Ling Xiao

Association of the brain-derived neurotrophic factor gene and bipolar disorder with early age of onset in mainland China

Several evidences have suggested that the brain-derived neurotrophic factor (BDNF) gene may be involved in the pathogenesis of bipolar disorder (BPD), but not all studies get the same result. The paper investigated two genetic polymorphisms of BDNF, C-270T and Val66Met, in a case-control design for their association with BPD. Sixty-seven patients of early age of onset and 130 patients of late age of onset were selected for study and 208 healthy individuals were used as controls. No significantly statistical differences of these two polymorphisms were found in genotypes or allele frequencies between either overall patients or late age of onset patients and normal control subjects. However, the frequency of the Val allele of the Val66Met polymorphism was found to have significantly increased in the subgroup patients with early age of onset as compared with the controls (genotype: chi(2)=6.602, d.f.=2, P=0.037; allele: chi(2)=6.223, d.f.=1, P=0.015). The study demonstrates that the BDNF C-270T and Val66Met polymorphisms are unlikely to contribute to the genetic predisposition to BPD as a whole. But Val66Met may be associated with susceptibility to the early age of onset subset of the disorder, further studies designed to explore the relationship in a larger population may be warranted.

Negative life events and corticotropin-releasing-hormone receptor1 gene in recurrent major depressive disorder

Major depressive disorder (MDD) is a long-term, recurrent condition that often takes a chronic course. It seems imperative that research should be focused on gaining a better understanding of what predicts recurrent MDD. As a major mediator of the stress response, corticotropin-releasing-hormone receptor 1 (CRHR1) has been demonstrated to be an important contributor to the pathogenesis of MDD. In this study, we show a significant increase in the G-allele (rs242939) of the CRHR1 gene in the recurrent MDD group compared with the control group, and an overrepresentation of G-G-T hyplotype of the CRHR1 gene in recurrent MDD. We also demonstrate the interaction of the CRHR1 gene and negative life events in recurrent MDD. These results suggest that the CRHR1 gene could modify the susceptibility to developing recurrent MDD following negative life events in adulthood.

Electro-acupuncture versus sham electro-acupuncture for auditory hallucinations in patients with schizophrenia: a randomized controlled trial

OBJECTIVE To compare the efficacy of electro-acupuncture with that of sham electro-acupuncture for auditory hallucinations in patients with schizophrenia partially responsive or non-responsive to risperidone. DESIGN Patient- and assessor-blinded randomized controlled trial. SETTING Hospital-based practice. PARTICIPANTS Schizophrenia patients with auditory hallucinations who are partially responsive or non-responsive to risperidone monotherapy (n = 60). INTERVENTIONS All patients were randomly allocated to a real electro-acupuncture group or a sham electro-acupuncture group and treated for 30 sessions within six weeks. MAIN OUTCOME MEASURES The primary outcome measure was the Psychotic Symptom Rating Scales Auditory Hallucination Subscale. Secondary outcomes included the Positive and Negative Syndrome Scale and side-effects. A clinical response was defined as >20% reduction score (from baseline) on the total score of the Psychotic Symptom Rating Scales Auditory Hallucination Subscale. RESULTS Sixty patients were selected for randomized real electro-acupuncture treatment (n = 30) or sham electro-acupuncture treatment (n = 30). Patients in the real electro-acupuncture group experienced greater improvement in the Psychotic Symptom Rating Scales Auditory Hallucination Subscale total score, physical characteristics factor score and the Positive and Negative Syndrome Scale positive symptom score than the sham electro-acupuncture group at both week 4 and week 6. The clinical response rates in the real electro-acupuncture group and sham electro-acupuncture group were 43.3% (n = 30) and 13.3% (n = 30), respectively (chi(2) = 6.648, P =0.027). There was no significance between-group difference in side-effects. CONCLUSION Electro-acupuncture might provide improvement in auditory hallucinations and positive symptom for patients with schizophrenia partially responsive or non-responsive to risperidone monotherapy.Objective: To compare the efficacy of electro-acupuncture with that of sham electro-acupuncture for auditory hallucinations in patients with schizophrenia partially responsive or non-responsive to risperidone.Design: Patient- and assessor-blinded randomized controlled trial.Setting: Hospital-based practice.Participants: Schizophrenia patients with auditory hallucinations who are partially responsive or non-responsive to risperidone monotherapy (n = 60).Interventions: All patients were randomly allocated to a real electro-acupuncture group or a sham electro-acupuncture group and treated for 30 sessions within six weeks.Main outcome measures: The primary outcome measure was the Psychotic Symptom Rating Scales Auditory Hallucination Subscale. Secondary outcomes included the Positive and Negative Syndrome Scale and side-effects. A clinical response was defined as >20% reduction score (from baseline) on the total score of the Psychotic Symptom Rating Scales Auditory Hallucination Subscale.Results: Sixty patien...

Functional −141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter and schizophrenia in a Chinese Han population:

Objective The association between a putative functional promoter polymorphism, −141C insertion/deletion (Ins/Del), in the dopamine receptor D2 gene (DRD2) and schizophrenia was investigated in a Chinese Han population. Methods The polymorphism was studied in unrelated schizophrenia patients and unrelated healthy controls. Linkage relationships were explored in core families of the schizophrenic patients using the transmission disequilibrium test. The Positive and Negative Syndrome Scale was used to evaluate the severity of the disorder. Results The Del allele was significantly less frequently found in patients (13/120; 11%) than in controls (18/100; 18%). In the 32 core families studied, 16 parents were Ins/Del heterozygotes. Parents transmitted the Ins and Del alleles to their children in 10 and six cases, respectively. Data from core families did not demonstrate linkage. Age, age at onset of schizophrenia and sex were not significantly different between carriers of the Ins and Del alleles. The group with the Ins allele had a significantly higher positive symptom score (75.3 ± 23.4 versus 53.9 ± 21.9) and excitement score (83.6 ± 16.8 versus 50.3 ± 24.6) than the Del group. Groups did not differ significantly in negative symptom and general psychopathology scores. Conclusions The DRD2 −141C Ins/Del polymorphism may affect susceptibility to schizophrenia in a Chinese Han population.

WSKY, a traditional Chinese decoction, rescues cognitive impairment associated with NMDA receptor antagonism by enhancing BDNF/ERK/CREB signaling

Warm‑supplementing kidney yang (WSKY) is an herbal prescription that has been used in Traditional Chinese Medicine for the treatment of psychiatric conditions. A previous study by our group found that WSKY significantly improved cognitive function of schizophrenia patients. In the present study, the effects of WSKY on cognitive function and their underlying mechanisms were investigated. WSKY was administered to an MK‑801‑induced rat model of chronic schizophrenia for 14 days. Memory performance was assessed using the Morris water maze (MWM) test. The expression of brain‑derived neurotrophic factor (BDNF), activation of cAMP response element binding protein (pCREB/CREB) and activation of extracellular signal‑regulated kinase (pERK/ERK) in the hippocampus was detected using western blot analysis. In the acquisition phase of the MWM test, the escape latency was significantly increased in the MK‑801‑treated group compared with the normal control group (P<0.01). Treatment with WSKY for 14 days at doses of 100 or 250 mg/kg rescued this cognitive impairment (P<0.05). In the probe test, 250 mg/kg WSKY treatment increased the time spent in the target quadrant (P<0.05) and number of platform crossings (P<0.01). Western blot analysis demonstrated that the levels of BDNF expression in the hippocampus of rats without behavioral tests were elevated following 14 days of WSKY treatment, and the effect of WSKY treatment on hippocampal BDNF expression was presented in an inverted U‑shaped dose‑response pattern. The pERK1/2 in the hippocampus was significantly enhanced following 100 mg/kg (P<0.01) and 250 mg/kg (P<0.01) WSKY treatment, while only 250 mg/kg WSKY increased the phosphorylation of CREB (P<0.01). The results of the present study indicated that WSKY enhances cognitive performance via the upregulation of BDNF/ERK/CREB signaling, and that WSKY has potential therapeutic implications for cognitive impairment of schizophrenia.

Preliminary investigation of the influence of CREB1 gene polymorphisms on cognitive dysfunction in Chinese patients with major depression

Research has increasingly focused on the role of the cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein in learning and memory, particularly its role in cognitive disorders and neurodegeneration, such as Huntingtons disease, Alzheimers disease, Rubinstein–Taybi syndrome, and Coffin–Lowry syndrome. The cognitive dysfunction of patients with major depressive disorder (MDD), which is widely recognized, is not completely in accordance with depressive severity, and the dysfunction persists upon clinical remission in some patients. However, few studies have focused on the role of CREB on cognitive function in patients with MDD. This study aimed to investigate the influence of CREB1 polymorphism on cognitive function in patients with MDD. The current study comprised 113 patients with MDD. The severity of depression was measured using the 17-item Hamilton Depression Rating Scale, and cognitive function was assessed using the Stroop Neuropsychological Screening Test, verbal fluency test, and tests of immediate logical memory and visual reproduction. All subjects were genotyped with regard to CREB1 polymorphisms (rs10932201, rs2551645, rs2254137, rs6740584, and rs2551640). For the verbal fluency test, the results showed significant differences for all single-nucleotide polymorphism genotypic groups. For the Stroop color-word task, a significant difference was found only for rs6740584. No significant differences were found for the Stroop color task, the immediate logical memory test or the visual reproduction test. In conclusion, there was an effect of CREB1 polymorphism on selective attention and retrieval of long-term memory, but not on immediate memory.

Blunted Behavioral and Molecular Responses to Chronic Mild Stress in Adult Rats with Experience of Infancy Maternal Separation

Childhood adversity has profound and persistent effects on brain functions and has been implicated in the etiology of depression. Brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) play critical roles during brain development to maintain neuronal function and structural integrity in adulthood. We therefore investigated the long-term effects of early life adversity on the depression-related behavior and the expression of BDNF and CREB in the hippocampus. Male Sprague-Dawley newborn rats were subjected to maternal separation for 3 h/day on postnatal days 2-14. After the postnatal day 90, rats with or without the experience of infancy maternal separation received a series of unpredictable chronic mild stress (CMS) for 21 days. Sucrose preference and spontaneous activity in the open field test were recorded, and the expression of BDNF and CREB in the hippocampus was measured by real-time RT-PCR and Western blot analyses. Before exposure to CMS, the rats with maternal separation showed the significant decreases in sucrose preference, spontaneous activity, and hippocampal expression of BDNF and CREB, compared to the animals without maternal separation. In contrast, the rats without maternal separation showed greater decreases of the above indictors after CMS, the levels of which were lower than those observed in the rats with maternal separation. Thus, early life adversity leads to long-term decreases in the capacity of enjoying sweetness, spontaneous activity, and hippocampal expression of BDNF and CREB. Moreover, childhood neglect may decrease the neurobehavioral plasticity, thereby blunting the responses to adulthood stress and increasing the susceptibility to depression.

F-actin may play an important role in IL-1β-stimulated hippocampal neurons

OBJECTIVES The aim of this study was to investigate whether IL-1β treatment affects F-actin in hippocampal neurons. MATERIALS AND METHODS Primary culture of hippocampal neurons were prepared from rat embryos, and the effect of different concentrations of IL-1β on the cell phenotype was investigated. Cell viability was monitored by CCK-8 activity analysis. Western blotting and immunofluorescence were performed to analyze protein levels and morphological changes in cells treated with IL-1β. RESULTS IL-1β increased viability at low doses and these increases were severely blunted at higher concentrations. Similarly, the expression of F-actin was increased at low concentrations and decreased at high concentrations. CONCLUSIONS IL-1β has a critical role in regulating hippocampal neuron viability by stimulating F-actin expression. These data suggest that IL-1β secretion at low doses is beneficial for the expression of F-actin, which can improve the survival of hippocampal neurons during stress. However,these effect were severely blunted at higher concentrations.

Altered corticostriatal pathway in first-episode paranoid schizophrenia: Resting-state functional and causal connectivity analyses

Neuroimaging studies suggest the abnormal structure and function of basal ganglion may contribute to the pathophysiology of schizophrenia. However, little is investigated about the both aberrant functional and causal connectivity of striatum in first-episode paranoid schizophrenia (FEPS). Resting-state functional magnetic resonance imaging was used to characterize the functional connectivity (FC) and casual connectivity within the corticostriatal circuit in 31 patients with FEPS and 33 healthy controls. Degree centrality (DC) was used to explore the regions influenced in schizophrenia at the whole-brain level. Subsequently, a seed-based Granger causality analysis was performed to analyze the causal connectivity. We identified reduced DC of the bilateral putamen in the patients, compared to the controls. In the causal connectivity analysis, we found causal dysconnectivity between the putamen and several regions of default mode network, right orbital part of inferior frontal cortex and right fusiform in the patients. Further, the abnormal causal effect was associated with cognitive impairment in FEPS. The present study highlighted the abnormal functional and causal integrity of the striatum in the patients with FEPS during resting state and suggests a potentially implicated role for the cortical-striatal circuit, especially the striatal-default mode network loop, in the pathophysiology of schizophrenia.

Sex-dependent impact of different degrees of maternal separation experience on OFT behavioral performances after adult chronic unpredictable mild stress exposure in rats

Early-life social-environmental factors are important for normal development, and different degrees of early-life stress experience have different impacts on adult behaviors and stress responsiveness. The aim of present study was to investigate the long-term effects of different degrees of maternal separation (MS) on male and female rats and subsequent responsiveness to chronic unpredictable mild stress (CUMS) exposure in adults. Sprague-Dawley (SD) newborn pups were exposed to either 15 min/day of MS (MS15), 360 min/day of MS (MS360) or no separation (NS) during postnatal day (PND)4-PND10. At PND56, behavioral tasks, including sucrose preference test (SPT), forced swimming test (FST) and open field test (OFT), were used to explore depressive and anxiety-like behaviors. Then the rats received a series of CUMS for 28 days, behavioral tasks were recorded after CUMS. Prior to CUMS, the behavioral performances in male and female rats were consistent, MS360 led to increased immobile time in FST and decreased activity in OFT, while MS15 rats exhibited behavioral performances similar to NS group. After CUMS, sexual dimorphism was observed in the OFT behavioral responses to adult stress re-exposure, but no differences in FST were observed. CUMS male rats with MS360 experiences showed the worst behavioral performances in OFT compared to those of the other male rats groups, while CUMS female rats without MS experience showed the worst behavioral performances in OFT compared to those of the other female rats groups. Both CUMS male and female rats with MS15 experiences showed better trend in OFT performances than those of CUMS rats with MS360 experience and without MS experiences. These results suggest that brief MS experiences increase the OFT behavioral resilience of rats to adult stress re-exposure, and prolonged MS promotes OFT behavioral resilience of female rats to adult stress re-exposure, while increases vulnerability of male rats to adult stress re-exposure.