bluuebunny/crossref_metadata_2025_split huggingface dataset:
On the relationship of first-episode psychosis to the amphetamine-sensitized state: a dopamine D2/3 receptor agonist radioligand study
Authors: Weidenauer Ana , Bauer Martin , Sauerzopf Ulrich , Bartova Lucie , Nics Lukas , Pfaff Sarah , Philippe Cecile , Berroterán-Infante Neydher , Pichler Verena , Meyer Bernhard M. , Rabl Ulrich , Sezen Patrick , Cumming Paul , Stimpfl Thomas , Sitte Harald H. , Lanzenberger Rupert , Mossaheb Nilufar , Zimprich Alexander , Rusjan Pablo , Dorffner Georg , Mitterhauser Markus , Hacker Marcus , Pezawas Lukas , Kasper Siegfried , Wadsak Wolfgang , Praschak-Rieder Nicole , Willeit Matthäus 
Published: February 2020

AbstractSchizophrenia is characterized by increased behavioral and neurochemical responses to dopamine-releasing drugs. This prompted the hypothesis of psychosis as a state of “endogenous” sensitization of the dopamine system although the exact basis of dopaminergic disturbances and the possible role of prefrontal cortical regulation have remained uncertain. To show that patients with first-episode psychosis release more dopamine upon amphetamine-stimulation than healthy volunteers, and to reveal for the first time that prospective sensitization induced by repeated amphetamine exposure increases dopamine-release in stimulant-naïve healthy volunteers to levels observed in patients, we collected data on amphetamine-induced dopamine release using the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO and positron emission tomography. Healthy volunteers (n = 28, 14 female) underwent a baseline and then a post-amphetamine scan before and after a mildly sensitizing regimen of repeated oral amphetamine. Unmedicated patients with first-episode psychosis (n = 21; 6 female) underwent a single pair of baseline and then post-amphetamine scans. Furthermore, T1 weighted magnetic resonance imaging of the prefrontal cortex was performed. Patients with first-episode psychosis showed larger release of dopamine compared to healthy volunteers. After sensitization of healthy volunteers their dopamine release was significantly amplified and no longer different from that seen in patients. Healthy volunteers showed a negative correlation between prefrontal cortical volume and dopamine release. There was no such relationship after sensitization or in patients. Our data in patients with untreated first-episode psychosis confirm the “endogenous sensitization” hypothesis and support the notion of impaired prefrontal control of the dopamine system in schizophrenia.
Effects of a patient-derived de novo coding alteration of CACNA1I in mice connect a schizophrenia risk gene with sleep spindle deficits
Authors: Ghoshal Ayan , Uygun David S. , Yang Lingling , McNally James M. , Lopez-Huerta Violeta G. , Arias-Garcia Mario A. , Baez-Nieto David , Allen Andrew , Fitzgerald Megan , Choi Soonwook , Zhang Qiangge , Hope Jen M. , Yan Karena , Mao Xiaohong , Nicholson Thomas B. , Imaizumi Kazuo , Fu Zhanyan , Feng Guoping , Brown Ritchie E. , Strecker Robert E. , Purcell Shaun M. , Pan Jen Q. 
Published: February 2020

AbstractCACNA1I, a schizophrenia risk gene, encodes a subtype of voltage-gated T-type calcium channel CaV3.3. We previously reported that a patient-derived missense de novo mutation (R1346H) of CACNA1I impaired CaV3.3 channel function. Here, we generated CaV3.3-RH knock-in animals, along with mice lacking CaV3.3, to investigate the biological impact of R1346H (RH) variation. We found that RH mutation altered cellular excitability in the thalamic reticular nucleus (TRN), where CaV3.3 is abundantly expressed. Moreover, RH mutation produced marked deficits in sleep spindle occurrence and morphology throughout non-rapid eye movement (NREM) sleep, while CaV3.3 haploinsufficiency gave rise to largely normal spindles. Therefore, mice harboring the RH mutation provide a patient derived genetic model not only to dissect the spindle biology but also to evaluate the effects of pharmacological reagents in normalizing sleep spindle deficits. Importantly, our analyses highlighted the significance of characterizing individual spindles and strengthen the inferences we can make across species over sleep spindles. In conclusion, this study established a translational link between a genetic allele and spindle deficits during NREM observed in schizophrenia patients, representing a key step toward testing the hypothesis that normalizing spindles may be beneficial for schizophrenia patients.
A truncating Aspm allele leads to a complex cognitive phenotype and region-specific reductions in parvalbuminergic neurons
Authors: Garrett Lillian , Chang Yoon Jeung , Niedermeier Kristina M. , Heermann Tamara , Enard Wolfgang , Fuchs Helmut , Gailus-Durner Valerie , Angelis Martin Hrabě de , Huttner Wieland B. , Wurst Wolfgang , Hölter Sabine M. 
Published: February 2020

AbstractNeurodevelopmental disorders are heterogeneous and identifying shared genetic aetiologies and converging signalling pathways affected could improve disease diagnosis and treatment. Truncating mutations of the abnormal spindle-like microcephaly associated (ASPM) gene cause autosomal recessive primary microcephaly (MCPH) in humans. ASPM is a positive regulator of Wnt/β-Catenin signalling and controls symmetric to asymmetric cell division. This process balances neural progenitor proliferation with differentiation during embryogenesis, the malfunction of which could interfere with normal brain development.ASPMmutations may play a role also in other neurodevelopmental disorders, nevertheless, we lack the details of how or to what extent. We therefore assessed neurodevelopmental disease and circuit endophenotypes in mice with a truncatingAspm1–7mutation.Aspm1–7mice exhibited impaired short- and long-term object recognition memory and markedly enhanced place learning in the IntelliCage®. This behaviour pattern is reminiscent of a cognitive phenotype seen in mouse models and patients with a rare form of autism spectrum disorder (ASD) as well as in mouse models of altered Wnt signalling. These alterations were accompanied by ventriculomegaly, corpus callosum dysgenesis and decreased parvalbumin (PV)+ interneuron numbers in the hippocampal Cornu Ammonis (CA) region and thalamic reticular nucleus (TRN). PV+ cell number correlated to object recognition (CA and TRN) and place learning (TRN). This opens the possibility that, as well as causing MCPH, mutantASPMpotentially contributes to other neurodevelopmental disorders such as ASD through altered parvalbuminergic interneuron development affecting cognitive behaviour. These findings provide important information for understanding the genetic overlap and improved treatment of neurodevelopmental disorders associated with ASPM.
Cognition- and circuit-based dysfunction in a mouse model of 22q11.2 microdeletion syndrome: effects of stress
Authors: Tripathi Anushree , Spedding Michael , Schenker Esther , Didriksen Michael , Cressant Arnaud , Jay Therese M. 
Published: February 2020

AbstractGenetic microdeletion at the 22q11 locus is associated with very high risk for schizophrenia. The 22q11.2 microdeletion (Df(h22q11)/+) mouse model shows cognitive deficits observed in this disorder, some of which can be linked to dysfunction of the prefrontal cortex (PFC). We used behavioral (n = 10 per genotype), electrophysiological (n = 7 per genotype per group), and neuroanatomical (n = 5 per genotype) techniques to investigate schizophrenia-related pathology of Df(h22q11)/+ mice, which showed a significant decrease in the total number of parvalbumin positive interneurons in the medial PFC. The Df(h22q11)/+ mice when tested on PFC-dependent behavioral tasks, including gambling tasks, perform significantly worse than control animals while exhibiting normal behavior on hippocampus-dependent tasks. They also show a significant decrease in hippocampus-medial Prefrontal cortex (H-PFC) synaptic plasticity (long-term potentiation, LTP). Acute platform stress almost abolished H-PFC LTP in both wild-type and Df(h22q11)/+ mice. H-PFC LTP was restored to prestress levels by clozapine (3 mg/kg i.p.) in stressed Df(h22q11)/+ mice, but the restoration of stress-induced LTP, while significant, was similar between wild-type and Df(h22q11)/+ mice. A medial PFC dysfunction may underlie the negative and cognitive symptoms in human 22q11 deletion carriers, and these results are relevant to the current debate on the utility of clozapine in such subjects.
Targeted exome sequencing identifies five novel loci at genome-wide significance for modulating antidepressant response in patients with major depressive disorder
Authors: Xu Zhi , Xie Chunming , Xia Lu , Yuan Yonggui , Zhu Hong , Huang Xiaofa , Li Caihua , Tao Yu , Qu Xiaoxiao , Zhang Fengyu , Zhang Zhijun 
Published: February 2020

AbstractIn order to determine the role of single nucleotide variants (SNVs) in modulating antidepressant response, we conducted a study, consisting of 929 major depressive disorder (MDD) patients, who were treated with antidepressant drugs (drug-only) or in combination with a repetitive transcranial magnetic stimulation (plus-rTMS), followed by targeted exome sequencing analysis. We found that the “plus-rTMS” patients presented a more effective response to the treatment when compared to the ‘drug-only’ group. Our data firstly demonstrated that the SNV burden had a significant impact on the antidepressant response presented in the “drug-only” group, but was limited in the “plus-rTMS” group. Further, after controlling for overall SNV burden, seven single nucleotide polymorphisms (SNPs) at five loci,IL1A, GNA15, PPP2CB, PLA2G4C, andGBA, were identified as affecting the antidepressant response at genome-wide significance (P < 5 × 10−08). Additional multiple variants achieved a level of correction for multiple testing, includingGNA11, also shown as a strong signal for MDD risk. Our study showed some promising evidence on genetic variants that could be used as individualized therapeutic guides for MDD patients.
Personality, lifestyle and job satisfaction: causal association between neuroticism and job satisfaction using Mendelian randomisation in the UK biobank cohort
Authors: Rukh Gull , Dang Junhua , Olivo Gaia , Ciuculete Diana-Maria , Rask-Andersen Mathias , Schiöth Helgi Birgir 
Published: February 2020

AbstractJob-related stress has been associated with poor health outcomes but little is known about the causal nature of these findings. We employed Mendelian randomisation (MR) approach to investigate the causal effect of neuroticism, education, and physical activity on job satisfaction. Trait-specific genetic risk score (GRS) based on recent genome wide association studies were used as instrumental variables (IV) using the UK Biobank cohort (N = 315,536). Both single variable and multivariable MR analyses were used to determine the effect of each trait on job satisfaction. We observed a clear evidence of a causal association between neuroticism and job satisfaction. In single variable MR, one standard deviation (1 SD) higher genetically determined neuroticism score (4.07 units) was associated with −0.31 units lower job satisfaction (95% confidence interval (CI): −0.38 to −0.24; P = 9.5 × 10−20). The causal associations remained significant after performing sensitivity analyses by excluding invalid genetic variants from GRSNeuroticism (β(95%CI): −0.28(−0.35 to −0.21); P = 3.4 x 10−15). Education (0.02; −0.08 to 0.12; 0.67) and physical activity (0.08; −0.34 to 0.50; 0.70) did not show any evidence for causal association with job satisfaction. When genetic instruments for neuroticism, education and physical activity were included together, the association of neuroticism score with job satisfaction was reduced by only −0.01 units, suggesting an independent inverse causal association between neuroticism score (P = 2.7 x 10−17) and job satisfaction. Our findings show an independent causal association between neuroticism score and job satisfaction. Physically active lifestyle may help to increase job satisfaction despite presence of high neuroticism scores. Our study highlights the importance of considering the confounding effect of negative personality traits for studies on job satisfaction.
Potential chemokine biomarkers associated with PTSD onset, risk and resilience as well as stress responses in US military service members
Authors: Zhang Lei , Hu Xian-Zhang , Li Xiaoxia , Chen Ze , Benedek David M. , Fullerton Carol S. , Wynn Gary ,   Biomarker team, Naifeh James A. , Wu Hongyan , Benfer Natasha , Ng Tsz Hin H. , Aliaga Poblo , Dinh Hieu , Kao Tzu-Cheg , Ursano Robert J. 
Published: February 2020

AbstractCytokines, including chemokines, are small secreted proteins, which specifically effect on the interactions and communications between cells. Pro-inflammatory cytokines are produced predominantly by activated macrophages and are involved in the upregulation of inflammatory reactions. Dysregulation of cytokines is associated with post-traumatic stress disorder (PTSD). Here, we use both before-and-after and case–control studies to search for potential chemokine biomarkers associated with PTSD onset, risk, and resilience as well as stress responses in US military service members deployed to Iraq and Afghanistan. Blood samples and scores of the PTSD Checklist (PCL) were obtained from soldiers pre- and post deployment (pre, post). Forty chemokines were measured using the Bio-Plex Pro Human Chemokine Panel Assays. The before-and-after analysis showed potential markers (CCL2, CCL15, CCL22, CCL25, CXCL2, and CXCL12) are associated with PTSD onset, and CCL3, CXCL11, and CXCL16 are related to stress response. The case–control study demonstrated that CCL13, CCL20, and CXCL6 were possible PTSD risk markers, and CX3CL1 might be a resilience marker. In addition, CCL11, CCL13, CCL20, and CCL25 were correlated with the PCL scores, indicating their association with PTSD symptom severity. Our data, for the first time, suggest that these dysregulated chemokines may serve as biomarkers for PTSD onset, risk, and resilience as well as stress responses, and may benefit developing approaches not only for PTSD diagnosis but also for PTSD treatment.
Delaying memory decline: different options and emerging solutions
Authors: Schneider Felicitas , Horowitz Alan , Lesch Klaus-Peter , Dandekar Thomas 
Published: February 2020

AbstractMemory decline can be a devastating disease and increases in aging Western populations. Memory enhancement technologies hold promise for this and other conditions. Approaches include stem cell transplantation, which improved memory in several animal studies as well as vaccination against Alzheimer´s disease (AD) by β-amyloid antibodies. For a positive clinical effect, the vaccine should probably be administered over a long period of time and before amyloid pathologies manifest in the brain. Different drugs, such as erythropoietin or antiplatelet therapy, improve memory in neuropsychiatric diseases or AD or at least in animal studies. Omega-3 polyunsaturated fatty acid-rich diets improve memory through the gut–brain axis by altering the gut flora through probiotics. Sports, dancing, and memory techniques (e.g., Method of Loci) utilize behavioral approaches for memory enhancement, and were effective in several studies. Augmented reality (AR) is an auspicious way for enhancing memory in real time. Future approaches may include memory prosthesis for head-injured patients and light therapy for restoring memory in AD. Memory enhancement in humans in health and disease holds big promises for the future. Memory training helps only in mild or no impairment. Clinical application requires further investigation.
Significance of the orexinergic system in modulating stress-related responses in an animal model of post-traumatic stress disorder
Authors: Cohen Shlomi , Matar Michael A. , Vainer Ella , Zohar Joseph , Kaplan Zeev , Cohen Hagit 
Published: February 2020

AbstractConverging evidence indicates that orexins (ORXs), the regulatory neuropeptides, are implicated in anxiety- and depression-related behaviors via the modulation of neuroendocrine, serotonergic, and noradrenergic systems. This study evaluated the role of the orexinergic system in stress-associated physiological responses in a controlled prospective animal model. The pattern and time course of activation of hypothalamic ORX neurons in response to predator-scent stress (PSS) were examined using c-Fos as a marker for neuronal activity. The relationship between the behavioral response pattern 7 days post-exposure and expressions of ORXs was evaluated. We also investigated the effects of intracerebroventricular microinfusion of ORX-A or almorexant (ORX-A/B receptor antagonist) on behavioral responses 7 days following PSS exposure. Hypothalamic levels of ORX-A, neuropeptide Y (NPY), and brain-derived neurotrophic factor (BDNF) were assessed. Compared with rats whose behaviors were extremely disrupted (post-traumatic stress disorder [PTSD]-phenotype), those whose behaviors were minimally selectively disrupted displayed significantly upregulated ORX-A and ORX-B levels in the hypothalamic nuclei. Intracerebroventricular microinfusion of ORX-A before PSS reduced the prevalence of the PTSD phenotype compared with that of artificial cerebrospinal fluid or almorexant, and rats treated with almorexant displayed a higher prevalence of the PTSD phenotype than did untreated rats. Activated ORX neurons led to upregulated expressions of BDNF and NPY, which might provide an additional regulatory mechanism for the modulation of adaptive stress responses. The study indicates that the activated ORX system might promote adaptive responses to PSS probably via stimulation of BDNF and NPY secretion, and early intervention with ORX-A reduces the prevalence of the PTSD phenotype and increases the prevalence of adaptive phenotypes. The findings provide some insights into the mechanisms underlying the involvement of the ORX system in stress-related disorders.
Genetic evidence of gender difference in autism spectrum disorder supports the female-protective effect
Authors: Zhang Yi , Li Na , Li Chao , Zhang Ze , Teng Huajing , Wang Yan , Zhao Tingting , Shi Leisheng , Zhang Kun , Xia Kun , Li Jinchen , Sun Zhongsheng 
Published: February 2020

AbstractAutism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a male-to-female prevalence of 4:1. However, the genetic mechanisms underlying this gender difference remain unclear. Mutation burden analysis, a TADA model, and co-expression and functional network analyses were performed on de novo mutations (DNMs) and corresponding candidate genes. We found that the prevalence of putative functional DNMs (loss-of-function and predicted deleterious missense mutations) in females was significantly higher than that in males, suggesting that a higher genetic load was required in females to reach the threshold for a diagnosis. We then prioritized 174 candidate genes, including 60 shared genes, 91 male-specific genes, and 23 female-specific genes. All of the three subclasses of candidate genes were significantly more frequently co-expressed in female brains than male brains, suggesting that compensation effects of the deficiency of ASD candidate genes may be more likely in females. Nevertheless, the three subclasses of candidate genes were co-expressed with each other, suggesting a convergent functional network of male and female-specific genes. Our analysis of different aspects of genetic components provides suggestive evidence supporting the female-protective effect in ASD. Moreover, further study is needed to integrate neuronal and hormonal data to elucidate the underlying gender difference in ASD.
Epigenetic signatures of attachment insecurity and childhood adversity provide evidence for role transition in the pathogenesis of perinatal depression
Authors: Robakis Thalia K. , Zhang Siming , Rasgon Natalie L. , Li Tongbin , Wang Tao , Roth Marissa C. , Humphreys Kathryn L. , Gotlib Ian H. , Ho Marcus , Khechaduri Arineh , Watson Katherine , Roat-Shumway Siena , Budhan Vena V. , Davis Kasey N. , Crowe Susan D. , Ellie Williams Katherine , Urban Alexander E. 
Published: February 2020

AbstractEarly life adversity and insecure attachment style are known risk factors for perinatal depression. The biological pathways linking these experiences, however, have not yet been elucidated. We hypothesized that overlap in patterns of DNA methylation in association with each of these phenomena could identify genes and pathways of importance. Specifically, we wished to distinguish between allostatic-load and role-transition hypotheses of perinatal depression. We conducted a large-scale analysis of methylation patterns across 5 × 106individual CG dinucleotides in 54 women participating in a longitudinal prospective study of perinatal depression, using clustering-based criteria for significance to control for multiple comparisons. We identified 1580 regions in which methylation density was associated with childhood adversity, 3 in which methylation density was associated with insecure attachment style, and 6 in which methylation density was associated with perinatal depression. Shorter telomeres were observed in association with childhood trauma but not with perinatal depression or attachment insecurity. A detailed analysis of methylation density in the oxytocin receptor gene revealed similar patterns of DNA methylation in association with perinatal depression and with insecure attachment style, while childhood trauma was associated with a distinct methylation pattern in this gene. Clinically, attachment style was strongly associated with depression only in pregnancy and the early postpartum, whereas the association of childhood adversity with depression was time-invariant. We concluded that the broad DNA methylation signature and reduced telomere length associated with childhood adversity could indicate increased allostatic load across multiple body systems, whereas perinatal depression and attachment insecurity may be narrower phenotypes with more limited DNA methylation signatures outside the CNS, and no apparent association with telomere length or, by extension, allostatic load. In contrast, the finding of matching DNA methylation patterns within the oxytocin receptor gene for perinatal depression and attachment insecurity is consistent with the theory that the perinatal period is a time of activation of existing attachment schemas for the purpose of structuring the mother–child relationship, and that such activation may occur in part through specific patterns of methylation of the oxytocin receptor gene.