Development Of Depressive-like Behavior Research Articles

Prenatal co-exposure to diisodecyl phthalate and ozone contribute to depressive behavior in offspring mice through oxidative stress and TWIST1 participation

Exposure to diisodecyl phthalate (DIDP) during early pregnancy may be a risk factor for depressive behavior in offspring. While ozone (O3) exposure also raises the probability of depressive behavior during the preceding DIDP-induced process. In the present study, we investigated the effects of prenatal exposure to DIDP and O3 on the development of depressive-like behavior in offspring mice. The study found that prenatal exposure to both DIDP and O3 significantly increased depressive-like behavior in the offspring mice compared to either DIDP or O3 alone. Prenatal exposure to DIDP and O3 obviously increased the levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol, and decreased the levels of brain-derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), dopamine (DA) and norepinephrine (NE) in the brain tissues of offspring mice. Transcriptome analysis further revealed significant alterations in genes related to oxidative stress and TWIST1 (a helix-loop-helix transcription factor) in response to the combined exposure to DIDP and O3. HPA axis activation, dysregulation of neurodevelopmental factors, oxidative stress and TWIST1 involvement, collectively contributed to the development of depression-like behaviors in offspring mice following prenatal exposure to DIDP and O3. Moreover, the study also verified the potential role of oxidative stress using vitamin E as an antioxidant. The findings provide valuable evidence for the relationship between co-exposure to DIDP and O3 and depression, highlighting the importance of considering the combined effects of multiple environmental pollutants in assessing their impact on mental health outcomes.

Inhibitory Neurons in Nucleus Tractus Solitarius Are Involved in Decrease of Heart Rate Variability and Development of Depression-Like Behaviors in Temporal Lobe Epilepsy.

Diminished heart rate variability (HRV) has been observed in epilepsy, especially in epilepsy with depressive disorders. However, the underlying mechanism remains elusive. We studied HRV, spontaneous recurrent seizures, and depression-like behaviors in different phases of pilocarpine-induced temporal lobe epilepsy (TLE) in mice. Single-cell RNA sequencing analysis was used to identify various nerve cell subsets in TLE mice with and without depression. Differentially expressed gene (DEG) analysis was performed in epilepsy, depression, and HRV central control-related brain areas. We found decreased HRV parameters in TLE mice, and alterations were positively correlated with the severity of depression-like behaviors. The severity of depression-like behaviors was correlated with the frequency of spontaneous recurrent seizure. Characteristic expression of mitochondria-related genes was significantly elevated in mice with depression in glial cells, and the enrichment analysis of those DEGs showed an enriched GABAergic synapse pathway in the HRV central control-related brain area. Furthermore, inhibitory neurons in the nucleus tractus solitarius, which is an HRV central control-related brain area, were specifically expressed in TLE mice combined with depression compared with those in mice without depression. A significantly enriched long-term depression pathway in DEGs from inhibitory neurons was found. Our study reported correlations between HRV and epilepsy-depression comorbidity in different phases of TLE. More importantly, we found that HRV central control-related inhibitory neurons are involved in the development of depression in TLE, providing new insights into epilepsy comorbid with depression.

Histamine 3 receptor antagonism mitigates neuroinflammation and depression-like behavior in a mouse model of food allergy

Abstract Histamine (HA) is a major allergic response mediator as well as a neuromodulatory neurotransmitter and a blood-brain barrier (BBB) regulator. Consequently, dysregulation of the central histaminergic system could offset brain homeostasis and function. Indeed, mood and behavioral disorders are often comorbid with conditions that elevate systemic HA, such as mastocytosis and allergy. We have previously shown elevated levels of brain HA and its receptor subtype H3 (H3R) in a mouse model of cow’s milk allergy (CMA). Additionally, neuroinflammation and cortical demyelination were observed in association with depression-like behavior in CMA mice. However, whether the elevated HA and H3R were responsible for the development of these cellular and behavioral pathologies is unknown. We hypothesized that the elevated brain HA leads to central histaminergic dysfunction through H3R, ultimately resulting in cortical demyelination and aberrant behaviors. To investigate the role of H3R, CMA mice were treated daily with thioperamide, a selective BBB-permeable H3R antagonist, to block the action of HA through this receptor. Despite the production of allergen-specific IgE, thioperamide prevented depression-like behavior. Thioperamide also ameliorated CMA-associated cortical demyelination and axonal loss compared to saline-treated mice. Our findings strongly suggested that H3R signaling contributed to cortical demyelination and the development of depression-like behaviors in our CMA mice. Targeting HA production or signaling may provide a therapeutic strategy to reduce the risk of neurodegeneration and associated brain dysfunction in susceptible individuals. Supported by grants from NIH (1R01AI168563-01, P20GM113123-06, and P20GM103442).

Delayed Formation of Neonatal Reflexes and of Locomotor Skills Is Associated with Poor Maternal Behavior in OXYS Rats Prone to Alzheimer's Disease-like Pathology.

Postnatal brain development is characterized by high plasticity with critical windows of opportunity where any intervention may positively or adversely influence postnatal growth and lead to long-lasting consequences later in life. Poor maternal care is among these interventions. Here, we found that senescence-accelerated OXYS rats prone to an Alzheimer's disease-like pathology are characterized by more passive maternal behavior and insufficient care for pups as compared to control (Wistar) rats. OXYS pups demonstrated a delay in physical development (of auricle detachment, of emergence of pelage and incisors, of eye opening, and of vaginal opening in females) and late manifestation of reflexes and locomotor skills. All observed behavioral abnormalities are connected either with poor coordination of limbs' movements or with a decrease in motivation and development of depression-like behavior. It is possible that their manifestations can be promoted by the features of maternal behavior of OXYS rats. Overall, these early-life events may have long-lasting consequences and contribute to neurodegeneration and development of the Alzheimer's disease-like pathology later in life.

Attenuation of the levels of pro-inflammatory cytokines prevents depressive-like behavior during ethanol withdrawal in mice

Clinical studies indicate that alcohol-dependent patients may develop depressive symptoms during abstinence, which may increase the likelihood of relapse. It is known that both in alcohol exposure and depression, there is an increase in the levels of pro-inflammatory cytokines in the brain. However, the putative contribution of increased levels of pro-inflammatory cytokines in the development of depressive-like behavior during ethanol withdrawal has not been evaluated. In the present study, we aimed to investigate if ethanol withdrawal-induced depressive-like behavior is related to increased levels of pro-inflammatory cytokines in the brain. Male mice were treated with vehicle (saline 0.9%, v.o.) or ethanol (2 g/kg, v.o.) for 14 days. After 5 days of cessation of the ethanol treatment, mice were subjected to the forced swim test (FST), tail suspension test (TST), and open field test (OFT) and then sacrificed. Their brains were analyzed for the levels of pro-inflammatory cytokines. Ethanol withdrawal mice showed increased immobility time in the FST and TST than by the control group, indicating increased depressive-like behavior. No alterations in OFT were observed. Ethanol withdrawal increased the levels of tumor necrosis factor-alpha (TNF-α) in the hippocampus and striatum, interleukin-1 beta (IL-1β) in the hippocampus, and IL-6 in the prefrontal cortex and hippocampus. Treatment of mice with nimesulide (5 or 10 mg/kg/day), a cyclooxygenase-2 inhibitor, during ethanol withdrawal prevented the increase in immobility time in the TST. Similar results were observed in the FST upon nimesulide treatment, although with a higher dose. Nimesulide treatment (10 mg/kg) prevented the ethanol withdrawal-induced alterations in the levels of TNF-α, IL-1β, and IL-6 in the hippocampus, prefrontal cortex, and striatum. Treatment of mice with an atypical antidepressant drug, vilazodone (0.3 or 1 mg/kg) prevented the increase in depressive-like behavior induced by ethanol withdrawal in the TST. In the FST, the increase in immobility time was prevented only by 1 mg/kg vilazodone treatment. Vilazodone prevented the increase in the levels of TNF-α, IL-1β, and IL-6 in the hippocampus, IL-6 in the prefrontal cortex, and TNF-α in the striatum. In conclusion, these data indicate that increased levels of pro-inflammatory cytokines may play a role in the development of depressive-like behavior during ethanol withdrawal in mice.

Innate immune stimulation by monophosphoryl lipid A prevents chronic social defeat stress-induced anxiety-like behaviors in mice

BackgroundInnate immune pre-stimulation can prevent the development of depression-like behaviors in chronically stressed mice; however, whether the same stimulation prevents the development of anxiety-like behaviors in animals remains unclear. We addressed this issue using monophosphoryl lipid A (MPL), a derivative of lipopolysaccharide (LPS) that lacks undesirable properties of LPS but still keeps immune-enhancing activities.MethodsThe experimental mice were pre-injected intraperitoneally with MPL before stress exposure. Depression was induced through chronic social defeat stress (CSDS). Behavioral tests were conducted to identify anxiety-like behaviors. Real-time polymerase chain reaction (PCR) and biochemical assays were employed to examine the gene and protein expression levels of pro-inflammatory markers.ResultsA single MPL injection at the dose of 400 and 800 μg/kg 1 day before stress exposure prevented CSDS-induced anxiety-like behaviors, and a single MPL injection (400 μg/kg) five but not 10 days before stress exposure produced similar effect. The preventive effect of MPL on anxiety-like behaviors was also observed in CSDS mice who received a second MPL injection 10 days after the first MPL injection or a 4 × MPL injection 10 days before stress exposure. MPL pre-injection also prevented the production of pro-inflammatory cytokines in the hippocampus and medial prefrontal cortex in CSDS mice, and inhibiting the central immune response by minocycline pretreatment abrogated the preventive effect of MPL on CSDS-induced anxiety-like behaviors and pro-inflammatory cytokine productions in the brain.ConclusionsPre-stimulation of the innate immune system by MPL can prevent chronic stress-induced anxiety-like behaviors and neuroinflammatory responses in the brain in mice.

Electrolytic lesions of the bilateral ventrolateral orbital cortex not only directly reduce depression-like behavior but also decreased desperate behavior induced by chronic unpredicted mild stress in rats

BackgroundPrevious studies have revealed that ventrolateral orbital cortex (VLO) may play an important role in the regulation of emotional behavior. However, it is not known what effect VLO damage will have on emotion regulation.ResultsData showed that damage of VLO increased the anxiety-like behavior in open field test and elevated plus maze, and decreased the depressive behavior in forced swimming test and learned helplessness test. Besides, the impulsive aggressive behaviors were also increased while the attack latency decreased after VLO lesion. What’s more, damage of VLO decreased depressive behaviors induced by chronic unpredicted mild stress in rats.ConclusionsThese results suggest that the integrity of VLO plays an important role in emotional regulation, and the damage of VLO may inhibit the development of depression-like behavior.

The Role of Neutrophil Extracellular Traps in Lipopolysaccharide-Induced Depression-like Behaviors in Mice.

Peripheral inflammation plays a key role in the development of depression-like behaviors. However, the mechanisms underlying these effects remain largely unknown. Here, we found that the level of citrullinated histone H3 (cit-H3) significantly increased in the plasma of wildtype mice treated with lipopolysaccharide (LPS), which indicated that neutrophil extracellular traps (NETs) were formed. Moreover, the LPS-induced depression-like and asocial behaviors were significantly alleviated in the mice deficient of NETs. Mechanistically, NETs formation aggravated peripheral inflammation by increasing the concentrations of TNF-α, IL-1β and IL-6 in plasma, which are major proinflammatory cytokines that can enter the brain, resulting in microglia activation and reduced astrocytes. Following this, increased TNF-α and IL-1β were released into brain, inducing neuroinflammation and finally depression-like behaviors. Prohibiting NETs by PAD4 ablation significantly prevented LPS-induced microglia activation and the loss of astrocytes. Our results propose the role for peripheral NETs in LPS-induced depression-like behavior, and that NETs might be a potential target to prevent inflammation-induced major depressive disorder.

Neonatal Proinflammatory Stress and Expression of Neuroinflammation-Associated Genes in the Rat Hippocampus.

Differential effect of the neonatal proinflammatory stress (NPS) on the development of neuroinflammation in the hippocampus and induction of the depressive-like behavior in juvenile and adult male and female rats was studied. NPS induction by bacterial lipopolysaccharide in the neonatal period upregulated expression of the Il6 and Tnf mRNAs accompanied by the development of depressive-like behavior in the adult male rats. NPS increased expression of the mRNAs for fractalkine and its receptor in the ventral hippocampus of the juvenile male rats, but did not affect expression of mRNAs for the proinflammatory cytokines and soluble form of fractalkine. NPS downregulated expression of fractalkine mRNA in the dorsal hippocampus of juvenile males. No significant effects of NPS were found in the female rats. Therefore, the NPS induces long-term changes in the expression of neuroinflammation-associated genes in different regions of the hippocampus, which ultimately leads to the induction of neuroinflammation and development of depressive-like behavior in male rats.

Hippocampal mitogen-activated protein kinase phosphatase-1 regulates behavioral and systemic effects of chronic corticosterone administration

Clinical reports indicate a bidirectional relationship between mental illness and chronic systemic diseases. However, brain mechanisms linking chronic stress and development of mood disorders to accompanying peripheral organ dysfunction are still not well characterized in animal models. In the current study, we investigated whether activation of hippocampal mitogen-activated protein kinase phosphatase-1 (MKP-1), a key factor in depression pathophysiology, also acts as a mediator of systemic effects of stress. First, we demonstrated that treatment with the glucocorticoid receptor (GR) agonist dexamethasone or acute restraint stress (ARS) significantly increased Mkp-1 mRNA levels within the rat hippocampus. Conversely, administration of the GR antagonist mifepristone 30 min before ARS produced a partial blockade of Mkp-1 upregulation, suggesting that stress activates MKP-1, at least in part, through upstream GR signaling. Chronic corticosterone (CORT) administration evoked comparable increases in hippocampal MKP-1 protein levels and produced a robust increase in behavioral emotionality. In addition to behavioral deficits, chronic CORT treatment also produced systemic pathophysiological effects. Elevated levels of renal inflammation protein markers (NGAL and IL18) were observed suggesting tissue damage and early kidney impairment. In a rescue experiment, the effects of CORT on development of depressive-like behaviors and increased NGAL and IL18 protein levels in the kidney were blocked by CRISPR-mediated knockdown of hippocampal Mkp-1 prior to CORT exposure. In sum, these findings further demonstrate that MKP-1 is necessary for development of enhanced behavioral emotionality, while also suggesting a role in stress mechanisms linking brain dysfunction and systemic illness such as kidney disease.

The Influence of Cross-Fostering on Alcohol Consumption and Depressive-Like Behaviors in HA and LA Mice: The Role of the Endogenous Opioid System.

The development of alcohol dependence and depression is determined by various genetic and environmental factors. In the presented study, we used high analgesia (HA) and low analgesia (LA) mouse lines, characterized by different endogenous opioid system activity and divergent blood–brain barrier permeability, to determine the influence of cross-fostering of these lines raised by surrogate mothers on ethanol consumption and development of depressive-like behaviors. We also investigated ethanol drinking by biological parents or surrogate mothers. Furthermore, we investigated whether these parental changes would alter the effect of naloxone on ethanol intake and depressive-like behaviors in offspring. Our results reveal that cross-fostering of HA and LA raised by surrogate mothers has a greater impact on depressive-like behaviors than ethanol consumption. Ethanol intake by biological parents substantially affected depressive-like behaviors and ethanol consumption in offspring. Moreover, ethanol intake by biological parents or an adoptive mother modified the effect of naloxone on ethanol consumption and preference and depressive-like behaviors in the HA offspring only. Together, these results indicate that cross-fostering differentially affects the effect of naloxone on alcohol consumption and the development of depression.

Prophylactic ( R,S )‐ketamine Protects Against Fear Overgeneralization 8.5.5

The adolescent stage is a sensitive time period for brain development. During this phase, the brain's high plasticity makes adolescents more susceptible to external factors, one of these being stress. Anxiety and mood disorders such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) mainly stem from exposure to stress. Studies have shown that a single injection of (R,S)-ketamine, an NMDA antagonist, prior to stress protects against the development of depressive-like behavior and attenuates learned fear. However, most of these studies were conducted in post-natal day 60 (P60) adult mice. We sought to identify the neural correlates of fear in post-natal day 35 (P35) adolescent mice and which neural alterations correlate to fear generalization. In the experiment, ArcCreERT2 P60 and P35 mice were administered a pattern separation (PS) paradigm. The mice were then sacrificed, and their brains were processed on either day 3 (D3) or day 10 (D10) following context A or B exposures, respectively. Through cell quantification and hippocampal analysis, we saw that during the PS task, both groups of mice exhibited comparable levels of freezing following one-shock in the aversive context A. However, when compared to P60 mice, the P35 mice tend to over-generalize fear. P35 mice distinguish between the two contexts on Day 8, whereas P60 mice distinguish between the two contexts starting on Day 6. This behavioral phenotype seems to be mainly mediated by CA3 but not the Dentate Gyrus in the hippocampus. Our data indicate that P35 adolescent mice over-generalize fear when compared to P60 adult mice. It also reveals that the CA3 in the hippocampus is what mediates contextual discrimination in these adolescent mice. In the future, these results encourage us to introduce ketamine to P35 adolescent mice. This would allow us to explore the mechanisms involved in fear generalization between P35 and P60 mice and if ketamine would have the same effect on them. 8.5.5

Development of depression-like behavior and altered hippocampal neurogenesis in a mouse model of chronic neuropathic pain

Chronic-pain patients often suffer from depression. In rodent models of neuropathic pain, animals develop depression-like and anxiety behaviors, indicating a relationship between chronic pain and affective disorders. However, the underlying neurobiological mechanisms linking chronic pain and depression are not yet fully understood. Neurogenesis in the hippocampus is a fundamental process related to brain plasticity. Reduced neurogenesis has been associated with the development of mood disorders and cognitive impairments. The current study aims to elucidate the underlying long-term changes in brain plasticity induced by neuropathic pain in mice at a time point when depression-like behavior has already developed. Furthermore, our focus is set on alterations in neurogenesis in the hippocampus. We found that manifestation of anxiety- and depressive-like behavior as well as cognitive impairment co-occur with decreased survival of newly generated cells but not with impaired proliferative activity or reduced number of immature neurons in the dentate gyrus area of the hippocampus. Moreover, we detected an impairment of differentiation of newly generated cells into mature calbindin-positive neurons, accompanied with a shift towards increased differentiation into astroglial cells. These findings indicate that a reduction in mature functional neurons, rather than reduced proliferation or neuronal progenitor cells, are the long-term changes in hippocampal plasticity that manifest in neuropathic pain conditions after depression-like behavior has developed.

Cav1.2 Activity and Downstream Signaling Pathways in the Hippocampus of An Animal Model of Depression.

Functional and morphological modifications in the brain caused by major mood disorders involve many brain areas, including the hippocampus, leading to cognitive and mood alterations. Cav1.2 channel expression has been found to increase in animals with depressive-like behaviors. Calcium influx through these channels is associated with changes in excitation-transcriptional coupling by several intracellular signal pathways that are regulated by its C-terminus region. However, which of these signaling pathways is activated during the development of depressive-like behaviors is not known. Here, we evaluate the phosphorylation and expression levels of crucial kinases and transcription factors at the hippocampus of rats after 21 days of chronic restraint stress. Our results show that rats subjected to CRS protocol achieve less body weight, have heavier adrenal glands, and exhibit depression-like behaviors such as anhedonia, behavioral despair and decreased social interaction. Cav1.2 mRNA and protein expression levels, plus l-type calcium current amplitude, are also increased in treated rats when compared with control animals. Out of the three main signaling pathways activated by l-type currents, we only observed an increment of CaM-NFAT axis activity with the concomitant increment in Fas ligand expression. Thus, our results suggest that CRS activates specific pathways, and the increased expression of Cav1.2 could lead to neuronal death in the hippocampus.

Depression-like behavior is associated with lower Per2 mRNA expression in the lateral habenula of rats.

Circadian rhythm dysfunction is primary symptom of depression and is closely related to depression onset. The role of the lateral habenula (LHb) of the thalamus in the pathogenesis of depression has been a research topic of great interest. The neuronal activity of this structure has circadian characteristics, which are related to the regulation of circadian rhythms. However, in depression model of rats, the role of clock genes in the LHb has not been assessed. To address this gap, we used a clomipramine (CLI) injection-induced depression model in rats to assess the daily expression of rhythmic genes in the LHb and depression-like behavior in rats at multiple time points. In determining the role of the Per2 gene in the development of depression-like behavior in the LHb, we found that the expression of this clock gene differed in a circadian manner. Per2 expression was also significantly decreased in CLI-treated rats in late afternoon (17:00) and in the middle of the night (1:00). Furthermore, silencing Per2 in the LHb of normal rats induced depression-like behavior at night, suggesting that Per2 may play an important role in the pathogenesis of depression. Collectively, these results indicate that decreased Per2 expression in the LHb may be related to increased depression-like behavior at night in depression model of rats.

Minocycline prevents the depressive-like behavior through inhibiting the release of HMGB1 from microglia and neurons

BackgroundOur previous study reports the causal role of high mobility group box 1 (HMGB1) in the development of depression; and we find glycyrrhizic acid (GZA) can be a potential treatment for major depressive disorder (MDD) considering its inhibition of HMGB1 activity. This study aims to further explore the exact cell types that release HMGB1 in the hippocampus. MethodsWe detected the effects of microglia conditioned medium on primary astrocytes and neurons. The effects of minocycline on depressive-like behaviors were tested in BABLB/c mice after four weeks of chronic unpredictable mild stress (CUMS) exposure. Furthermore, the immunofluorescence (IF) assays, hematoxylin-eosin (HE) and TUNEL staining were used to observe hippocampal slices to evaluate the release of HMGB1. The cytoplasmic translocations of HMGB1 protein were assayed by western-blot. ResultsExposure to CUMS caused an active release of HMGB1 from microglia and neurons in the hippocampus. After minocycline administration for inhibiting the activation of microglia, both microglia and neurons reduced the release of HMGB1 and the protein level of central and peripheral HMGB1 recovered accordingly. Along with blocking the release of HMGB1, behavioral and cognitive deficits induced by CUMS were improved significantly by minocycline. In addition, the supernatant of primary microglia stimulated the secretion of HMGB1 in primary neurons, not in astrocytes, at 24 h after 4 h-LPS treatment. ConclusionAll the evidence supported our hypotheses that microglia and neurons are the main cell sources of HMGB1 release under CUMS condition, and that the release of HMGB1 by microglia may play an important role in the development of depressive-like behavior.

Tactile stimulation of adult rats modulates hormonal responses, depression-like behaviors, and memory impairment induced by chronic mild stress: Role of angiotensin II

Physical touch can help to decrease the effects of stress. The aim of this study was to evaluate the influence of tactile stimulation on the hormonal and behavioral responses of young adult rats submitted to chronic mild unpredictable stress (CMS), considering the role of angiotensin II (Ang II). In Experiment 1, male rats were divided into 4 groups: control, stress, tactile stimulation (TS), and stress + TS. CMS was applied for three weeks. Tactile stimulation was applied for seven weeks, five days a week. After the CMS protocol, depression-like behaviors were evaluated by forced swimming and sucrose consumption tests. Learning and memory were evaluated using the Y-maze test. Fifteen days after the CMS procedure, the animals were euthanized and the levels of stress hormones were determined. The hypothalamus was isolated for determination of the Ang II concentration. In Experiment 2, control and stressed rats, with or without treatment using losartan (angiotensin II type 1 receptor blocker), were evaluated using the same behavioral tests and the hypothalamus Ang II concentration was also determined. CMS increased plasma corticosterone, norepinephrine, and epinephrine concentrations, induced depression-like behaviors, impaired learning and memory, and increased the Ang II concentration in the hypothalamus. Tactile stimulation attenuated these stress-induced effects. Losartan treatment effectively prevented increase of the hypothalamic Ang II concentration and the development of depression-like behavior, and also reduced the impairment of learning and memory in the stressed animals. The results indicated that tactile stimulation seemed to protect adult rats against hormonal and behavioral chronic stress effects, and that Ang II could be involved in the CMS effects.

Hippocampal metabolic alteration in rat exhibited susceptibility to prenatal stress

BackgroundNumerous studies have shown that prenatal stress (PS) can cause emotional and behavioral abnormalities including depression and depressive-like behaviors in offspring. However, the mechanism underlying the pathophysiology of depression remains largely unknown. In recent years, small metabolic molecules have played an increasingly important role in explaining the pathogenesis of depression. Thus, we detected hippocampal metabolic alteration in rat of depression caused by PS. MethodsTo explore the potential molecular markers and pathways that link the metabolic to the pathogenesis of depression, we monitored changes in hippocampus metabolites during the development of depressive-like behaviors in rats exposed to PS via UHPLC-Q-TOF/MS approach. Sucrose preference test (SPT) was used to screen out the susceptibility rats exposed to PS, open field test (OFT), forced swimming test (FST) and tail suspension test (TST) were used to verify the validity of animal model of depression. ResultsA total of 38 differential metabolites were detected in the susceptibility rats exposed to PS compared with that in controls. Most of these differential metabolites were related to Retrograde endocannabinoid signaling, Central carbon metabolism in cancer, Arginine biosynthesis, Choline metabolism in cancer, ABC transporters, Alanine, aspartate and glutamate metabolism pathways. In addition, the results of Spearman correlation analysis indicated that L-aspartate, N-Acetylaspartylglutamate, choline and betaine aldehyde were most associated with depressive-like behaviors. ConclusionThis study demonstrates that hippocampal metabolites in the Alanine, aspartate and glutamate metabolism pathways may play a crucial role in the depressive-like behaviors.

131. OTX2, Child Abuse, and Psychosis

Using unbiased transcriptomics the transient down-regulation of the Orthodenticle homeobox 2 (Otx2) gene was putatively associated with the development of depressive-like behaviors in a mouse model of early life stress. Given that genes associated with schizophrenia have recently been shown to have OTX2-binding sites, and child abuse is a potent predictor of psychotic symptoms and schizophrenia diagnoses, we examined the association of peripheral indices OTX2 in relation to measures of psychotic symptoms in a cohort of children participating in a study of risk and resilience in maltreated children.

Role of DNA hypomethylation in lateral habenular nucleus in the development of depressive-like behavior in rats

BackgroundLateral habenula nucleus (LHb) has recently been noted for its role in stress-induced depressive disorder. Yet little is known about the mechanisms by which external stimuli or depression induces pathological alteration in the LHb. MethodsChronic unpredictable mild stress (CUMS) was employed to model depressive-like behaviors in adult rats. We examined expressions of DNA methyltransferases (Dnmts) mRNA and protein and global DNA methylation levels in LHb of CUMS-induced depressive rats. Then 5-aza-2′-deoxycytidine (5-aza), a Dnmts inhibitor, was infused into the LHb of native rats to test the effects of hypomethylation in the LHb. The gene expressions in the LHb and the levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in dorsal raphe nucleus (DRN) were examined in 5-aza infusion rats by quantitative real-time PCR and high performance liquid chromatography, respectively. ResultsRats were exposed to CUMS for 21 days and depressive-like behaviors were induced as expected. We observed significant decrease in mRNA and protein expressions of Dnmt1 and DNA hypomethylation in LHb of depressive rats. These phenomenon suggests that CUMS-induced depressive-like behaviors are related with DNA hypomethylation in the LHb. Local 5-aza infusion into LHb of native rat resulted in global DNA hypomethylation in the LHb and induced depressive-like behaviors which are featured with lack of interest and investment in the environment, behavioral despair and anhedonia. Moreover, DNA hypomethylation in the LHb increased transcription of β calcium/calmodulin dependent protein kinase II and glutamate receptor 1 in the LHb and attenuated the levels of 5-HT and 5-HIAA in the DRN. Our data suggested that alteration of DNA methylation in the LHb may control 5-HT neuronal activity in the DRN to regulate emotional state. ConclusionsDNA hypomethylation in the LHb is involved in the development of depressive-like behavior and suitable methylation state contributes to the emotional stabilization.