Zhongliang Zhu

Prolactin, a potential mediator of reduced social interactive behavior in newborn infants following maternal perinatal depressive symptoms

BACKGROUNDnThe hormone prolactin (PRL) plays a crucial role for the initiation and maintenance of maternal behavior, and is also associated with the etiology of mood disorders in women, especially for depression. The present study aimed to determine whether maternal peripheral prolactin would be associated with newborn behavior disorders following maternal perinatal depressive symptoms, and further to explore the efficacy of the Newborn Behavioral Observations (NBO) in improving newborn social interactive behavior.nnnMETHODSnInterview and the 24-item Hamilton Rating Scale for Depression (HAMD) were used to assess the hospitalized pregnant women waiting for delivery at 37-42weeks of gestation. A total of 255 subjects were recruited, diagnosed with depression (n=135), and control group (n=120). Within 2 weeks postpartum, mothers were asked to fill with Maternal Attachment Inventory (MAI) to measure maternal care. Neonatal Behavioral Assessment Scale (NBAS) were used to evaluate newborn behavior. The depressed mother-newborns dyad was randomly assigned to NBO intervention and control group. Serum prolaction in mothers and cortisol in mothers and newborns were measured.nnnRESULTSnThe newborns of mothers exposed to maternal perinatal depressive symptoms displayed the reduced newborn social interactive behavior accompanied by decreased maternal serum PRL as well as increased maternal and neonatal serum cortisol. The NBO could be an effective intervention tool.nnnLIMITATIONSnOur study could not be double-blind. The mothers knew which group their infant were in.nnnCONCLUSIONSnMaternal peripheral PRL had the potential to be a mediator in reduced social interactive behavior in newborn infants following maternal perinatal depressive symptoms.

Alterations of proliferation and differentiation of hippocampal cells in prenatally stressed rats

PURPOSEnTo clarify the alterations of proliferation and differentiation of hippocampal cells in prenatally stressed rats.nnnMETHODSnWe investigated the impact of prenatal restraint stress on the hipocampal cell proliferation in the progeny with 5-bromo-2-deoxyuridine (BrdU), which is a marker of proliferating cells and their progeny. In addition, we observed the differentiation of neural stem cells (NSCs) with double labeling of BrdU/neurofilament (NF), BrdU/glial fibrillary acidic protein (GFAP) in the hipocampus.nnnRESULTSnPrenatal stress (PS) increased cell proliferation in the dentate gyrus (DG) only in female and neuron differentiation of newly divided cells in the DG and CA4 in both male and female. Moreover, the NF and GFAP-positive cells, but not the BrdU-positive cells, BrdU/NF and BrdU/GFAP-positive cells, were found frequently in the CA3 and CA1 in the offspring of each group.nnnCONCLUSIONSnThese results possibly suggest a compensatory adaptive response to neuronal damage or loss in hippocampus induced by PS.

Hippocampal GR- and CB1-mediated mGluR5 differentially produces susceptibility and resilience to acute and chronic mild stress in rats

The molecular mechanism of individual response of susceptibility and resilience under psychological stress remains controversial and unclear. The present study aimed to explore the relationship of metabotropic glutamate receptor 5 (mGluR5) with glucocorticoid receptor (GR) or cannabinoid receptor (CB1) and further indicate the molecular mechanism of susceptibility and resilience to acute stress (AS) and chronic mild stress (CMS). Sucrose preference test and open field test were used to evaluate the response of susceptibility and resilience under stress in rats. The mRNA levels and protein expressions of mGluR5, GR, and CB1 were detected. AS induced a 35% reduction in the sucrose intake of rats, and these rats were considered as susceptible to stress; 21% of the rats showed resilience to the stress. Thirty-three percent of rats in the CMS group showed reduced sucrose water intake and were considered susceptible, while 20% of rats were considered resilient. Hippocampal mGluR5 mRNA and protein levels were increased in the susceptible rats. Pharmacological testing showed that GR was positively associated with mGluR5 in susceptible rats in the CMS group, while CB1 was negatively related to mGluR5 in susceptible rats in the AS group. The results suggested that GR and CB1 in the hippocampus might regulate mGluR5 protein and mRNA levels, which might be related to individual responses of susceptibility and resilience under AS and CMS.

Hippocampal Acetylation may Improve Prenatal-Stress-Induced Depression-Like Behavior of Male Offspring Rats Through Regulating AMPARs Expression

This study is to determine the role and mechanism of hippocampal acetylation in prenatal stress (PS) induced depression-like behavior of male offspring rats. PS-induced depression rat model was established. Sucrose preference and forced swim test were used to observe the behavior changes of male offspring rats. Hippocampal acetylation was induced by Trichostatin A injection. Quantitative real-time PCR and Western blot were used to determine the changes of AMPARs in acetylated hippocampus. The behavioral tests proved that AMPA was involved in the PS-induced depression-like behavior in offspring rats. Hippocampal acetylation significantly increased the preference to sucrose of PS-induced offspring rats and reduced the immobile time in forced swimming test, suggesting that acetylation could improve PS-induced depression-like behaviors. In addition, PS inhibited the expression levels of GluA1-3 subunits of AMPARs in the offspring hippocampus, while Hippocampal acetylation could reverse this effect by increasing GluA1-3 expression. PS-induced reduction of GluA1-3 subunits of AMPARs may be an important potential mechanism of offspring depression. Hippocampal acetylation may improve PS-induced offspring depression-like behavior through the enhanced expression of AMPARs (GluA1-3 subunits).

Prenatal Stress Impairs Spatial Learning and Memory Associated with Lower mRNA Level of the CAMKII and CREB in the Adult Female Rat Hippocampus

Prenatal stress (PS) results in various behavioral and emotional alterations observed in later life. In particular, PS impairs spatial learning and memory processes but the underlying mechanism involved in this pathogenesis still remains unknown. Here, we reported that PS lowered the body weight in offspring rats, particularly in female rats, and impaired spatial learning and memory of female offspring rats in the Morris water maze. Correspondingly, the decreased CaMKII and CREB mRNA in the hippocampus were detected in prenatally stressed female offspring, which partially explained the effect of PS on the spatial learning and memory. Our findings suggested that CaMKII and CREB may be involved in spatial learning and memory processes in the prenatally stressed adult female offspring.

H3K9 acetylation of Tph 2 involved in depression-like behavior in male, but not female, juvenile offspring rat induced by prenatal stress

Increasing evidence has shown that prenatal stress (PS) could cause depression-like behavior in the offspring, which is sex-specific. However, the underlying mechanisms remain to be elucidated. This study is to investigate the involvement of tryptophan hydroxylase 2 (Tph2) H3K9 acetylation (H3K9ac) modification on PS-induced depression-like behavior in juvenile offspring rats (JOR). PS models were established, with or without trichostatin A (TSA) treatment. Animal behavior was assessed by the sucrose preference test (SPT) and forced swimming test (FST). The mRNA and protein expression levels of TPH2 in the dorsal raphenucleus (DRN), hippocampus, and prefrontal cortex were detected with quantitative real-time PCR and Western blot analysis, respectively. The Tph2 H3K9ac levels in the hippocampus were also analyzed. SPT and FST showed significantly reduced sucrose preference and significantly prolonged immobility in PS-induced male juvenile offspring rats (MJOR). Moreover, the mRNA and protein expression levels of TPH2 in the DRN and hippocampus were significantly declined, while the hippocampal Tph2 H3K9ac levels were significantly declined in the PS-induced MJOR. Furthermore, the PS-induced effects in MJOR could be reversed by the microinjection of TSA. However, no significant effects were observed for the female juvenile offspring rats (FJORs). In conclusion, our results showed that the Tph2 H3K9ac modification is only involved in PS-induced depression-like behavior in MJOR, in a sex-specific manner. These findings might contribute to the understanding of the disease pathogenesis and clinical treatment in future.

The Impact and Mechanism of Methylated Metabotropic Glutamate Receptors 1 and 5 in the Hippocampus on Depression-Like Behavior in Prenatal Stress Offspring Rats

An increasing number of epidemiological investigations and animal models research suggest that prenatal stress (PS) could cause depression-like behavior in the offspring, which is sex specific. However, the underlying mechanisms remain to be elucidated. This study is to investigate the promoter methylation of metabotropic glutamate receptor 1 (mGluR1) and metabotropic Glutamate Receptor 5 (mGluR5) gene modification on PS induced depression-like behavior in offspring rats (OR). PS models were established, with or without 5-aza-2′-deoxycytidine (5-azaD, decitabine) treatment. Animal behavior was assessed by the sucrose preference test (SPT), forced swimming test (FST), and open field test (OFT). The mRNA and protein expression levels of mGluR1 and mGluR5 in the hippocampus of offspring were detected with quantitative real-time PCR and Western blot analysis, respectively. The promoter methylation in the hippocampus of mGluR1 and mGluR5 OR were also analyzed. SPT showed significantly reduced sucrose preference in PS induced OR. FST showed significantly prolonged immobility time in PS induced OR. OFT showed significantly reduced central residence time in PS induced OR and no significantly influence in rearing as well as in frequency of micturition. Moreover, the mRNA, protein expression levels, and gene promoter methylation level of mGluR1 and mGluR5 in the hippocampus were significantly increased in the PS induced male OR, while no significantly influence in the PS induced female OR. Furthermore, the PS induced effects in male OR could be reversed by the microinjection of 5-azaD. In conclusion, our results showed that the promoter methylation of mGluR1 and mGluR5 gene modification is only involved in PS induced depression-like behavior in male OR in a sex-specific manner. These findings might contribute to the understanding of the disease pathogenesis and clinical treatment in future.

Involvement of prolactin in newborn infant irritability following maternal perinatal anxiety symptoms

BACKGROUNDnNewborn irritability could be an unique and special status and/or adverse neurobehavioral outcomes which was independent of serious disease. To determine whether maternal perinatal anxiety symptoms was associated with newborn irritability, and whether the alteration of serum prolactin in newborns were involved in newborn irritability.nnnMETHODSn205 pregnant women were recruited: normal group (nu202f=u202f100), and anxiety group (nu202f=u202f105), which was randomly divided to Newborn Behavioral Observations (NBO)+anxiety group(nu202f=u202f65) and control+anxiety group(nu202f=u202f40). Newborn Irritability was assessed by Neonatal Behavioral Assessment Scale(NBAS). Serum prolactin, cortisol and 5-HT in mothers and infants were measured.nnnRESULTSn1. The scores of irritability items in the newborns of anxiety group were higher than that of the normal group (pu202f<u202f0.05). 2. Lower serum PRL, 5-HT and higher serum cortisol were found in the newborns of anxiety group compared with that of the control group both postpartum 2d and 15 (pu202f<u202f0.05). 3. The level of serum PRL in newborn infants were significantly and negatively correlated to the scores of irritability items (pu202f<u202f0.05). 4. After 7 rounds of NBO interventions, the anxiety scores of mothers and the scores of irritability items of newborns in the NBO intervention group were all lower than those of the control group (pu202f<u202f0.05) .nnnLIMITATIONSnIn future experiments, we should explore the effect of PRL in the breast milk on newborn infant serum PRL.nnnCONCLUSIONSnProlactin could be a potential mediator in newborn irritability following maternal perinatal anxiety symptoms.

PM2.5 exposure during pregnancy induces hypermethylation of estrogen receptor promoter region in rat uterus and declines offspring birth weights

Particulate matter 2.5 (PM2.5) exposures during pregnancy could lead to declined birth weight, intrauterine developmental restriction, and premature delivery, however, the underlying mechanisms are still not elucidated. There are few studies concerning the effects of PM2.5 exposure on maternal and child health in Xian (one of the cities with severe air pollution of PM2.5 in North China). Then, this study aimed to investigate the effect of PM2.5 exposure in Xian on the offspring birth weights and the possibly associated epigenetic mechanisms. We found the Low and High groups: the offspring with declined birth weights; the decreased mRNA and protein expression of the estrogen receptor (ERs) and eNOs in the uterus; the decreased endometria vascular diameter maximum (EVDM); the increased mRNA and protein expressions of the DNMT1 and 3b in the uterus; the elevated methylation levels of the CpG sites in the CpG island of ERα promoter region in the uterus. However, no differences were observed in the mRNA or protein expressions of ERβ and DNMT3a between the Clean and PM2.5 exposure groups, as well as endometriavascular density (EVD). Additionally, PM2.5 level was negatively correlated with the ERα protein expression, EVDM and offspring birth weight, as well as the methylation level of the CpG sites in the CpG island of ERα promoter region and the ERα protein expression in the uterus; whereas the ERα protein expression was positively correlated with the offspring birth weight, as well as PM2.5 level and the methylation level of the CpG sites in the CpG island of ERα promoter region in the uterus. Taken together, elevated methylation level of the CpG sites in the CpG island of ERα promoter region reduces ERα expression in the uterus, which could be one of the epigenetic mechanisms that pregnant PM2.5 exposure reduces the offspring birth weights.

NO involvement in the inhibition of ghrelin on voltage-dependent potassium currents in rat hippocampal cells

Ghrelin is a peptide hormone that plays an important role in promoting appetite, regulating distribution and rate of use of energy, cognition, and mood disorders, but the relevant neural mechanisms of these function are still not clear. In this study, we examined the effect of ghrelin on voltage-dependent potassium (K+) currents in hippocampal cells of 1-3 days SD rats by whole-cell patch-clamp technique, and discussed whether NO was involved in this process. The results showed that ghrelin significantly inhibited the voltage-dependent K+ currents in hippocampal cells, and the inhibitory effect was more significant when l-arginine was co-administered. In contrast, N-nitro- l-arginine methyl ester increased the ghrelin inhibited K+ currents and attenuated the inhibitory effect of ghrelin. While d-arginine (D-AA) showed no significant impact on the ghrelin-induced decrease in K+ current. These results show that ghrelin may play a physiological role by inhibiting hippocampal voltage dependent K+ currents, and the NO pathway may be involved in this process.