Maternal Separation Research Articles

Sex-dependent effects of postweaning exposure to an enriched environment on visceral pain and anxiety- and depression-like behaviors induced by neonatal maternal separation.

BackgroundNeonatal maternal separation (NMS) can lead to visceral pain and anxiety- and depression-like behaviors. An enriched environment (EE) can alleviate NMS-induced pain and mental disorders, but previous studies have mostly been performed in male animals. Therefore, the aim of this study was to investigate whether the effects of EE were sex dependent at different stages of development.MethodsFemale and Male C57BL/6 J mice that had been subjected to NMS alone and those subjected to both NMS and exposed to EE were used in this study. The visceral pain threshold test (PTT), open field test (OFT), sucrose preference test (SPT), and forced swimming test (FST) were conducted to evaluate visceral pain, anxiety-like behavior, and depression-like behavior in mice, respectively.ResultsCompared with the male mice in the NMS group without EE exposure, those exposed to EE from postnatal day (P)21 to 41 showed an increase of the visceral pain threshold in the PTT, an increase of the central time and central distance in the OFT, an increase of the sucrose preference rate in the SPT, and a decrease of the time of immobility in the FST. Compared with both female and male mice in the NMS group without EE exposure, those exposed to EE from P21 to P61 had an increase of the visceral pain threshold in the PTT, an increase of the central time and central distance in the OFT, an increase in the sucrose preference rate in the SPT, and a decrease of the time of immobility in the FST.ConclusionsEE is more effective in male NMS mice, while longer EE is required in female NMS mice for positive effects.

Postpartum depression in rats causes poor maternal care and neurochemical alterations on dams and long-lasting impairment in sociability on the offspring

Postpartum depression is a mentally disabling disease with multifactorial etiology that affects women worldwide. It can also influence child development and lead to behavioral and cognitive alterations. Despite the high prevalence, the disease is underdiagnosed and poorly studied. To study the postpartum depression caused by maternal separation model in rats, dams were separated from their litter for 3 h daily starting from lactating day (LD) 2 through LD12. Maternal studies were conducted from LD5 to LD21 and the offspring studies from postnatal day (PND) 2 through PND90. The stress caused by the dam-offspring separation led to poor maternal care and a transient increase in anxiety in the offspring detected during infancy. The female offspring also exhibited a permanent impairment in sociability during adult life. These changes were associated with neurochemical alterations in the prefrontal cortex and hippocampus, and low TSH concentrations in the dams, and in the hypothalamus, hippocampus and striatum of the offspring. These results indicate that the postpartum depression resulted in a depressive phenotype, changes in the brain neurochemistry and in thyroid economy that remained until the end of lactation. Changes observed in the offspring were long-lasting and resemble what is observed in children of depressant mothers.

Effects of fast-acting antidepressant drugs on a postpartum depression mice model

Postpartum depression (PPD) is a severe psychiatric disorder with devastating consequences on child development and mother’s health. Dysregulation of glutamatergic and GABAergic signalling has been described in the corticolimbic system of PPD patients, who also show a downregulation of allopregnanolone levels in serum. Consequently, a synthetic allopregnanolone-based treatment is the current eligible drug to treat PPD patients. Alternatively, ketamine appears to be a promising medication for preventing PPD, nevertheless the differences in efficacy between both treatments remains unknown due to the lack of comparative studies. On this basis, the present study aims to compare the effectiveness of allopregnanolone and ketamine on a PPD-like mouse model. Our results show that postpartum females undergoing a maternal separation with early weaning (MSEW) protocol show increased despair-like behaviour, anhedonia and disrupted maternal care. Such symptoms are accompanied by lower allopregnanolone serum levels, reduction of vesicular transporters of GABA (VGAT) and glutamate (VGLUT1) in the infralimbic cortex (IL), as well as decreased hippocampal cellular proliferation. Furthermore, both drugs prevent despair-like behaviour while only ketamine reverts anhedonia. Both treatments increase hippocampal neurogenesis, while only allopregnanolone raises VGAT and VGLUT1 markers in IL. These findings suggest that ketamine might be even more effective than allopregnanolone, which points out the necessity of including ketamine in clinical studies for PPD patients. Altogether, we propose a new mice model that recapitulates the core symptomatology and molecular alterations shown in PPD patients, which allows us to further investigate both the neurobiology of PPD and the therapeutic potential of antidepressant drugs.

Early life stress exacerbates behavioural and neuronal alterations in adolescent male mice lacking methyl-CpG binding protein 2 (Mecp2).

The methyl-CpG binding protein 2 gene (MECP2) encodes an epigenetic transcriptional regulator implicated in neuronal plasticity. Loss-of-function mutations in this gene are the primary cause of Rett syndrome and, to a lesser degree, of other neurodevelopmental disorders. Recently, we demonstrated that both Mecp2 haploinsuficiency and mild early life stress decrease anxiety-like behaviours and neuronal activation in brain areas controlling these responses in adolescent female mice. Here, we extend this work to males by using Mecp2-null and wild type adolescent mice subjected to maternal separation and their non-stressed controls. We assessed their behavioural responses in a battery of anxiety-provoking tests. Upon exposure to an elevated plus maze in aversive conditions, we evaluated changes in c-FOS expression in stress- and anxiety-related brain regions. In addition, we assessed the impact of maternal separation in neuronal maturation using doublecortin and reelin as surrogate markers. Mutant males showed reduced motor abilities, increased activation of the olfactory bulbs, probably due to breathing abnormalities, and decreased activation of the paraventricular thalamic nucleus, when compared to wild type mice. In addition, maternal separation increased the number of immature doublecortin-like neurons found in Mecp2-null animals. Moreover, this work shows for the first time that reelin is decreased in the mutant animals at the olfactory tubercle, piriform cortex and hippocampal dentate gyrus, an effect also associated to maternal separation. Taken together, our results suggest that maternal separation exacerbates some phenotypical alterations associated with lack of MeCP2 in adolescent males.

Sinisan alleviates depression-like behaviors by regulating mitochondrial function and synaptic plasticity in maternal separation rats

BackgroundSinisan (SNS) consists of four kinds of herbs, which is the core of antidepressant prescription widely used in traditional Chinese medicine clinic treatment for depression induced by early life stress. However, the role and precise mechanism of SNS antidepressant have not yet been elucidated. PurposeThis study aimed to investigate the mechanism SNS on antidepressant of regulating mitochondrial function to improve hippocampal synaptic plasticity. Methods90 Sprague-Dawley (SD) rats male pups on Post-Natal Day (PND) 0 were randomly divided into Control group (ddH20), Model group (ddH20), Fluoxetine group (5.0 mg/kg fluoxetine), and SNS-L group (2.5 g/kg SNS), SNS-M group (5.0 g/kg SNS) and SNS-H group (10.0 g/kg SNS), 15 animals per group. Maternal separation (MS) from PND1 to PND21, drug intervention from PND60 to PND90, and behavior tests including sucrose preference test, open field test and forced swimming test from PND83 to PND90 were performed. Synaptic structure and mitochondrial structure were observed by TEM. The expression levels of PSD-95 and SYN were detected by immunohistochemistry and western blot test, the adenosine triphosphate (ATP) content in the hippocampus was detected by assay kits, and the expression levels of Mfn2, Drp1 and Fis1 protein were detected by western bolt test. ResultsSNS can alleviate depression-like and anxiety-like behaviors in MS rats, improve the damage of synapses and mitochondria, reduce the decrease of ATP in hippocampus, and reverse the expression levels of PSD-95, SYN, Mfn2, Drp1, and Fis1 proteins. ConclusionSNS reduced the risk of early life stress induced depression disorder via regulating mitochondrial function and synaptic plasticity. Targeting mitochondrial may be a novel prospective therapeutic avenue for antidepressant.

Antibiotic-induced microbiota depletion in normally-reared adult rats mimics the neuroendocrine effects of early life stress

Early life stress induced by maternal separation (MS) causes neuroendocrine, behavioral, and metabolic alterations that are related to gut dysbiosis. MS also increases microglial activation and decreases neurogenesis. Whether these long-term alterations are maintained or worsened in the absence of gut microbiota remains unknown. Hence, this study evaluated the effect of MS symptomatology after antibiotic-induced microbiota depletion (AIMD) in adult rats. Control and maternally separated (3 h per day from postnatal day one to 14, MS180) rats were subjected to AIMD for one month, then assessed for behavioral, metabolic, and neuroendocrine responses. Effects of MS180 and AIMD on gut microbiota were confirmed by qPCR. The data indicate that MS180 caused a passive coping strategy in the forced swimming test and decreased hippocampal neurogenesis. In addition, fasting glucose, cholesterol, and corticosterone levels increased, which correlated with a decrease in Lactobacillus spp counts in the caecum. AIMD also increased immobility in the forced swimming test, decreased hippocampal neurogenesis, and augmented corticosterone levels. However, it had no effects on glucose homeostasis or plasma lipid levels. Furthermore, the MS180-induced long-term effects on behavior and neurogenesis were not affected by microbiota depletion. Meanwhile, the metabolic imbalance was partially reversed in MS180 + AIMD rats. These results show that AIMD mimics the behavioral consequences of MS180 but may prevent metabolic imbalance, suggesting that gut dysbiosis could be part of the mechanisms involved in the maintenance of the long-term consequences of early life stress.

Maternal separation affects anxiety-like behavior beginning in adolescence and continuing through adulthood and related to Dnmt3a expression

Early life stress, including maternal separation, is among one of the main causes of anxiety in adolescents. DNA methyltransferase 3A (Dnmt3a) is a key molecule that regulates DNA methylation and is found to be associated with anxiety-like behavior. It is not clear whether maternal separation affects anxiety levels in mice at different developmental stages or whether Dnmt3a plays a role in this process. Here, by using the open field test to explore the effect of maternal separation on anxiety-like behavior in mice of different ages, it was found that maternal separation could successfully induce anxiety-like behavior in adolescent mice, which continued through adulthood. By using Western blot, we found that the levels of Dnmt3a in the hippocampus and cortex showed different trends in maternal separation mice on postnatal day (P)17. Furthermore, by using immunostaining, we found that the expression levels of Dnmt3a in the cortex and hippocampus were significantly different and decreased to varying degrees with the age of mice, which was the reason for different trends. Our results provide an experimental basis for further development of anxiety/depression treatment programs more suitable for adolescence.NEW & NOTEWORTHY Most anxiety disorders begin in adolescence and continue through adulthood, and research on adolescent anxiety's pathogenesis and treatment options is insufficient. In this research, our results show that maternal separation can successfully induce anxiety-like behavior in adolescent mice that continues through adulthood, further accompanied by abnormal expression of Dnmt3a, which provides an experimental basis for further development of anxiety/depression treatment programs more suitable for adolescence.

Influence of early maternal separation on susceptibility to the activity-based anorexia model in male and female Sprague Dawley rats

A principal animal paradigm employed in Anorexia Nervosa (AN) study is the activity-based anorexia (ABA) model. The model's efficacy in recapitulating the core features of AN in humans allows for the study of the parameters involved in the disorder. The current study examined the susceptibility to the ABA protocol in the presence of a significant stressor (maternal separation) in male and female Sprague Dawley rats. More importantly, we analysed the sex-differences on activity levels during different periods of the ABA protocol to determine the period(s) influencing the most pathological weight loss. Both components of the ABA protocol contributed to the subjects’ bodyweight loss. Stress in the first two weeks of development conferred a protective effect in males. Time spent and activity levels on the running wheel were higher in females compared to males. Hyperactivity in ABA subjects was observed during the food-anticipatory activity (FAA) and postprandial activity in males and during the FAA and nocturnal activity periods in females. This study aids in understanding the effect of intensity of activity during specific periods on the pathological weight loss in ABA rats. These observations are informative for therapies aimed at ameliorating body mass index in AN patients.

Involvement of toll-like receptor 5 in mouse model of colonic hypersensitivity induced by neonatal maternal separation.

BACKGROUNDChronic abdominal pain is the most common cause for gastroenterology consultation and is frequently associated with functional gastrointestinal disorders including irritable bowel syndrome and inflammatory bowel disease. These disorders present similar brain/gut/microbiota trialogue alterations, associated with abnormal intestinal permeability, intestinal dysbiosis and colonic hypersensitivity (CHS). Intestinal dysbiosis can alter colon homeostasis leading to abnormal activation of the innate immunity that promotes CHS, perhaps involving the toll-like receptors (TLRs), which play a central role in innate immunity.AIMTo understand the mechanisms between early life event paradigm on intestinal permeability, fecal microbiota composition and CHS development in mice with TLRs expression in colonocytes.METHODSMaternal separation model (NMS) CHS model, which mimics deleterious events in childhood that can induce a wide range of chronic disorders during adulthood were used. Colonic sensitivity of NMS mice was evaluated by colorectal distension (CRD) coupled with intracolonic pressure variation (IPV) measurement. Fecal microbiota composition was analyzed by 16S rRNA sequencing from weaning to CRD periods. TLR mRNA expression was evaluated in colonocytes. Additionally, the effect of acute intrarectal instillation of the TLR5 agonist flagellin (FliC) on CHS in adult naive wildtype mice was analyzed.RESULTSAround 50% of NMS mice exhibited increased intestinal permeability and CHS associated with intestinal dysbiosis, characterized by a significant decrease of species richness, an alteration of the core fecal microbiota and a specific increased relative abundance of flagellated bacteria. Only TLR5 mRNA expression was increased in colonocytes of NMS mice with CHS. Acute intrarectal instillation of FliC induced transient increase of IPV, reflecting transient CHS appearance.CONCLUSIONAltogether, these data suggest a pathophysiological continuum between intestinal dysbiosis and CHS, with a role for TLR5.

Autotheory and the maternal: my impossible mother–daughter separation

This special edition of the Journal of Psychosocial Studies is based on 2019 Association for the Psychoanalysis of Culture and Society (APCS) conference presentations on the theme of displacement. Having listened to the presentations, I offer this paper as my own response to similar issues of mother–daughter displacement. Inspired by the panel’s analysis of the maternal in interpersonal relations and professional affinities, I begin by exploring my intersectional adult identities of daughter, mother and teacher to expose my ambivalence towards my career in literature and psychoanalysis. I continue by applying psychoanalytic theory to the pedagogical transference in my classroom space and uncover my own misguided attempt at maternal separation. Drawing correlations with Maggie Nelson’s (2015) The Argonauts, I conclude by contemplating autotheory as a space of self-writing that is particularly suitable for explorations of the maternal in both form and content. Autotheory, I argue, as exemplified in the panel and my response, extends the impossibility of mother–daughter separation into a meaningful shared plurality.

Enriched environment alleviates adolescent visceral pain, anxiety- and depression-like behaviors induced by neonatal maternal separation.

BackgroundNeonatal maternal separation (NMS), a major kind of early life stress, increases the risk of visceral pain, anxiety- and depression-like behaviors in adulthood. An enriched environment (EE) has been shown to successfully rescue the brain from various early life psychological stressors. Therefore, this study aimed to investigate whether NMS induces visceral pain, anxiety- and depression-like behaviors in adolescents and to evaluate the impact of EE in infancy on these symptoms.MethodsMale C57BL/6 J mice that had been subjected to NMS were used in this study. The visceral pain threshold test (PTT), open field test (OFT), and sucrose preference test (SPT) were conducted to evaluate visceral pain, anxiety- and depression-like behaviors in mice, respectively. An enzyme linked immunosorbent assay (ELISA) for tumor necrosis factor-α (TNF-α), interleukin-1β, (IL-1β), and interleukin-10 (IL-10) was performed to assess neuroinflammatory responses. Then, the effects of EE (free-turning running wheels, pipes, stairs, and various colored ocean balls, etc.) on NMS-induced behaviors and neuroinflammatory factors were examined.ResultsThe impacts of NMS included adolescent visceral pain, anxiety- and depression-like behaviors. The medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and paraventricular nucleus (PVN) were biased towards pro-inflammatory features. Further, EE alleviated adolescent visceral pain, anxiety- and depression-like behaviors. The application of EE up-regulated the expression of IL-10, and down-regulated the expression of IL-1β and TNF-α in mPFC, BLA, and PVN.ConclusionsThe effects of NMS include adolescent visceral pain, anxiety- and depression-like behaviors, accompanied by an imbalance of neuroinflammation. Intervention with EE in pediatric mice relieved these symptoms by reducing neuroinflammation in the central nervous system.

Upregulation of Netrin-1 in the hippocampus mediates the formation of visceral hypersensitivity induced by maternal separation

Early adverse life events (EALs), such as maternal separation (MS), can cause visceral hypersensitivity, which is thought to be a key pathophysiological mechanism of irritable bowel syndrome (IBS). Previous studies mainly focused on EALs-induced visceral hypersensitivity in adulthood but did not consider that it may have occurred in the preadult period. We previously found that rats who experienced MS suffered from visceral hypersensitivity starting from the post-weaning period. Moreover, the hippocampus is considered to be critical in regulating the formation of visceral hypersensitivity induced by MS. But the underlying mechanisms throughout different life periods are unclear. In this study, behavioral tests, RNA-seq, lentiviral interference, and molecular biology techniques were applied to investigate the molecular mechanism in the hippocampus underlying MS-induced long-lasting visceral hypersensitivity. It was found that both visceral sensitivity and anxiety-like behaviors were significantly increased in MS rats in post-weaning, prepubertal, and adult periods, especially in the prepubertal period. Subsequently, RNA-seq targeting the hippocampus identified that the expression level of Netrin-1 was significantly increased in all periods, which was further confirmed by quantitative real-time PCR and Western blot. Knocking-down hippocampal Netrin-1 in the post-weaning period by lentivirus interference alleviated visceral hypersensitivity and anxiety-like behaviors of MS rats in the later phase of life. In addition, deleted in colorectal cancer (DCC), instead of neogenin-1(Neo-1) or uncoordinated (UNC5), was proved to be the specific functional receptor of Netrin-1 in regulating visceral hypersensitivity, whose upregulation may result in the most severe symptoms in the prepubertal period. Furthermore, the activation of the Netrin-1/DCC pathway could enhance long-term potentiation (LTP) in the hippocampus, probably via recruitment of the AMPA receptor subunit GluA1, which finally resulted in the formation of visceral hypersensitivity. These novel findings suggest that long-lasting over-expression of Netrin-1 can mediate visceral hypersensitivity and anxiety disorder from the post-weaning period to adulthood by activating DCC/GluA1 pathway in the hippocampus. Moreover, early intervention of Netrin-1 in the post-weaning period could lead to significant symptom relief afterward, which provides evidence that the Netrin-1/DCC/GluA1 signaling pathway may be a potential therapeutic target for the treatment of visceral hypersensitivity in clinics.

Neonatal maternal deprivation facilitates the expression of a panic-like escape behavior in adult rats

A wealth of evidence associates disruptions of the parent-infant relationship (e.g. childhood parental loss or parental neglect) with the later appearance of panic disorder. In rodents, neonatal maternal separation and maternal deprivation (MD) are reported to increase the expression of anxiety-related defensive responses in adult animals. However, little is known about the long-term consequences of these early-life stressors in animal models of panic. We here investigated the effects of a single 24 h-episode of MD on post-natal day 11 (PND 11) in adult male Wistar rats submitted to two animal models that associate escape expression with panic attacks: the elevated T-maze and exposure to severe hypoxia (7% O2). We also investigated the involvement of serotonin (5-HT) in the observed changes. Although neonatal MD did not affect the behavioral responses measured in the elevated T-maze, it facilitated the expression of escape during hypoxia exposure, indicating a panicogenic-like effect. Pre-test administration of the 5-HT synthesis inhibitor, para-chlorophenylalanine (PCPA; 4 daily injections of 100 mg/kg) facilitated escape attempts in non-deprived animals during the hypoxia challenge, but did not interfere with the expression of this behavior in maternally-deprived rats. The levels of 5-HT1A receptors in key panic- and anxiety-associated areas, the dorsal periaqueductal gray and amygdala, respectively, were not different between previously deprived and non-deprived animals. Plasma corticosterone levels were significantly increased by hypoxia exposure, independently of the animals’ previous stress condition or PCPA administration. Therefore, MD on PND 11 predisposes the adult animal to the panic-evoking effects of severe hypoxia, a stimulus also reported to induce panic attacks in humans. The lack of PCPA effect on the pro-escape consequence of MD may be indicative that 5-HT signaling is impaired in the stressed animal.

Evaluation of rosmarinic acid against myocardial infarction in maternally separated rats.

Depression and coronary heart diseases are the common comorbid disorder affecting humans globally. The present study evaluated the effectiveness of rosmarinic acid (RA) against myocardial infarction (MI) in comorbid depression induced by maternal separation in rats. Maternal stress is one of the childhood crises that may be a potential risk factor for coronary heart disease in later part of life. As per protocol, 70-80% of pups were separated daily for 3h between postnatal day 1 (PND1) and postnatal day 21 (PND21). Forced-swim test, sucrose preference test, and electrocardiography were performed during the experiment. Body weight was measured on PND0, PND35, and PND55. Orally rosmarinic acid (25mg/kg and 50mg/kg) and fluoxetine (10mg/kg) was done from PND35 to PND55. On PND53 and PND54, isoproterenol (100mg/kg, subcutaneously) was administered to induce myocardial infarction. On PND55, blood was collected and animals sacrificed, and plasma corticosterone, brain-derived neurotrophic factor, cardiac biomarkers, interleukine-10, and anti-oxidant parameters were measured. Rosmarinic acid and fluoxetine ameliorated the maternal separation-induced increase in immobility period, anhedonia, body weight, ST elevation, corticosterone, creatine kinase-MB (CK-MB), and lactate dehydrogenase (LDH). At the same time, both drugs elevated the tissue levels of BDNF, IL-10, glutathione, and superoxide dismutase activity. This study provides the first experimental evidence that maternal stress is an independent risk factor of cardiac abnormalities in rats. Moreover, maternal stress synergistically increases the severity of cardiac abnormalities induced by isoproterenol. Interestingly, fluoxetine and rosmarinic acid effectively ameliorated behavioral anomalies and myocardial infarction in maternally separated rats. Schematic representation of possible molecular mechanism of action of rosmarinic acid against MS-induced myocardial infarction. RA, rosmarinic acid; MS, maternal separation; PND, postnatal days; ISO, isoproterenol; BDNF, brain-derived neurotrophic factor; GSH, glutathione; SOD, superoxide dismutase; IL-10, interleukin-10; MI, myocardial infarction.

Neonates at high risk of hypoglycaemia: Is admission necessary?

To evaluate the practice of routine admission of infants at high risk of hypoglycaemia by determining the incidence of hypoglycaemia, factors that predict necessary admission and breastfeeding outcomes. A retrospective cohort study of neonates admitted to a tertiary neonatal unit for high risk of hypoglycaemia. Clinical data, including blood glucose concentrations, body fat percentage and time to initiation of feeding, were collected for 122 infant-maternal dyads for a 3-year period from April 2016 to May 2019. Descriptive statistical analysis and binary logistic regression analysis were undertaken. Hypoglycaemia developed in 39.3% of the neonates identified as high risk. Overall, 69 out of 122 admissions were potentially avoidable. Initial blood glucose was the most significant predictive factor for necessary admission with odds ratio of 3.26 (95% confidence interval (CI) 1.04-10.17) for an initial glucose of 1.6-2.0 and 27.05 (95% CI 5.06-144.42) for initial glucose ≤1.5. Exclusive breastfeeding rates at discharge were lower in admitted infants (59%) compared to the overall hospital rate (75.6%). Neonates at high risk of hypoglycaemia should be monitored with their mothers as most infants needing admission are detected by initial blood glucose concentration. This would reduce infant-maternal separation and potentially improve breastfeeding rates.

Tong-Xie-Yao-Fang alleviates diarrhea-predominant irritable bowel syndrome in rats via the GCN2/PERK-eIF2α-ATF4 signaling pathway

BackgroundDiarrhea-predominant irritable bowel syndrome (IBS-D) is a common functional gastrointestinal disease. Tong-Xie-Yao-Fang (TXYF), the traditional Chinese herbal medicine prescription, is a classic and effective prescription for the treatment of IBS-D, but its mechanism of action is not fully clarified. ObjectiveTo evaluate the efficacy of TXYF in the treatment of IBS-D and to explore its potential mechanism of action. MethodsChanges in the serum levels of 50 free amino acids were targeted for detection by high-performance liquid chromatography (HPLC), and the expression of glucose-regulated protein 78 (GRP78), general control nonderepressible 2 (GCN2), and endoplasmic reticulum-resident kinase (PERK) was detected by immunohistochemistry examinations in healthy volunteers and IBS-D patients. The IBS-D rat was constructed by the three-factor superposition method of neonatal maternal separation, 2,4,6-trinitrobenzene sulfonic acid enema, and chronic unpredictable stress stimulation. The treatment effect of TXYF on IBS-D rats was observed by recording the body weight, grasp force, fecal water content (FWC), and abdominal withdrawal reflex (AWR) of rats before and after treatment. The effects of GCN2/PERK-eukaryotic initiation factor-2 (eIF2α) -activating transcription Factor 4 (ATF4) pathway proteins and gene expression were analyzed by western blotting, reverse transcription–polymerase chain reaction (RT–qPCR), and immunohistochemistry evaluations. ResultsCompared with healthy volunteers, IBS-D patients exhibited lower levels of cysteine, γ-aminoacetic acid (GABA), homoproline, and lysine, and immunohistochemistry showed strong activation of GRP78, a marker of endoplasmic reticulum stress. Differential expression of GCN2 and PERK proteins was detected in IBS-D patients and rat colons. In the IBS-D rats, TXYF improved the body weight and grasp force, reduced the FWC, and improved the AWR score. TXYF increased the levels of p-GCN2 and GCN2 and reduced the levels of GRP78, p-PERK, PERK, p-eIF2α, and eIF2α, thereby affecting the expression of the apoptosis-related transcription factors ATF4, CHOP, Caspase-3, and Bcl-2. ConclusionOur study showed that TXYF improved IBS-D by inhibiting apoptosis. The anti-apoptosis effects were potentially mediated by regulating the GCN2/PERK-eIF2a-ATF4 signaling pathway.

Application Effect of Low Frequency Electrical Stimulation Pulse Intervention Combined with Manual Massage Nursing in Postpartum Pubic Combined Maternal Separation

Application Effect of Low Frequency Electrical Stimulation Pulse Intervention Combined with Manual Massage Nursing in Postpartum Pubic Combined Maternal Separation

Behavioral and hormonal effects of prenatal and maternal separation stresses in postpartum rats

ABSTRACT The aim of this study was to evaluate the hormone and anxiety levels of rat dams who were exposed to prenatal and maternal separation stress paradigms. Sprague–Dawley rat dams were divided into Prenatal Stress (PS), Maternal Separation (MS), Prenatal Stress and Maternal Separation (PS+MS), and Control (C) groups. All animals were subjected to the open field test on the 21st postnatal day. Same-day blood samples were obtained from the tail vein in order to examine corticotrophin-releasing hormone (CRH), estradiol, oxytocin, epinephrine, norepinephrine, prolactin, progesterone, brain-derived neurotrophic factor (BDNF), endorphin, and vasopressin levels of animals via enzyme-linked immunosorbent assay (ELISA). Oxytocin levels were the highest in the control group and the lowest in the MS group. CRH levels in the MS group were significantly higher than in the PS group (p < .05). Intriguingly, the BDNF level was the lowest in the control and highest in the MS group. While there was a strong correlation in the CRH, vasopressin, BDNF levels in the control group, various relations were observed in the stress groups. Stressed animals exhibited several behavioral anomalies including decreased fear responses such as freezing, enhanced duration, and increased number of entries into the central zone of the open field test apparatus. PS dams exhibited reductions in estradiol and norepinephrine levels relative to control or MS dams.

The First 1000 Days of Life and the Risk of Future Drug Consumption

Context: The first 1000 days of life last from the beginning of pregnancy to the age of two, a unique step that shapes the basis for a person’s health over their lifetime. Numerous studies have indicated the relationship between one’s first 1000 days of life and the consequent adverse outcomes in adulthood. However, to the extent that we have reviewed it, not a single study has shown the relationship between various aspects of an individual’s first 1000 days of life and the probability of drug consumption in adult life. Hence, the primary purpose of this narrative review was to understand the role of the first 1000 days of life on vulnerability to drug abuse later in life. Evidence Acquisition: This article is a narrative review that has identified the role of the first 1000 days of life on susceptibility to substance abuse later in life. The articles were extracted from valid databases, including PubMed, Scopus, Science Direct, Web of Science, and Embase. Results: Various significant research has pointed to the mother’s distress and anxiety during pregnancy through embryonic planning, influencing the planning of the hypothalamic-pituitary-adrenal (HPA) axis and epigenetic changes. The intestinal microbiota is a part of a complex link named the microbiota-gut-brain axis that can affect drug abuse through the variety and number of intestinal microbiota. On the other hand, a mother’s drug consumption during pregnancy can function as chronic stress by affecting the enteric nervous system (ENS), which activates the concurrent axis of HPA and dopamine pathways by changing the reward circuit and the subsequent increase in drug abuse. The results indicated that various factors, such as exposure to adverse childhood experiences (ACEs), parental separation, and attachment insecurity, increase the probability of drug abuse in adulthood. Nevertheless, the quality of nurturing care during the first 1000 days of life and the mother’s warm relationship with children may hinder the increase in addiction in society. Conclusions: The first 1000 days of one's life are a crucial and delicate stage. If these days are tainted with unpleasant events, the various mechanisms can reduce a person's resilience to drug abuse in later life. How the first 1000 days of an infant’s life and the quality of this period, such as prenatal stress, substance use during pregnancy, ACEs, maternal-infant bonding, maternal separation (MS), and intestinal microbiota, can affect drug abuse in the future. As a result, focusing on the first 1000 days of life is critical to adapting prevention strategies. Health policymakers can design suitable entries during pregnancy and early childhood to reduce the probability of drug abuse.

NUCB2/Nesfatin-1 Regulation of Chronic Visceral Hyperalgesia.

Objective We previously described that different concentration Nucleobindin-2 (NUCB2)/Nesfatin-1 gradients differently regulated visceral hypersensitivity in irritable bowel syndrome. Therefore, this study is aimed at evaluating the effect of NUCB2/Nesfatin-1 on model rats with chronic visceral hyperalgesia. Methods Neonatal and mature Sprague-Dawley rats were randomly divided into the healthy control and chronic visceral hyperalgesia model groups. The model was built by combining maternal separation with the acetic acid enema. The models were identified by the distension volume threshold to reach abdominal withdraw reflex (AWR) score = 3, histological staining, and myeloperoxidase (MPO) detection. The visceral sensitivity to chronic visceral hyperalgesia was then evaluated. Result Rats in the model group responded more strongly to pulling stimulation than healthy controls; the distension volume threshold causing AWR3 response in model rats was lower than the control group before NUCB2/Nesfatin-1 intervention. After intervention, the distension volume threshold was significantly lower in the NUCB2/Nesfatin-1 central intervention group than in the NUCB2/Nesfatin-1 peripheral intervention group, and the peak value of external oblique muscle electrical activity was significantly higher. Additionally, compared with the male intervention group, in the female intervention group, the volume threshold was significantly lower and the peak value was higher. Conclusion NUCB2/Nesfatin-1 could regulate visceral sensitivity in chronic visceral hyperalgesia model rats; its regulatory effect correlated with the type of NUCB2/Nesfatin-1 intervention approaches (central or peripheral) and sex (male or female).