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Interaction of oxidative stress and BDNF on executive dysfunction in patients with chronic schizophrenia

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 111 ()

Executive dysfunction is increasingly recognized as one of the widely observed dimensions of cognitive impairments in the course of schizophrenia (SCZ). However, the potential molecular pathological mechanisms remain elusive. Previous studies have demonstrated that decreased brain-derived neurotrophic factor (BDNF) and oxidative damage may be associated with the psychopathology and cognitive impairment of SCZ. The present study aims to assess whether the interaction between BDNF and oxidative damage is involved in the disruption of executive function (EF) in patients with chronic SCZ. Serum BDNF and plasma oxidative stress markers were measured in 189 patients and 60 control subjects. EFs were evaluated by Wisconsin card sorting tests (WCST), Stroop word/color test (Stroop), and verbal fluency tests (VFT). The results showed that patients performed worse in the VFT, WCST and Stroop tests than healthy subjects. Moreover, patients had lower activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) and lower BDNF levels, but higher malondialdehyde (MDA) levels than healthy controls. In patients, BDNF was negatively correlated with SOD (p < 0.01). For patients, catalase (CAT) activity was negatively associated with WCST error score (p = 0.02) and BDNF was positively correlated to VFT score (p = 0.02). However, all these correlations between biomarkers and EF domains did not pass Bonferroni corrections. Finally, multiple regression analyses identified BDNF x SOD activity and BDNF x MDA as influencing factors for VFT score in patients (both p < 0.05). Our results highlight the complex interplay between OS parameters and BDNF in the pathophysiology of EF impairment in SCZ, consistent with its neurodevelopmental hypothesis.

Oxytocin amplifies sex differences in human mate choice

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 112 ()

Infidelity is the major cause of breakups and individuals with a history of infidelity are more likely to repeat it, but may also present a greater opportunity for short-term sexual relationships. Here in a pre-registered, double-blind study involving 160 subjects we report that while both sexes valued faithful individuals most for short-term and long-term relationships, both single men and those in a relationship were more interested in having short-term relationships with previously unfaithful individuals than women. Oxytocin administration resulted in men rating the faces of unfaithful women as more attractive and likeable but in women rating those of unfaithful men as less attractive and also finding them less memorable. Oxytocin also increased single men's interest in having short-term relationships with previously unfaithful women whereas it increased single women's interest in having long-term relationships with faithful men. Thus, oxytocin release during courtship may first act to amplify sex-dependent priorities in attraction and mate choice before subsequently promoting romantic bonds.

Plasma luteinizing hormone level affects the brain activity of patients with polycystic ovary syndrome

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 112 ()

Objective: Cognitive function has been reported to be impaired in women with polycystic ovary syndrome (PCOS). This study aimed to investigate the effect of PCOS on brain activity and explore the relationship between brain activity and sex hormone levels in women with PCOS (WPCOS). Methods: Twenty-one women aged 18-45 years old with new-diagnosed PCOS were enrolled. Plasma levels of six sex hormones including luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were tested during the 2-5 days of their menstrual periods. Twenty-seven healthy controls (HC) were recruited. Every subject underwent a resting-state functional magnetic resonance imaging (fMRI). The amplitude of low-frequency fluctuation (ALFF) of the whole brain was evaluated followed by the functional connectivity (FC) analysis. Finally, the correlation between the ALFF, FC of the significant areas and the plasma hormone levels were analyzed. Results: The patients showed increased ALFF value in the left inferior temporal gyrus (ITG.L) and decreased ALFF value in the left inferior occipital gyrus (ITG.L) as well as the superior frontal gyrus (SFG.R, P < 0.005). For the FC analysis, patients showed decreased FC in SFG.R with the right middle frontal gyrus (MFG.R, P < 0.05). The FC between SFG.R and MFG.R was negatively correlated with LH level (R= -0.594, P = 0.005) and with the LH/FSH ratio (R= -0.521, P = 0.015). Conclusion: PCOS can induce changes in activities of brain regions responsible for visuospatial working memory, face processing and episodic memory. The reduced functional connectivity within the right frontal lobe is related with the high LH level in WPCOS.

Inhibition of JNK ameliorates depressive-like behaviors and reduces the activation of pro-inflammatory cytokines and the phosphorylation of glucocorticoid receptors at serine 246 induced by neuroinflammation

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 113 ()

Depression is associated with immune dysregulation and the aberrant activity of the hypothalamic-pituitary-adrenal (HPA) axis. However, the neurobiological molecular mechanisms underlying these associations remain unclear. c-Jun amino-terminal kinase (JNK), an important modulator in inflammation and stress responses, is often critically implicated in the development of central nervous system diseases. However, whether and how JNK mediates neuroinflammation-induced depression remains largely unknown. In this study, we investigated the role of JNK in depressive-like behaviors induced by central lipopolysaccharide (LPS) infusion. The results showed that LPS infusion led to depressive-like behaviors, accompanied by increased proinflammatory cytokine expression, increased JNK activation, and upregulated glucocorticoid receptor (GR) phosphorylation at serine 246 (pGR-Ser(246)) in the habenula (Hb), amygdala (Amyg) and medial prefrontal cortex (mPFC). Treatment with SP600125, a known JNK inhibitor, prevented the LPS-induced hyper-activation of JNK and alleviated depressive-like behaviors. Moreover, LPS-induced increases in the expression levels of TNF-alpha, IL-1 beta and pGR-Ser(246) in these brain regions were reduced when the rats were treated with SP600125. Our results show, for the first time, that JNK activities in the Hb, Amyg, and mPFC are involved in the modulation of neuroinflammation-induced depression and participate in the regulation of the expression of proinflammatory cytokines and GR phosphorylation, which are pathological factors associated with depression. Our findings provide new insights into the mechanism of neuroinflammation-associated depression and suggest that the JNK pathway may be a potential target for treating inflammation-related depression.

Interaction between TNF-alpha and oxidative stress status in first-episode drug-naive schizophrenia

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 114 ()

There has been evidence that the disturbances of TNF-alpha and the oxidative stress (OxS) status are involved in the mechanism of schizophrenia. However, the results of their levels in schizophrenia are still controversial, and their interactions have not yet been examined, especially in first-episode drug-naive (FEDN) patients. We therefore applied Enzyme-linked immunosorbent assays (ELISAs) method to compare peripheral blood serum TNF-alpha, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA) levels in 119 FEDN patients with schizophrenia and 135 healthy controls. We found that TNF-alpha and MDA were higher, whereas GSH-Px was lower, in FEDN patients with schizophrenia compared to healthy controls (TNF-alpha, 2.21 +/- 0.33 vs. 2.11 +/- 0.36, Bonferroni p = 0.04; MDA, 2.95 +/- 0.87 vs. 2.68 +/- 0.76, Bonferroni p = 0.04, GSH-Px, 177.33 +/- 28.84 vs. 188.32 +/- 29.34, Bonferroni p = 0.03). Furthermore, TNF-alpha levels had an independent positive association with negative symptoms (r = 0.37, Bonferroni p< 0.001). Finally, GSH-Px levels were negatively associated with the presence of schizophrenia (B =-0.014, Wald statistic = 9.22, p = 0.002, 95 %CI = 0.97-0.99), while the interaction of TNF-alpha with MDA was a risk factor for schizophrenia (B = 0.22, Wald statistic = 10.06, p = 0.002, 95 %CI = 1.09-1.43). Our results suggest that TNF-alpha and disturbance of oxidative stress status as well as their interaction may be involved in the pathophysiology of schizophrenia.

Oxytocin modulates responsibility attribution and hypothetical Resource allocation during cooperation

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 114 ()

Reasonable responsibility attribution and resource allocation in intragroup contexts benefit the evolution of group cooperation. Oxytocin (OT) has been shown to promote prosocial behavior; however, it remains unclear whether OT affects responsibility attribution and hypothetical resource allocation. In the present study, participants were intranasally administered OT or placebo (PLC) before a response task with a partner. The participant could win a certain amount of money depending on the group's performance, which was determined by the faster player. The contribution was manipulated to be similar in the first phase, while the participants could individually contribute more in the second phase. Our results show that both groups attributed more credit to the player who performed better in a trial. Moreover, reward magnitude only enhanced effort-based attribution in the OT group. Although both groups proposed to distribute money based on individual efforts, the PLC group increased their effort-based allocation when they contributed more, regardless of the fact that the money was eventually equally distributed. Our study demonstrates that OT modulates responsibility attribution and hypothetical resource allocation in different manners, suggesting that OT has different effects on a participant's perception of individual contribution and fairness when allocating a reward during social cooperation in a real effort task.

Oxytocin alters the effect of payoff but not base rate in emotion perception

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 114 ()

Emotion perception, inferring the emotional state of another person, can be formalized as decision under uncertainty: another person's scowling face may indicate anger or concentration and the optimal inference is contingent on the decision consequences (payoff) and how likely real anger is encountered (base rate). Although emerging evidence suggests that the neuropeptide oxytocin influences human perception of emotional facial expressions, whether such effect relates to the alternated process of payoff or base rate still remains unclear. In addition, little is known about oxytocin's effect on metacognitive process involved in emotion perception. One hundred and twenty-two healthy male adults (sixty-two in Experiment 1 and sixty in Experiment 2, respectively) received 24 international units (IU) of intranasal oxytocin or placebo (between-subjects) in a randomized and double-blind study. We independently and systematically manipulated the payoff and base rate levels in an emotion categorization task and measured participants' response bias via categorization choice and metacognitive sensitivity via confidence report. Compared to the placebo group, oxytocin specifically induced a categorization bias under the payoff, but not base rate manipulation. In contrast, oxytocin had no effect on subjects' confidence rating, indicating that the metacognitive sensitivity can be dissociated from emotion perception. Our results pinpoint the specific role of oxytocin in payoff evaluation, but not target likelihood estimation and provide a potential theoretical framework to bridge oxytocin research in emotion perception, social cognition and value-based decisions.

Olanzapine increases AMPK-NPY orexigenic signaling by disrupting H1R-GHSR1a interaction in the hypothalamic neurons of mice

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 114 ()

Second generation antipsychotics, particularly olanzapine, induce severe obesity, which is associated with their antagonistic effect on the histamine H1 receptor (H1R). We have previously demonstrated that oral administration of olanzapine increases the concentration of neuropeptide Y (NPY) in the hypothalamus of rats, accompanied by hyperphagia and weight gain. However, it is unclear if the increased NPY after olanzapine administration is due to its direct effect on hypothalamic neurons and its H1R antagonistic property. In the present study, we showed that with an inverted U-shape dose-response curve, olanzapine increased NPY expression in the NPY-GFP hypothalamic neurons; however, this was not the case in the hypothalamic neurons of H1R knockout mice. Olanzapine inhibited the interaction of H1R and GHSR1a (ghrelin receptor) in the primary mouse hypothalamic neurons and NPY-GFP neurons examined by confocal fluorescence resonance energy transfer (FRET) technology. Furthermore, an H1R agonist, FMPH inhibited olanzapine activation of GHSR1a downstream signaling pAMPK and transcription factors of NPY (pFOXO1 and pCREB) in the hypothalamic NPY-GFP cell. However, an olanzapine analogue (E-Olan) with lower affinity to H1R presented negligible enhancement of pCREB within the nucleus of NPY neurons. These findings suggest that the H1R antagonist property of olanzapine inhibits the interaction of H1R and GHSR1a, activates GHSR1a downstream signaling pAMPK-FOXO1/pCREB and increases hypothalamic NPY: this could be one of the important molecular mechanisms of H1R antagonism of olanzapine-induced obesity in antipsychotic management of psychiatric disorders.

PDLIM5 improves depression-like behavior of prenatal stress offspring rats via methylation in male, but not female

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 115 ()

Objective: Prenatal stress (PS) contributes to depression-like behavior in the offspring. PDLIM5 is involved in the onset of mental disorders. This study is to investigate the role and mechanism of PDLIM5 in depression-like behavior of PS offspring rats. Methods: PS model was used to analyze the effects of different treatments to PS offspring rats with different sex, including PDLIM5, PDLIM5 shRNA and 5-aza-2'-deoxycytidine (5-azaD). The depression-like behavior was assessed by the sucrose preference test (SPT) and forced swimming test (FST). The mRNA and protein expression levels of PDLIM5 in the hippocampus of PS offspring rats were detected by qRT-PCR and western blot, respectively. The methylation of PDLIM5 promoter were analyzed by bisulfite sequencing. Results: Our data revealed that PS offspring rats showed a significant decrease in sucrose preference and a prolonged immobility time. Injection of PDLIM5 significantly improved the depression-like behavior in PS offspring rats, whereas administration of PDLIM5 shRNA aggravated it. In addition, PDLIM5 expression was decreased at the mRNA and protein levels, and the methylation level of PDLIM5 promoter was increased in hippocampus of PS male but not female offspring rats. Furthermore, microinjection of 5-azaD improved the PS induced depression-like behavior in offspring rats. Moreover, in male PS offspring rats, microinjection of 5-azaD reversed the effect of PS on PDLIM5 expression and promoter methylation. Conclusion: PDLIM5 can significantly improve the depression-like behavior of both male and female PS offspring rats, while the PDLIM5 promoter methylation is only observed in male PS offspring rats. Our study may provide new mechanism for the pathogenesis of depression and experimental evidence for sex-based precise treatment.

Single dose testosterone administration increases men's facial femininity preference in a Chinese population

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 115 ()

Sex hormones are thought to influence human mate preferences. Previous studies have reported mixed results regarding the association between men's testosterone levels and their mate preferences. The present study investigated the effect of testosterone administration on men's facial femininity preference. Heterosexual Chinese male participants (n = 140) received a single dose of 150 mg testosterone or placebo gel in a double-blind, placebo-controlled, between-participant design. Results showed that Chinese men demonstrated general preferences for feminized women's faces, consistent with previous results from the Western population. More importantly, men showed stronger attraction to femininity in women's faces three hours after testosterone administration than at the beginning of the session. In the placebo group, no significant change in facial femininity preferences was found between time points. These results indicate that exogenous testosterone increases men's facial femininity preferences in a Chinese population.

PTSD and the klotho longevity gene: Evaluation of longitudinal effects on inflammation via DNA methylation

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 117 ()

Background: Longevity gene klotho (KL) is associated with age-related phenotypes including lifespan, cardiometabolic disorders, cognition, and brain morphology, in part, by conferring protection against inflammation. We hypothesized that the KL/inflammation association might be altered in the presence of psychiatric stress and operate via epigenetic pathways. We examined KL polymorphisms, and their interaction with posttraumatic stress disorder (PTSD) symptoms, in association with KL DNA methylation in blood. We further examined KL DNA methylation as a predictor of longitudinal changes in a peripheral biomarker of inflammation (C-reactive protein; CRP). Methods: The sample comprised 309 white non-Hispanic military veterans (93.5 % male; mean age: 32 years, range: 19-65; 30 % PTSD per structured diagnostic interview); 111 were reassessed approximately two years later. Results: Analyses revealed a methylation quantitative trait locus at rs9527025 (C370S, previously implicated in numerous studies of aging) in association with a Cytosine-phosphate-Guanine site (cg00129557; B=-.65, p=1.29 x 10(-20)), located within a DNase hypersensitivity site in the body of KL. There was also a rs9527025 x PTSD severity interaction (B=.004, p=.035) on methylation at this locus such that the minor allele was associated with reduced cg00129557 methylation in individuals with few or no PTSD symptoms while this effect was attenuated in those with elevated levels of PTSD. Path models revealed that methylation at cg00129557 was inversely associated with CRP over time (B = -.14, p=.005), controlling for baseline CRP. There was also an indirect effect of rs9527025 X PTSD on subsequent CRP via cg00129557 methylation (indirect B = -.002, p=.033). Conclusions: Results contribute to our understanding of the epigenetic correlates of inflammation in PTSD and suggest that KL methylation may be a mechanism by which KL genotype confers risk vs. resilience to accelerated aging in those experiencing traumatic stress.

Disinhibition of PVN-projecting GABAergic neurons in AV region in BNST participates in visceral hypersensitivity in rats

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 117 ()

Ample evidence suggests that early life stress (ELS) is a high-risk factor for the development of visceral pain disorders, whereas the mechanism underlying neuronal circuit remains elusive. Herein, we employed neonatal colorectal distension (CRD) to induce visceral hypersensitivity in rats. A combination of electrophysiology, pharmacology, behavioral test, molecular biology, chemogenetics and optogenetics confirmed that CRD in neonatal rats could predispose the elevated firing frequency of the parvocellular corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of hypothalamus (PVN) in adulthood, with the CRH neurons activated and the frequency of spontaneous inhibitory postsynaptic currents (sIPSC) diminished, both contributing to chronic visceral hypersensitivity. Moreover, following administration of exogenous GABA (300 mM/0.5 mu L) and GABAA receptor agonist muscimol (3 mM/0.5 mu L) in PVN, visceral hyperalgesia was abrogated. In addition, the PVN-projecting GABAergic neurons were mainly distributed in the anterior ventral (AV) region in the bed nucleus of stria terminalis (BNST), and the excitability of these GABAergic neurons was weakened in visceral hypersensitivity. Specific depletion of the GABAergic neurons in AV region precipitated visceral hyperalgesia. Moreover, chemogenetic activation of the PVN-projecting neurons alleviated the visceral hypersensitivity. Photoactivation of PVN-projecting GABAergic neurons abated the visceral hypersensitivity in neonatal-CRD rats, whereas photoinhibition evoked visceral hyperalgesia in naive rats. Our findings demonstrated that disinhibition of the PVN-projecting GABAergic neurons in AV region contributed to the excitation of CRH neurons, thereby mediating visceral hypersensitivity. Our study might provide a novel insight into the neuronal circuits involved in the ELS-induced visceral hypersensitivity.

Gut microbiome-derived lactate promotes to anxiety-like behaviors through GPR81 receptor-mediated lipid metabolism pathway

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 117 ()

Accumulating evidence suggests that chronic stress could perturb the composition of the gut microbiota and induce host anxiety- and depression-like behaviors. In particular, microorganism-derived products that can directly or indirectly signal to the nervous system. This study sought to investigate whether high levels of Lactobacillus and lactate in the gut of rats under chronic unpredictable stress (CUS) were the factors leading to anxiety behavior. We collected faeces and blood samples in a sterile laboratory bench to study the microbiome and plasma metabolome from adult male rats age and environment matched healthy individuals. We sequenced the V3 and V4 regions of the 16S rRNA gene from faeces samples. UPLC-MS metabolomics were used to examine plasma samples. Search for potential biomarkers by combining the different data types. Finally, we found a regulated signaling pathway through the relative expression of protein and mRNA. Both lactate feeding and fecal microbiota transplantation caused behavioral abnormalities such as psychomotor malaise, impaired learning and memory in the recipient animals. These rats also showed inhibition of the adenylate cyclase (AC)-protein kinase A (PKA) pathway of lipolysis after activation of G protein-coupled receptor 81 (GPR81) by lactate in the liver, as well as increased tumor necrosis factor alpha (TNF-alpha), compared with healthy controls. Furthermore, we showed that sphingosine-1-phosphate receptor 2 (S1PR2) protein expression in hippocampus was reduced in chronic unpredictable stress compared to control group and its expression negatively correlates with symptom severity. Our study suggest that the gut microbiome-derived lactate promotes to anxiety-like behaviors through GPR81 receptor-mediated lipid metabolism pathway.

PPAR gamma-mediated microglial activation phenotype is involved in depressive-like behaviors and neuroinflammation in stressed C57BL/6J and ob/ob mice

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 117 ()

Background: There is an increased risk for obese patients with chronic low-grade inflammation to develop depression. Stress induces microglial activation and neuroinflammation that play crucial roles in the pathogenesis of depression. Peroxisome proliferator-activated receptor gamma (PPAR gamma), a nuclear transcription factor, regulates microglial polarization and neuroinflammation. Our study aimed to investigate the role of PPAR gamma in the development of depressive symptoms and neuroinflammation induced by chronic unpredictable mild stress (CUMS) in wild-type/C57BL/6J (wt) and leptin-deficient (ob/ob) mice. Methods: CUMS was used to build a depression model with wt and ob/ob mice. Depressive-like behaviors were evaluated by sucrose preference test, open field test, tail suspension test, and Morris water maze test. Cytokines, the activated microglial state, and nuclear factor-kappa B (NF-kappa B) and PPAR gamma expression in the prefrontal cortex (PFC) and hippocampus (HIP) were examined by enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and western blotting. Additionally, pioglitazone, an agonist of PPAR gamma, was used as a treatment intervention. Results: After CUMS, ob/ob mice exhibited severe behavioral disorders and spatial memory impairment, and higher levels of pro-inflammatory cytokines, M1/M2 ratios, and NF-kappa B activation, as well as lower levels of anti-inflammatory cytokines and PPAR gamma expression in the PFC and HIP compared to wt mice. Administration of pioglitazone relieved these alterations in wt and ob/ob mice. Conclusions: CUMS was able to induce severe depressive-like behaviors, neuroinflammation, and reduced expression of PPAR gamma in ob/ob mice as compared to wt mice. This suggests that PPAR gamma mediates the microglial activation phenotype, which might be related to the susceptibility of stressed ob/ob mice to develop depressive disorder.

Rapid membrane effect of estrogens on stimulation of corticotropin-releasing hormone

期刊: PSYCHONEUROENDOCRINOLOGY, 2020; 117 ()

Background: Classic nuclear-initiated estrogen signaling stimulates corticotropin-releasing hormone (CRH) gene expression as a transcription factor. However, the possible mechanism by which membrane-initiated estrogen signaling (MIES) influences CRH expression remains unclear. There are indications that MIES may upregulate nitric oxide (NO) production through the phosphatidylinositol 3-hydroxy kinase (PI3K) and potentially through the mitogen-activated protein kinase (MAPK) pathway. Objectives: We investigated the effect of MIES-mediated kinase pathways on CRH expression with or without NO synthesis. Method: In SK-N-SH cell culture, estradiol-bovine serum albumin (E2-BSA) was used as the specific membrane estrogen receptor activator, with a specific NO donor, and/or inhibitors for NO synthase (NOS), PI3K, MAPK, protein kinase A (PKA), and protein kinase C (PKC). Results: E2-BSA significantly increased NO and CRH levels in the medium and NOS1-mRNA levels in the cells. In addition, NO donor up-regulated CRH expression, while NOS-inhibitor down-regulated it. When the inhibitor of MAPK and/or the inhibitor of PI3K was added to the medium, only the latter appeared to significantly block the stimulating effect of E2-BSA on NO synthesis, and this was accompanied by an increased CRH expression in the medium. We further studied the effect of the MIES-PKC-mediated pathway on CRH expression, with or without NOS-inhibitor, while the MIES-PKA(-PI3K) pathway served as a control. We found that MIES-PKC upregulated CRH expression independent of NO synthesis. Conclusion: MIES can efficiently upregulate CRH expression via various intracellular kinase pathways and may thus be a crucial component in the stress response.

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