Depression-like Behavior In Offspring Research Articles

Hippocampal Crhr1 conditional gene knockout ameliorated the depression-like behavior and pathological damage in male offspring mice caused by chronic stress during pregnancy

Numerous studies have demonstrated that chronic stress during pregnancy (CSDP) can induce depression and hippocampal damage in offspring. It has also been observed that high levels of corticotropin-releasing hormone (CRH) can damage hippocampal neurons, and intraperitoneal injection of a corticotropin releasing hormone receptor 1 (CRHR1) antagonist decreases depression-like behavior and hippocampal neuronal damage in a mouse depression model. However, whether CSDP causes hippocampal damage and depression in offspring through the interaction of CRH and hippocampal CRHR1 remains unknown and warrants further investigation. Therefore, hippocampal Crhr1 conditional gene knockout mice and C57/BL6J mice were used to study these questions. Depression-related indexs in male offspring mice were examined using the forced swim test (FST), sucrose preference test (SPT), tail suspension test (TST) and open field test (OFT). Serum CRH levels were measured by enzyme-linked immunosorbent assay (ELISA). Golgi-Cox staining was used to examine the morphological changes of hippocampal neuronal dendrites. Neuronal apoptosis in the hippocampal CA3 regions was detected by terminal deoxynucleotidy transferase dUTP nick end labeling (TUNEL) staining. The levels of mammalian target of rapamycin (mTOR), phosphorylated mTOR (p-mTOR) and protein kinase B (AKT) proteins were measured by Western blot analysis. This study showed that CSDP induces depression-like behavior, hippocampal neuronal dendrite damage and apoptosis in male offspring mice. Conditional gene knockout of hippocampal Crhr1 in mice reduced CSDP-induced depression-like behavior, hippocampal neuronal dendrite damage and apoptosis in male offspring, and counteracted the CSDP-induced decreased expression of p-Akt and mTOR activity in male offspring hippocampus. These findings demonstrated that CSDP might inhibit the Akt/mTOR pathway by increasing the levels of CRH, leading to increased CRH-mediated activation of hippocampal CRHR1, thereby inducing synaptic impairment and apoptosis in hippocampal neurons, which in turn leads to depression-like behavior in offspring.

GR/P300 Regulates MKP1 Signaling Pathway and Mediates Depression-like Behavior in Prenatally Stressed Offspring.

Accumulating evidence suggests that prenatal stress (PNS) increases offspring susceptibility to depression, but the underlying mechanisms remain unclear. We constructed a mouse model of prenatal stress by spatially restraining pregnant mice from 09:00-11:00 daily on Days 5-20 of gestation. In this study, western blot analysis, quantitative real-time PCR (qRT‒PCR), immunofluorescence, immunoprecipitation, chromatin immunoprecipitation (ChIP), and mifepristone rescue assays were used to investigate alterations in the GR/P300-MKP1 and downstream ERK/CREB/TRKB pathways in the brains of prenatally stressed offspring to determine the pathogenesis of the reduced neurogenesis and depression-like behaviors in offspring induced by PNS. We found that prenatal stress leads to reduced hippocampal neurogenesis and depression-like behavior in offspring. Prenatal stress causes high levels of glucocorticoids to enter the fetus and activate the hypothalamic‒pituitary‒adrenal (HPA) axis, resulting in decreased hippocampal glucocorticoid receptor (GR) levels in offspring. Furthermore, the nuclear translocation of GR and P300 (an acetylation modifying enzyme) complex in the hippocampus of PNS offspring increased significantly. This GR/P300 complex upregulates MKP1, which is a negative regulator of the ERK/CREB/TRKB signaling pathway associated with depression. Interestingly, treatment with a GR antagonist (mifepristone, RU486) increased hippocampal GR levels and decreased MKP1 expression, thereby ameliorating abnormal neurogenesis and depression-like behavior in PNS offspring. In conclusion, our study suggested that the regulation of the MKP1 signaling pathway by GR/P300 is involved in depression-like behavior in prenatal stress-exposed offspring and provides new insights and ideas for the fetal hypothesis of mental health.

A maternal high-fat diet during pregnancy and lactation induced depression-like behavior in offspring and myelin-related changes in the rat prefrontal cortex.

In accordance with the developmental origins of health and disease, early-life environmental exposures, such as maternal diet, can enhance the probability and gravity of health concerns in their offspring in the future. Over the past few years, compelling evidence has emerged suggesting that prenatal exposure to a maternal high-fat diet (HFD) could trigger neuropsychiatric disorders in the offspring, such as depression. The majority of brain development takes place before birth and during lactation. Nevertheless, our understanding of the impact of HFD on myelination in the offspring's brain during both gestation and lactation remains limited. In the present study, we investigated the effects of maternal HFD (60% energy from fat) on depressive-like and myelin-related changes in adolescent and adult rat offspring. Maternal HFD increased immobility time during the forced swimming test in both adolescent and adult offspring. Correspondingly, the depressive-like phenotype in offspring correlated with dysregulation of several genes and proteins in the prefrontal cortex, especially of myelin-oligodendrocyte glycoprotein (MOG), myelin and lymphocyte protein (MAL), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase), kallikrein 6, and transferrin in male offspring, as well as of MOG and kallikrein 6 in female offspring, which persist even into adulthood. Maternal HFD also induced long-lasting adaptations manifested by the reduction of immature and mature oligodendrocytes in the prefrontal cortex in adult offspring. In summary, maternal HFD-induced changes in myelin-related genes are correlated with depressive-like behavior in adolescent offspring, which persists even to adulthood.

The effect of prenatal stress on offspring depression susceptibility in relation to the gut microbiome and metabolome

Prenatal stress (PS) increases offspring susceptibility to depression, but the underlying mechanism remains unclear. Our previous results showed that PS can affect depression-like behavior in offspring through neurotransmitters and neuroinflammatory substances in the hippocampus and frontal cortex. In recent years there has been increasing evidence for a role of the gut microbiome in depression. The brain-gut axis theory suggests there is a need to further explore the mechanism involving the gut microbiome in the susceptibility of offspring to depression caused by PS. In the present study we used a stress model relevant to depression in which pregnant female rats undergo prenatal restraint stress and the offspring show susceptibility to depression. High-resolution gene sequencing for 16S ribosomal RNA markers and non-targeted metabolomic analysis were used to evaluate the fecal microbiome and the availability of metabolites, respectively. PS was found to induce depressive-like behavior in susceptible offspring (PS-S), as detected by the sucrose preference and forced swimming tests, as well as altering Alpha and Beta diversity. The different microbiota between the PS-S and control groups were mainly involved in membrane transport, carbohydrate metabolism, amino acid metabolism, and replication and repair pathways. In total, 237 and 136 important differential metabolites with significant influence on modeling analysis were obtained under positive and negative modes, respectively. The main canonical pathways found to be altered were glycerophospholipid metabolism and glycerolipid metabolism. These results suggest that gut microbiota might contribute to the onset of PS-induced depression-like behavior by affecting the glycerophospholipid and glycerolipid metabolic pathways.

Pre-mating nitenpyram exposure in male mice leads to depression-like behavior in offspring by affecting tryptophan metabolism in gut microbiota

Several studies have confirmed that the health status of the paternal affects the health of the offspring, however, it remains unknown whether paternal exposure to pesticides affect the offspring health. Here, we used untargeted metabolomics and 16S rRNA sequencing technology, combined with tail suspension test and RT-qPCR to explore the effects of paternal exposure to nitenpyram on the neurotoxicity of offspring. Our results found that the paternal exposure to nitenpyram led to the offspring's depressive-like behaviors, accompanied by the reduction of tryptophan content and the disorder of microbial abundance in the gut of the offspring. Further, we determined the expression of tryptophan metabolism-related genes tryptophanase (tnaA) and tryptophan hydroxylase 1 (TpH1) in gut bacteria and colonic tissues. We found that tryptophan is metabolized to indoles rather than being absorbed into colonocytes, which coursed the reduce of tryptophan availability after nitenpyram exposure. In conclusion, our study deepens our understanding of the intergenerational toxic effects of pesticides.

Effects of RhoA on depression-like behavior in prenatally stressed offspring rats

Depression is a common mental disease that can lead to suicide when severe. Exposure to prenatal stress (PS) can lead to depression-like behavior in offspring, but the mechanism is unclear. RhoA (Ras homology family member A) plays an important role in stress-induced changes in synaptic plasticity, participating in the development of depression by activating the downstream effector ROCK (Rho-associated protein kinase). This study explored the influence in the expression of RhoA and downstream molecules ROCK1/2 in prenatally stressed rats, and the effect of RhoA inhibitor simvastatin on depression-like behavior induced by PS. Depression-like behavior in offspring was detected by sucrose preference test, forced swimming test, and open-field test. The mRNA and protein expression of RhoA and ROCK1/2 in the hippocampus and prefrontal cortex of offspring rats were detected by qRT-PCR and western blotting, respectively. Our results showed that PS causes depression-like behavior in offspring rats, associated with elevated expression of RhoA, ROCK1/2 in the hippocampus and prefrontal cortex. After administration of simvastatin to PS rats, the expression of RhoA and ROCK2 was significantly reduced, alleviating depression-like behavior. Our study demonstrated that RhoA participates in the depression-like behavior in prenatally stressed offspring rats, which may be a potential target for antidepressant therapy.

Cross-fostering alleviates depression-like behavior mediated by EAAT2 and SNARE complex in prenatal stress offspring rat

Previous studies have shown that prenatal stress (PS) can potentially contribute to depression-like behavior in offspring and that this effect may be moderated by cross-fostering. However, the underlying mechanism of this effect remains to be determined. This study aimed to determine the effect of cross-fostering on the expression of EAAT2 and the SNARE complex in the hippocampus and the prefrontal cortex of PS offspring rats and to demonstrate functional effects on depression-like behavior. The impacts of cross-fostering were functionally assessed using the sucrose preference test (SPT), the forced swimming test (FST) and the elevated plus maze (EPM). Quantitative real-time PCR was used to determine changes in the expression of EAAT2 and SNAREs mRNA in the hippocampus and the prefrontal cortex of offspring rats. PS offspring rats showed significantly decreased sucrose preference and prolonged immobility time, while cross-fostering effectively increased sucrose preference and shorten the time of immobility. The expression of EAAT2 mRNA in PS offspring rats was markedly reduced, whilst the core mRNA expression of the SNARE complex increased. Our results provide strong evidence demonstrating that cross-fostering can alleviate depression-like behavior and regulate the abnormal expression levels of EAAT2 mRNA and SNARE complex in the hippocampus and the prefrontal cortex of PS offspring rats. Our findings contribute to further understanding of the pathogenesis of PS-induced depression and may help to inform the future development of novel treatment approaches.

Maternal exposure to high-fat diet modifies anxiety-like/depression-like behaviors and compounds of Serotonergic System in offspring: A preclinical systematic review.

Maternal nutrition affects offspring physiology and behavior including susceptibility to mental health-related states. Perinatal high-fat diet (HFD) consumption has been associated with lower levels of serotonin as well as the development of anxiety-like and depression-like behaviors in offspring. The aim of this systematic review was to investigate the effects of maternal HFD during pregnancy and/or lactation on these behaviors and on some aspects of the serotonergic system. Criteria for eligibility included studies of offspring of rodents and non-human primates exposed to HFD at least during pregnancy and/or lactation, offspring that showed outcomes related to anxiety-like and depression-like behaviors and to the serotonergic system. The searches were realized in the LILACS, Web of Science, Scopus, and PubMed databases. The systematic review protocol was registered on the CAMARADES website. The internal validity was assessed by the SYRCLE risk of bias tool. The Kappa index was used for analyzing agreement among the reviewers. In addition, the PRISMA statement was used to report this systematic review. Sixteen articles were included in this review. Most of which studied HFD prior to mating and during pregnancy and lactation. All studies analyzed outcomes related to emotional behavior; three analyzed outcomes related to serotonin system compounds. Maternal consumption of HFD was found to be associated with an inconsistent pattern of the expression of TPH2 as well as reduced the immunoreactivity of 5-HT in the prefrontal cortex and increased 5-HT1A receptor expression in the dorsal raphe of offspring. An association between an HFD and alterations in emotional behavior was found in most of the studies selected.

Long-term exercise from adolescence to adulthood reduces anxiety- and depression-like behaviors following maternal immune activation in offspring

Maternal immune activation is an environmental risk factor for the development of neuropsychiatric disorders such as anxiety and depression later in life. There is an urgent need to develop therapeutic strategies for treating or preventing psychiatric disorders with developmental origins. There is important information that physical exercise is a therapeutic strategy for treating anxiety and depression-related disorders. This study set out to determine the long-term effects of exercise on anxiety and depression-like behaviors following maternal immune activation in adult offspring. Pregnant mice were treated with lipopolysaccharides (LPS) or vehicle. Then offspring were subjected to a combination of different exercise protocols including voluntary running wheel, swimming, and treadmill exercises from adolescence to adulthood. Anxiety and depression-related symptoms in adult offspring were evaluated using open field, elevated plus maze, sucrose preference test, and forced swim test. The hypothalamic–pituitary–adrenal (HPA) axis reactivity was assessed by measuring corticosterone in serum. We also measured oxytocin, malondialdehyde, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 in the brain of adult offspring. Our findings indicated that long-term exercise significantly decreased anxiety- and depression-like behaviors in offspring prenatally exposed to maternal immune activation. The exercise also decreased corticosterone levels in the serum, and increased oxytocin and IL-10 levels in the brain of these offspring; whereas no significant alterations in TNF-α, IL-1β, IL-6 were found. Taken together, this study suggests that exercise might be a therapeutic strategy for the treatment of anxiety and depression-related behaviors following maternal immune activation in offspring.

Peripubertal stress following maternal immune activation sex-dependently alters depression-like behaviors in offspring

There is an increasing evidence that maternal immune activation can render the offspring more vulnerable to the impacts of peripubertal stress on behavioral abnormalities in adulthood. The aim of this study was to investigate the combined effects of maternal immune activation and peripubertal stress on depression-related behaviors in male and female offspring. Pregnant mice were treated with lipopolysaccharides (LPS) or vehicle, and then offspring were subjected to stressful conditions or left unstressed during peripubertal period. Four behavioral tests including novelty-suppressed feeding test, sucrose preference test, tail suspension test, and forced swim test were used to measure depression-related behaviors in offspring. The activity of hypothalamic–pituitary–adrenal (HPA) or - gonadal (HPG) axes were also evaluated by measuring basal and stress-induced corticosterone, testosterone and estradiol levels in the serum of offspring. Our findings revealed that mild maternal immune activation and peripubertal stress interacted synergistically to induce depression-related symptoms and HPA axis hyperactivity in male offspring, whereas no significant changes were observed in female offspring. We also found that this combination of environmental factors significantly decreased serum testosterone and estradiol levels in adult male and female offspring respectively. There were also significant correlations between behavioral parameters and hormones. Taken together, these findings show that the combination of two environmental risk factors can predispose the male offspring to increased depression-related symptoms in adulthood as compared to the females. This study suggests that the combination of maternal immune activation and peripubertal stress can alter depression-related behaviors and HPA axis function in a sex-dependent manner.

Morphine Exposure and Enhanced Depression-like Behaviour Confronting Chronic Stress in Adult Male Offspring Rat.

Introduction:Opioid addiction is an important concern in the World. Reports demonstrate that substance use disorder could influence genetic and environmental factors, and children of addicts have a higher rate of psychopathology. In this study, we investigated depression-like behavior among offspring of morphine-exposed rat parents.Methods:Adult male and female Wistar rats received morphine for 21 consecutive days and then let them were free of drugs for ten days. Offspring of these rats were divided into three distinct groups: maternal morphine-exposed, paternal morphine-exposed, and both maternal and paternal morphine-exposed. We used sucrose preference and Forced Swim Test (FST) to measure depression-like behavior. Also, we induced chronic mild stress using repeated corticosterone injection and evaluated depression-like behavior in offspring of morphine-exposed parents compared with offspring of healthy ones.Results:Results indicated that depression-like behaviors in the offspring of morphine-exposed rats were higher than those in the offspring of the control group in confronting with chronic mild stress. Additionally, mild chronic stress can produce an exaggerated effect on depression-like behavior in offspring of the morphine-exposed parent(s) compared with those of the control group.Conclusion:Our data support the previous hypothesis that the depression rate is higher in the children of addicts. We verified that even when mother or father was clean of opioid in the time of gestation, their children would be susceptible to depression. Dysregulation of hypothalamic-pituitary-adrenal axis and changing in neuronal features in the hippocampus increased depression-like behavior in the offspring of morphine-exposure parents.

Involvement of SNARE complex in the hippocampus and prefrontal cortex of offspring with depression induced by prenatal stress

BackgroundPrenatal stress (PS) exposure can cause depression-like behavior in offspring, and maladaptive responses including physiological and neurobiological changes. Glutamate neurotransmission is implicated in effects of PS and in antidepressant mechanisms; however, the mechanisms underlying its involvement remain unclear. In the synapse, the formation of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is essential for vesicular docking and neurotransmitter release. MethodsTo explore effects of PS on the SNARE complex, pregnant rats were assigned to a control or PS group. Both male and female offspring in each group were used in this study. PS rats were exposed to restraint stress three times daily for 45 min on days 14–20 of pregnancy. ResultsIn the PS offspring, the expression of the SNARE protein SNAP-25, vesicle-associated membrane protein (VAMP)-2, and Syntaxin 1a was significantly increased in the hippocampus and prefrontal cortex. These observations were associated with increased levels of proteins that chaperone SNARE complex formation, including Munc-18, α-synuclein, CSPα, complexin1, and complexin2. Immunoblotting of hippocampal and prefrontal cortex homogenates revealed significantly increased SNARE complex formation. vGluT1 protein expression was also significantly increased in the offspring. Additionally, PS was associated with increased mRNA expression of VAMP1, VAMP2, SNAP25, Syntaxin1a, and Syntaxin1b in the hippocampus and prefrontal cortex. Increased monomeric SNARE proteins, SNARE complex formation, vesicle-associated proteins, and vGluT1 may explain the increase in glutamate and its downstream excitotoxicity. ConclusionsThese results support the hypothesis that glutamate release and vesicular glutamate transporters play a role in PS-induced depression-like behavior of rat offspring.

Strain-dependent effects of prenatal maternal immune activation on anxiety- and depression-like behaviors in offspring

There is converging evidence that prenatal maternal infection can increase the risk of occurrence of neuropsychiatric disorders like schizophrenia, autism, anxiety and depression in later life. Experimental studies have shown conflicting effects of prenatal maternal immune activation on anxiety-like behavior and hypothalamic-pituitary-adrenal (HPA) axis development in offspring. We investigated the effects of maternal immune activation during pregnancy on anxiety- and depression-like behaviors in pregnant mice and their offspring to determine whether these effects are dependent on strain. NMRI and C57BL/6 pregnant mice were treated with either saline or lipopolysaccharide on gestational day 17 and then interleukin (IL)-6 and corticosterone (COR) levels; anxiety or depression in the pregnant mice and their offspring were evaluated. The results indicate that maternal inflammation increased the levels of COR and anxiety-like behavior in NMRI pregnant mice, but not in C57BL/6 dams. Our data also demonstrate that maternal inflammation elevated the levels of anxiety-and depression-like behaviors in NMRI offspring on the elevated plus-maze, elevated zero-maze, tail suspension test and forced swimming test respectively, but not in the open field and light-dark box. In addition, we did not find any significant change in anxiety- and depression-like behaviors of adult C57BL/6 offspring. Our findings suggest that prenatal maternal immune activation can alter the HPA axis activity, anxiety- and depression-like behaviors in a strain- and task-dependent manner in offspring and further comprehensive studies are needed to prove the causal relationship between the findings found here and to validate their relevance to neuropsychiatric disorders in humans.