is not known, however, if OT in this area also facilitates vaginal marking. In the present study, a specific oxytocin receptor antagonist (OTA) was injected into MPOA-AH of intact female Syrian hamsters to determine if oxytocin receptor-dependent signaling is critical for the normal expression of vaginal marking elicited by male, female, and clean odors. OTA injections significantly inhibited vaginal marking in response to male odors compared with vehicle injections. There was no effect of OTA on marking in response to either female or clean odors. When injected into the bed nucleus of the stria terminalis (BNST), a nearby region to MPOA-AH, OTA was equally effective in decreasing marking. Finally, the effects of OTA appear to be specific to vaginal marking, as OTA injections in MPOA-AH or BNST did not alter general locomotor activity, flank marking, or social odor investigation. Considered together, these results suggest that OT in MPOA-AH and/or BNST normally facilitates male odor-induced vaginal marking, providing further evidence that OT generally supports prosocial interactions among conspecifics.
The paraventricular hypothalamic nucleus (PVH) contains many neurons that innervate the brainstem, but information regarding their target sites remains incomplete. Here we labeled neurons in the rat PVH with an anterograde axonal tracer, Phaseolus vulgaris leucoagglutinin (PHAL), and studied their descending projections in reference to specific neuronal subpopulations throughout the brainstem. While many of their target sites were identified previously, numerous new observations were made. Major findings include: 1) In the midbrain, the PVH projects lightly to the ventral tegmental area, Edinger-Westphal nucleus, ventrolateral periaqueductal gray matter, reticular formation, pedunculopontine tegmental nucleus, and dorsal raphe nucleus. 2) In the dorsal pons, the PVH projects heavily to the pre-locus coeruleus, yet very little to the catecholamine neurons in the locus coeruleus, and selectively targets the viscerosensory subregions of the parabrachial nucleus. 3) In the ventral medulla, the superior salivatory nucleus, retrotrapezoid nucleus, compact and external formations of the nucleus ambiguous, A1 and caudal C1 catecholamine neurons, and caudal pressor area receive dense axonal projections, generally exceeding the PVH projection to the rostral C1 region. 4) The medial nucleus of the solitary tract (including A2 noradrenergic and aldosterone-sensitive neurons) receives the most extensive projections of the PVH, substantially more than the dorsal vagal nucleus or area postrema. Our findings suggest that the PVH may modulate a range of homeostatic functions, including cerebral and ocular blood flow, corneal and nasal hydration, ingestive behavior, sodium intake, and glucose metabolism, as well as cardiovascular, gastrointestinal, and respiratory activities.
Serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN) have been implicated in stress-induced changes in behavior. Previous research indicates that stressful stimuli activate 5-HT neurons in select subregions of the DRN. Uncontrollable stress is thought to sensitize 5-HT neurons in the DRN and allow for an exaggerated 5-HT response to future stimuli. In the current study, we tested the hypothesis that following aggressive encounters, losing male Syrian hamsters would exhibit increased c-Fos immunoreactivity in 5-HT DRN neurons compared to winners or controls. In addition, we tested the hypothesis that losers would have decreased 5-HT1A mRNA levels in the DRN compared to winners or controls. We found that a single 15-min aggressive encounter increased c-Fos expression in 5-HT and non-5-HT neurons in losers compared to winners and controls. The increased c-Fos expression in losers was restricted to ventral regions of the rostral DRN. We also found that four 5-min aggressive encounters reduced total 5-HT1A mRNA levels in the DRN in losers compared to winners and controls, and that differences in mRNA levels were not restricted to specific DRN subregions. These results suggest that social defeat activates neurons in select subregions of the DRN and reduces message for DRN 5-HT1A autoreceptors. Our results support the hypothesis that social stress can activate 5-HT neurons in the DRN, reduce 5-HT1A autoreceptor-mediated inhibition, and lead to hyperactivity of 5-HT neurons.
Previously, a hormone-simulated pregnancy (HSP), and the subsequent 'postpartum' withdrawal in estradiol has been shown to precipitate depressive-like behaviours in the forced swim test in female rats. In this study, we used the HSP and 'postpartum' withdrawal to investigate the impact on sucrose consumption, a model of anhedonia. Rats were assigned to "postpartum", "postpartum"+EB (estradiol benzoate), "postpartum"+IMI (imipramine; a tricyclic antidepressant), "postpartum"+DPN (diarylpropionitrile; an ERbeta agonist), or ovariectomized (OVX) controls and OVX+IMI treatments. All "postpartum" groups received daily hormone injections (estradiol and progesterone) over 23 days to simulate pregnancy, while IMI groups also received daily injections of imipramine. After Day 23, "postpartum" rats were withdrawn from the hormone regimen (mimicking the postpartum decrease in gonadal hormones), and then received daily injections of compounds indicated (DPN, EB, IMI). Rats were tested for consumption of, and preference for, sucrose weekly at baseline, during 'pregnancy' and on 'Postpartum' Days 2-3. During the 'postpartum' period rats in the "postpartum" group had lower sucrose consumption and preference compared to during late-'pregnancy', but no decrease in 'postpartum' consumption or preference was seen in any other groups except "postpartum"+IMI and a decrease in sucrose preference only in the postpartum+EB group from mid-'pregnancy' to 'postpartum'. The OVX +IMI group had decreased sucrose consumption relative to OVX controls, suggesting a negative effect of imipramine on sucrose consumption. Together, these results suggest an important, though complex, role for gonadal hormones in the behavioral changes accompanying this model of depression.
The ventrolateral bed nucleus of the stria terminalis (BSTvl) receives direct input from two specific subpopulations of neurons in the nucleus tractus solitarius (NTS). It is heavily innervated by aldosterone-sensitive NTS neurons, which are selectively activated by sodium depletion, and by the A2 noradrenergic neurons, which are activated by visceral and immune- and stress-related stimuli. Here, we used a retrograde neuronal tracer to identify other brain sites that innervate the BSTvl. Five general brain regions contained retrogradely labeled neurons: cerebral cortex (infralimbic and insular regions), rostral forebrain structures (subfornical organ, organum vasculosum of the lamina terminalis, taenia tecta, nucleus accumbens, lateral septum, endopiriform nucleus, dorsal BST, substantia innominata, and, most prominently the amygdala--primarily its basomedial and central subnuclei), thalamus (central medial, intermediodorsal, reuniens, and, most prominently the paraventricular thalamic nucleus), hypothalamus (medial preoptic area, perifornical, arcuate, dorsomedial, parasubthalamic, and posterior hypothalamic nuclei), and brainstem (periaqueductal gray matter, dorsal and central superior raphe nuclei, parabrachial nucleus, pre-locus coeruleus region, NTS, and A1 noradrenergic neurons in the caudal ventrolateral medulla). In the arcuate hypothalamic nucleus, some retrogradely labeled neurons contained either agouti-related peptide or cocaine/amphetamine-regulated transcript. Of the numerous retrogradely labeled neurons in the perifornical hypothalamic area, few contained melanin-concentrating hormone or orexin. In the brainstem, many retrogradely labeled neurons were either serotoninergic or catecholaminergic. In summary, the BSTvl receives inputs from a variety of brain sites implicated in hunger, salt and water intake, stress, arousal, and reward.
A single injection of 100 μg/kg estradiol benzoate (EB) either alone or in combination with 0.5 mg progesterone resulted in a significant reduction in the latency for the onset of maternal behavior in hysterectomized-ovariectomized virgin rats as compared to the latencies of groups which either remained intact or were hysterectomized, hysterectomized-ovariectomized, hysterectomized-ovariectomized and treated with 20 μg/kg EB, or ovariectomized-sham hysterectomized and injected with 100 μg/kg EB. In contrast to recent research, there was no shortening of the maternal latencies when ovariectomy or combined hysterectomy-ovariectomy was performed 8 weeks prior to testing while the administration of EB 8 weeks postoperatively was still effective in stimulating short-latency maternal care in hysterectomized-ovariectomized females and increased the percentage of ovariectomized sham hysterectomized animals responding maternally. It was concluded that estrogen is capable of inducing, not suppressing, maternal behavior in virgin rats and that the uterus may play an important but as yet undetermined role.
Two experiments were undertaken to examine the stimulation of home-cage and/or maternal aggressiveness by a hormonal treatment stimulating short-latency maternal behavior. Nonpregnant ovariectomized rats were treated with a 16-day regimen providing pregnancy levels of estrogen (E, 5-mm Silastic capsule) and progesterone (P, daily injection of 4 mg) followed by E and P withdrawal, with or without a terminal injection of estradiol benzoate (EB, 5 micrograms/kg). In Experiment 1, hormonally treated and control females were exposed continuously to pups and tested for aggression toward male intruders on the fifth day of pup exposure. Females receiving E/P/Oil and E/P/EB were highly aggressive whether or not they had yet shown maternal behavior, whereas vehicle-treated females were nonaggressive. In Experiment 2, hypophysectomized (HYPX) and Sham-HYPX females received either E/P/EB or a control treatment and were tested with male intruders (a) immediately preceding and (b) on the fifth day of continuous pup exposure. HYPX and Sham-HYPX females treated with E/P/EB were almost equally aggressive both preceding and following pup exposure (during which they initiated maternal care), whereas HYPX and Sham-HYPX vehicle-treated females were nonaggressive at both tests. In contrast, maternal behavior latencies were reduced by E/P/EB only among Sham-HYPX females. The results establish that an E/P/EB-treatment which elicits short-latency maternal responses also increases aggressiveness toward intruders. Pituitary products, although involved in the mediation of maternal responsiveness, do not contribute significantly to the stimulation of female aggressiveness by ovarian hormones.
Serial brain sections of female rats at late pregnancy, parturition or early lactation were immunostained for oxytocin. Immunoreactive perikarya were visible in the magnocellular nuclei in all experimental animals as well as in ovariectomized, nulliparous controls. During late pregnancy and at parturition additional immunostaining appeared in groups of perivascular neurons in the preoptic region, the lateral subcommissural nucleus, the perifornical region and scattered throughout the ventral portion of the hypothalamus. Immunostaining of almost all of these perivascular neurons disappeared by day two postpartum, while another population of oxytocin neurons, without association with blood vessels, appeared in these brain regions after parturition. Immunostaining of processes from oxytocinergic neurons in the periventricular nucleus increased markedly near parturition. Many of these processes projected toward the third ventricle. Oxytocinergic neuronal systems that are activated in late pregnancy and early postpartum may contribute to several physiological changes associated with parturition and lactation including the onset of maternal behavior.
This article reviews the current state of our knowledge about the hormonal basis of maternal behavior in the rat. Considered are the ovarian hormones estrogen and progesterone, the pituitary hormones beta-endorphin and prolactin, and the hormone oxytocin, secreted by several hypothalamic nuclei and associated brain regions. The hormones of pregnancy, estrogen and progesterone, prime the female to respond to a terminal rise in estrogen that stimulates a high level of maternal responsiveness even before parturition begins. Studies on the role of prolactin, using hypophysectomy, prolactin release blockers and anterior pituitary and prolactin replacement, indicate that prolactin is required for the ovarian hormones to be effective in stimulating maternal behavior. During the latter half of pregnancy, placental lactogen may displace prolactin in this role. Although prolactin serves as a chronic stimulus for maternal behavior, it also may act over a short period. Oxytocin stimulates maternal behavior in a specific strain of rat, but not in other strains, and only when administered introcerebroventricularly (ICV) in estrogen-primed females. The decline in the high brain levels of beta-endorphin around parturition has been proposed as a requirement for the onset of maternal behavior; morphine blocks the onset of maternal behavior and disrupts ongoing maternal behavior and maternal aggression in lactating females. However, blocking beta-endorphin action at parturition interferes with pup cleaning and eating of the placenta as well.
Plasma samples were obtained throughout pregnancy and pseudopregnancy from Sprague–Dawley (SD) rats and during pregnancy from rats of the Munich Wistar (MW) strain. The concentrations of progesterone, oestradiol, prolactin, plasma renin activity (PRA), aldosterone and corticosterone were measured by radioimmunoassay to establish hormonal profiles in the two strains of rat.
Circulating progesterone concentrations in both strains of rat were significantly higher during pregnancy than in virgin controls, except at term in the SD group. The hormonal pattern for pseudopregnancy was similar to that of the first half of pregnancy. Oestradiol concentrations were similar to, or lower than, those in virgin controls throughout pseudopregnancy and for the first 2 weeks of pregnancy in both strains of rat. Increased concentrations of steroid were seen only in the pregnant groups towards term. In SD rats, highest prolactin concentrations were apparent during the first half of pregnancy and pseudopregnancy, and at term in the pregnant group. Pregnant MW rats showed a different profile for this hormone, with low levels throughout pregnancy except at term. In all groups PRA rose to a peak at day 9 and decreased to day 16. Pregnant SD rats also showed a significant increase at term. Aldosterone concentrations were significantly increased at several stages of pregnancy in both strains of rat, particularly during the second half of gestation. Pseudopregnant animals showed a different hormone profile, with no significant changes until day 16 when lower concentrations were recorded. There was little variation in the circulating corticosterone concentration except in pregnant rats at term when levels fell.
These findings are discussed in relation to the known renal changes of pregnancy and pseudopregnancy.
J. Endocr. (1987) 113, 435–444
This study compared the polysaccharide and sugar taste preferences of humans and four rodent species (laboratory rats, Rattus norvegicus; Golden Syrian hamsters, Mesocricetus auratus; Mongolian gerbils, Meriones unguiculatus; Egyptian spiny mice, Acomys cahirinus). In Experiment 1 human subjects rated the pleasantness, sweetness, and flavor intensity of polysaccharide (Polycose), sucrose, and maltose solutions at concentrations of 0.0125 M to 0.4 M, and 1% to 32% concentrations. At the higher molar concentrations Polycose was rated as less sweet and less pleasant than the sucrose and maltose solutions; there were no differences in the flavor intensity ratings. With the percent concentrations Polycose was rated as less sweet and less flavorable as the sucrose and maltose solutions; there were no reliable differences in the pleasantness ratings. In Experiment 2, the Polycose, sucrose, and maltose preferences of rats, hamsters, gerbils, and spiny mice were compared using 24 hr two-bottle tests (saccharide vs. water) at concentrations of 0.001 M, 0.005 M, 0.01 M, and 0.1 M. In general, the rats displayed stronger preferences for Polycose and maltose than did the other three species. In addition, the gerbils showed a stronger Polycose preference at the 0.1 M concentration than did the hamsters and spiny mice, and the spiny mice display a weaker preference for sucrose than did the other three species. Within species comparisons revealed that all four species displayed preferences for Polycose that were as strong or stronger than their preferences for sucrose and maltose. With only a few exceptions, male and female rodents did not differ in their saccharide preferences. Thus, while rats show the most robust Polycose preference of the four rodent species, all four species were attracted to the taste of polysaccharides. Humans, on the other hand, reported that Polycose solutions were unpleasant. The results suggest that rodents have taste receptors for starch-derived polysaccharides that humans lack.
This study examines immunoreactive levels of oxytocin (OT) and arginine-vasopressin (AVP) from acid extracts of the paraventricular nucleus (PVN), supraoptic nucleus (SON), anterior commissural nucleus (ACN) and the suprachiasmatic nucleus (SCN) as well as selected extrahypothalamic sites in pregnant or postpartum (PP) rats. Animals are sacrificed between 08.30 and 10.30 h 16 or 22 days after sperm is detected in their vaginal smears or on the morning after parturition. Peptide levels of pregnant or PP animals are compared to levels of ovariectomized (OVXed) rats sacrificed and assayed simultaneously. OT immunoreactive levels in the PVN and SON are significantly elevated in late pregnancy and PP. OT content of the ACN is elevated on day 16, but drops to control levels by day 22 of pregnancy and day 1 PP. Concomitant with the falling OT content in the ACN at the end of pregnancy, samples from the ventral septum have significantly increased OT content on day 1 PP. In extracts including the nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (dMX) OT is also elevated on the day after parturition. AVP levels peak on the day before parturition in all hypothalamic nuclei examined. These increases are significantly greater than in OVXed controls in the PVN and SON. AVP levels in the lateral habenula are elevated both on day 16 of pregnancy and on the first day PP. From these data we conclude that nonapeptide levels are altered across late pregnancy and early postpartum in some hypothalamic synthesis sites and in certain limbic and brainstem sites. We also postulate that OT is transported out of the ACN to extrahypothalamic sites around the time of parturition.
Virgin rodents exhibiting cycling estrus have traditionally been used for comparative studies of reproductive behavior. However estrus occurs in other life-history contexts, some of which differ from cycling estrus (CE) in that (a) the female is disposed to behave both maternally and sexually and (b) they result in litter overlap (i.e., the simultaneous gestation and lactation of two litters). In this report, two of these other modes of estrus are examined, with emphasis on their evolutionary and ecological implications. By means of a literature search of the order Rodentia, postpartum estrus (PPE) and lactational estrus (LE) were documented in 15 families, 71 genera, and 141 species. Analysis of these data showed that PPE and LE were nonrandomly distributed across taxa. They were statistically overrepresented in the family Cricetidae and underrepresented in squirrels (Sciuridae) and in pocket mice and kangaroo rats (Heteromyidae). Analysis of the phenotypes by which PPE and LE are achieved suggests important differences between them and CE in several parameters of female reproductive effort and breeding strategy, including maternal and copulatory behavior, optimal timing of litters, and hormonal control of heat and lactation.
This review covers a description of the maternal behavior cycle in the hamster and relationships between the endocrine system and prepartum changes in activity, aggression, sexual receptivity, and maternal care. Postpartum maternal behavior consists of the mother's "normal" cannibalism of some portion of her litter, the formation of a bond between mother and her young, the development of behavioral synchrony between the mother and her pups, and maternal aggression toward conspecifics. The maternal responses of virgin female, male, and juvenile animals are described and methodological considerations in the testing of both virgin and parturient animals are presented. Finally, a theoretical framework for considering the regulation of maternal care in the hamster is presented. Two main phases of regulation are proposed; an onset phase that that originates prepartum and depends on the physiological conditions of pregnancy and a maintenance phase which provides for the continuation of maternal care during lactation and is based on both endogenous maternal factors and external litter-related stimuli. A transition period beginning at parturition facilitates the shift between the onset and maintenance phases.
The effects of pregnancy, parturition and lactation and exogenous treatments with oestradiol and progesterone on oxytocin (OXY) immunoreactivity and gene expression in the sheep brain were investigated. Immunocytochemistry was used to demonstrate that increased OXY-immunoreactivity occurred in cells of the paraventricular (PVN) and supraoptic nuclei (SON), the bed nucleus of the stria terminalis (BNST), the anterior commissural nuclei (ACN) and the periventricular part of the medial preoptic area (PvMP). Oxytocin immunoreactive terminals were also seen in the accessory olfactory nucleus, the glomerular and peri-glomerular layers of the olfactory bulb, the lateral septum, the zona incerta and the pars compacta of the substantia nigra. Compared to ovariectomized and late pregnant animals, the intensity of immunoreactivity was increased in all of these oxytocinergic elements at parturition, during lactation and following exogenous treatment with oestradiol. The OXY-immunoreactivity was also more intense in late pregnant animals compared to ovariectomized ones. Quantitative in situ hybridization histochemistry showed that cells in the PVN, SON, BNST and PvMP all showed significantly increased expression of OXY mRNA in animals at parturition and during lactation compared to late pregnant or ovariectomized animals. Expression levels in late pregnant animals were also significantly higher than in ovariectomized ones. Progesterone treatment significantly increased OXY mRNA in the PVN, SON, BNST and PvMP whereas oestradiol treatment was only effective in the PVN, BNST and PvMP. Combined treatment with these steroids did not significantly increase OXY mRNA levels in comparison with their administration alone.
Postnatal depression can have long-term adverse consequences for the mother, for the marital relationship, and for the infant's psychological development. Such depressions can be severe and resistant to both support and counselling and to therapy with antidepressant drugs. We investigated the antidepressant efficacy of oestrogen given transdermally.
In a double-blind, placebo-controlled study, 61 women with major depression, which began within 3 months of childbirth and persisted for up to 18 months postnatally, were allocated randomly active treatment (n=34; 3 months of transdermal 17 beta-oestradiol 200 micrograms daily alone, then 3 months with added cyclical dydrogesterone 10mg daily for 12 days each month) or placebo (n=27; placebo patches and tablets according to the same regimen). The women were assessed monthly by self-ratings of depressive symptoms on the Edinburgh postnatal depression scale (EPDS) and by clinical psychiatric interview (schedule for affective disorders and schizophrenia [SADS]-change scale).
On pretreatment assessments the women in both groups were severely depressed (mean EPDS score 21.8 [SD 3.0] active group, 21.3 [2.9] placebo group; SADS scores, 66.3 [11.4] and 64.3 [10.7]). During the first month of therapy the women receiving oestrogen improved rapidly, and to a significantly greater extent than controls (mean EPDS scores 13.3 [SD 5.7] vs 16.5 [5.3]. Patients receiving placebo also improved over time but, on average, their scores did not fall below the screening threshold for major depression for at least 4 months. The estimated overall treatment effect of oestrogen on the EPDS was 4.38 points (95% Cl 1.89-6.87). None of a range of other factors (age, psychiatric, obstetric and gynaecological history, severity and duration of current episode of depression, and concurrent antidepressant medication), influenced the response to oestrogen.
This study has shown that transdermal oestrogen is an effective treatment for postnatal depression. Further studies are required to establish the minimum effective dose and shortest necessary duration of treatment as well as the mechanism of antidepressant action of oestrogen.
Establishment of the behavioral significance of oxytocin neurotransmission in the brain has been a leading component in the emerging concept of neuropeptide regulation of behavior. Elucidating the behavioral effects of oxytocin has been facilitated by its profound regulation by estrogen in discrete brain areas and its subsequent role in estrogen-dependent responses. For example, female sexual behavior is estrogen dependent, estrogen markedly increases oxytocin binding in the ventromedial nucleus of the hypothalamus and infusion of oxytocin in this brain area increases female sexual behavior. A similar correlation exists for the role of oxytocin and estrogen in the regulation of maternal behavior. A possible underlying cause of these behavioral effects is that by acting as an anxiolytic, oxytocin reduces the inhibition inherent in social encounters. Behavioral tests in the laboratory frequently involve the exposure of the animal to a novel environment, such as a pup-retrieval apparatus or mating arena, combined with exposure to an unfamiliar conspecific. These stimuli are likely to induce a stress response and perhaps this anxiety is reduced by oxytocin. Recent evidence in mice suggests that oxytocin has anxiolytic properties in estrogen-treated females (McCarthy and Goldman, 1994) and supports the hypothesis that a unifying principal in oxytocin action in the brain is to facilitate social encounters by reducing the associated anxiety.
Seven women with histories of puerperal psychosis and four with histories of puerperal major depression were consecutively treated with high-dose oral estrogen immediately following delivery. None of the women had histories of nonpuerperal affective disorder, and all women were affectively well throughout the current pregnancy and at delivery. Despite the high risk for recurrent illness in this population, only one woman developed relapse of postpartum affective disorder. All others remained entirely well and required no treatment with psychotropic medications during the 1 year follow-up period. This low rate of relapse, 9% compared to an expected 35-60% without prophylaxis, suggests that oral estrogen may stem the rapid rate of change in estrogen following delivery, thereby preventing the potential impact on dopaminergic and serotonergic neuroreceptors. It is hypothesized that the rapid rate of change of estrogen after delivery creates an "estrogen withdrawal state." This may be a critical factor in driving acute puerperal affective psychosis and early-onset puerperal major depression.
The months following childbirth are a time of heightened vulnerability to depressive mood changes. Because of the abrupt and dramatic changes occurring in hormone levels after delivery, many studies have examined the role of hormonal factors in postpartum depression. The authors review the literature on potential hormonal etiologies in postpartum depression, in particular for progesterone, estrogen, prolactin, cortisol, oxytocin, thyroid, and vasopressin. While evidence for an etiologic role is lacking for most hormones, changes in certain hormonal axes may contribute to depressive mood changes in some women following childbirth.
Oxytocin receptors (OTR) are abundantly expressed in the ventromedial hypothalamus (VMH) in the rat brain. While expression of these receptors is estrogen-dependent, OTRs present in the central nucleus of the amygdala do not appear to be. We have isolated an OTR gene from a rat genomic library and analyzed its promoter region for response elements. Several regulatory elements of interest were identified, including a cAMP response element (CRE), a serum response element (SRE), several activator protein-1 elements (AP-1) in addition to a palindromic estrogen response element (ERE). In transfection assays, PKC and PKA activation by phorbol ester and forskolin treatment optimally enhanced transcription of the OTR gene. These results were further confirmed by Western blot analyses showing induction of endogenous OTRs in MCF7 cells with similar treatments.
The effect of hormone withdrawal following hormone-simulated "pregnancy" on "depressive-like behavior" in the Forced Swim Test (FST) was investigated in female Long-Evans rats. Females were randomly assigned to "pregnant", "pregnant"+estradiol benzoate (EB), and control groups. Both the "pregnant" and "pregnant"+EB groups received daily injections of the hormones estradiol and progesterone to simulate the 23-day gestational period in the rat. However, the "pregnant"+EB group continued to receive daily estradiol injections after "pregnancy". All groups were tested 48 h after the last injection of the pregnancy period in the FST and subsequently in the Open Field Test (OFT). Results revealed that the "pregnant" rats exhibited significantly increased immobility and decreased struggling and swimming behaviors as compared to the "pregnant"+EB and control groups. These findings could not be explained by an overall depression in general locomotor activity among "pregnant" rats, as the "pregnant" rats made more area crossings in the OFT. Thus "pregnant" rats exhibited behaviors consistent with "depressive-like" symptoms "post-partum" (after their hormone regime was discontinued). Continual treatment with high levels of estradiol in the "pregnant"+EB group, however, reversed the exhibition of these behaviors. These results imply that withdrawal from chronic high levels of pregnancy-associated hormones (estradiol and progesterone) can produce depressed symptomology in rodents, which can be prevented by prolonging exposure to high levels of estradiol through the post-partum period. These findings are the first demonstration of "depressive-like" symptoms in a rodent model of post-partum pregnancy and the ability of high levels of estradiol to attenuate these "depressive-like" symptoms.
The postpartum period is a time when women are vulnerable to depressive disorders, which can be severe and have long-lasting adverse sequelae. In spite of multiple contacts with health care providers, women with postpartum depression often remain unrecognized and untreated. To evaluate the association between estradiol and postpartum depression, we measured serum estradiol concentration and performed an open-label study of physiologic 17beta-estradiol.
Twenty-three women fulfilling ICD-10 criteria for major depression with postpartum onset were consecutively recruited from a psychiatric emergency unit. Serum estradiol concentrations were measured at baseline and weekly during sublingual 17beta-estradiol treatment for 8 weeks. The treatment effect was assessed using a clinician-rated depression symptom scale, the Montgomery-Asberg Depression Rating Scale (MADRS).
At baseline, all patients were severely depressed (mean MADRS total score = 40.7; range, 35-45) and had a low serum estradiol concentration (mean = 79.8 pmol/L; range, 23-140 pmol/L); in 16/23 patients, the concentration was even lower than the threshold value for gonadal failure. During the first week of estradiol treatment, depressive symptoms diminished significantly, resulting in a mean MADRS score of 11.0 (Z = -4.20, p < .001), and serum estradiol concentrations approached those of the follicular phase (mean +/- SD = 342 +/- 141 pmol/L). At the end of the second week of treatment, the MADRS scores were compatible with clinical recovery in 19/23 patients.
This preliminary study shows that depression symptoms may be rapidly reduced in patients with postpartum depression who have documented estradiol deficiency by treatment with 17beta-estradiol and suggests that estradiol can have significance in the pathophysiology of this condition and may be an option in the treatment of women vulnerable to postpartum depression.
The origin of the dopaminergic innervation of the central extended amygdala (EAc; i.e., the lateral bed nucleus of the stria terminalis [BSTl]-central amygdaloid nucleus [Ce] continuum) and accumbens shell (AcSh) was studied in the rat by combining retrograde transport of Fluoro-Gold (FG) with tyrosine hydroxylase (TH) immunofluorescence. Perikaryal profiles (PP) immunoreactive to FG and to both FG and TH were counted in A8-A14 dopaminergic districts. Our results suggest that dopaminergic inputs to the EAc and AcSh arise from the ventral tegmental area-A10, substantia nigra, pars compacta-A9, and retrorubral nucleus-A8 groups as well as from the dorsal raphe nucleus and periaqueductal gray substance, housing the dorsocaudal part of A10 group (A10dc). Quantitative estimates reveal that the A10dc group contains approximately half of the total number of FG/TH double-labeled PP projecting to Ce and BSTl. By using an anti-dopamine serum, DR/PAG projections to Ce were confirmed to be in part dopaminergic. In contrast, modest numbers of FG/TH double-labeled PP were seen in the A10dc group after injections in the sublenticular extended amygdala, interstitial nucleus of the posterior limb of the anterior commissure or AcSh. Ventral mesencephalic projections to the EAc display a crude mediolateral topographic organization, whereas those to the AcSh are topographically organized along a mediolateral and an inverted dorsoventral dimension. The diencephalic dopaminergic groups do not innervate the EAc or AcSh, except for the periventricular gray-A11 which sends light dopaminergic projections to Ce and BSTl. Overall, the present results provide additional details on the organization of the mesolimbic dopaminergic system that critically controls behavioral responsiveness to salient environmental stimuli.
Dominant subordinate relationships are formed as the result of social conflict and are maintained at least in part by communication. At this time, little is known about the neural mechanisms that are responsible for coordinating the social behaviours (e.g. aggression) that occur in association with the formation and maintenance of these relationships. The purpose of the present study was to investigate the role of oxytocin (OXT) within the medial preoptic anterior hypothalamic continuum (MPOA-AH) in the control of aggression in female hamsters. OXT injected into the MPOA-AH immediately before testing significantly reduced the duration of aggression in a dose-dependent manner. Injection of an OXT antagonist 30 min before testing significantly increased the duration of aggression. In contrast, the duration of aggression was not altered when hamsters were tested either 30 min after injection of OXT or immediately following injection of an OXT-antagonist. These data support the hypothesis that OXT release within the MPOA-AH regulates social behaviours important in the formation and maintenance of dominant subordinate relationships in female hamsters.
This article reviews the literature regarding endocrine factors postulated or presumed to be relevant in postpartum depression (PPD), a condition affecting at least 10% of childbearing women. The phenomenology and epidemiology of PPD are also described. Data suggest that parturition-related endocrine changes are causally implicated in PPD in a vulnerable subgroup of women. More specifically, studies by our group and others suggest a role for changes in estradiol and progesterone in precipitating mood symptoms among women with PPD. The mechanisms underlying such differential sensitivities remain undetermined. Future directions for research are explored.