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1.
J Neural Transm (Vienna) ; 131(1): 59-71, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37507512

RESUMO

Congenital absence of monoamine oxidase A (MAO-A) activity predisposes to antisocial impulsive behaviour, and the MAOA uVNTR low-expressing genotype (MAOA-L) together with childhood maltreatment is associated with similar phenotypes in males. A possible explanation of how family environment may lead to such behaviour involves DNA methylation. We have assessed MAOA methylation and impulsive/antisocial behaviour in 121 males from the Estonian Children Personality Behaviour and Health Study. Of the 12 CpG sites measured, methylation levels at the locus designated CpG3 were significantly lower in subjects with antisocial behaviour involving police contact. CpG3 methylation was lower in subjects with alcohol use disorder by age 25, but only in MAOA-H genotype. No correlation between MAOA CpG3 methylation levels and adaptive impulsivity was found at age 15, but in MAOA-L genotype a positive correlation appeared by age 18. By age 25, this positive correlation was no longer observed in subjects with better family relationships but had increased further with experience of adversity within the family. MAOA CpG3 methylation had different developmental dynamics in relation to maladaptive impulsivity. At age 18, a positive correlation was observed in MAOA-L genotype with inferior family relationships and a negative correlation was found in MAOA-H with superior home environment; both of these associations had disappeared by age 25. CpG3 methylation was associated with dietary intake of several micronutrients, most notable was a negative correlation with the intake of zinc, but also with calcium, potassium and vitamin E; a positive correlation was found with intake of phosphorus. In conclusion, MAOA CpG3 methylation is related to both maladaptive and adaptive impulsivity in adolescence in MAOA-L males from adverse home environment. By young adulthood, this relationship with maladaptive impulsivity had disappeared but with adaptive impulsivity strengthened. Thus, MAOA CpG3 methylation may serve as a marker for adaptive developmental neuroplasticity in MAOA-L genotype. The mechanisms involved may include dietary factors.


Assuntos
Transtorno da Personalidade Antissocial , Ambiente Domiciliar , Adolescente , Adulto , Criança , Humanos , Masculino , Adulto Jovem , Transtorno da Personalidade Antissocial/genética , Dieta , Metilação de DNA , Genótipo , Comportamento Impulsivo , Monoaminoxidase/genética
2.
Mol Psychiatry ; 27(1): 1-18, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33972691

RESUMO

Activity in the healthy brain relies on a concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders; however, obtaining mechanistic insight into these disruptions, with translational value for the patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human-induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and MEF2C (PV-precursor marker protein) expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13 deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-ß1 and Integrin-ß3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type-specific contribution of disease genes to the E/I balance.


Assuntos
Caderinas , Neurônios GABAérgicos , Parvalbuminas , Caderinas/metabolismo , Neurônios GABAérgicos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas , Integrinas/metabolismo , Parvalbuminas/metabolismo , Sinapses/metabolismo
3.
J Neural Transm (Vienna) ; 130(9): 1113-1132, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37542675

RESUMO

Aggression is a complex social behavior, critically involving brain serotonin (5-HT) function. The neurobiology of female aggression remains elusive, while the incidence of its manifestations has been increasing. Yet, animal models of female aggression are scarce. We previously proposed a paradigm of female aggression in the context of gene x environment interaction where mice with partial genetic inactivation of tryptophan hydroxylase-2 (Tph2+/- mice), a key enzyme of neuronal 5-HT synthesis, are subjected to predation stress resulting in pathological aggression. Using deep sequencing and the EBSeq method, we studied the transcriptomic signature of excessive aggression in the prefrontal cortex of female Tph2+/- mice subjected to rat exposure stress and food deprivation. Challenged mutants, but not other groups, displayed marked aggressive behaviors. We found 26 genes with altered expression in the opposite direction between stressed groups of both Tph2 genotypes. We identified several molecular markers, including Dgkh, Arfgef3, Kcnh7, Grin2a, Tenm1 and Epha6, implicated in neurodevelopmental deficits and psychiatric conditions featuring impaired cognition and emotional dysregulation. Moreover, while 17 regulons, including several relevant to neural plasticity and function, were significantly altered in stressed mutants, no alteration in regulons was detected in stressed wildtype mice. An interplay of the uncovered pathways likely mediates partial Tph2 inactivation in interaction with severe stress experience, thus resulting in excessive female aggression.


Assuntos
Serotonina , Triptofano Hidroxilase , Camundongos , Ratos , Feminino , Animais , Serotonina/metabolismo , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo , Agressão/fisiologia , Encéfalo/metabolismo , Comportamento Social
4.
J Child Psychol Psychiatry ; 64(7): 998-1006, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36929374

RESUMO

BACKGROUND: Human aggression is influenced by an interplay between genetic predisposition and experience across the life span. This interaction is thought to occur through epigenetic mechanisms, inducing differential gene expression, thereby moderating neuronal cell and circuit function, and thus shaping aggressive behaviour. METHODS: Genome-wide DNA methylation (DNAm) levels were measured in peripheral blood obtained from 95 individuals participating in the Estonian Children Personality Behaviours and Health Study (ECPBHS) at 15 and 25 years of age. We examined the association between aggressive behaviour, as measured by Life History of Aggression (LHA) total score and DNAm levels both assessed at age 25. We further examined the pleiotropic effect of genetic variants regulating LHA-associated differentially methylated positions (DMPs) and multiple traits related to aggressive behaviours. Lastly, we tested whether the DNA methylomic loci identified in association with LHA at age 25 were also present at age 15. RESULTS: We found one differentially methylated position (DMP) (cg17815886; p = 1.12 × 10-8 ) and five differentially methylated regions (DMRs) associated with LHA after multiple testing adjustments. The DMP annotated to the PDLIM5 gene, and DMRs resided in the vicinity of four protein-encoding genes (TRIM10, GTF2H4, SLC45A4, B3GALT4) and a long intergenic non-coding RNA (LINC02068). We observed evidence for the colocalization of genetic variants associated with top DMPs and general cognitive function, educational attainment and cholesterol levels. Notably, a subset of the DMPs associated with LHA at age 25 also displayed altered DNAm patterns at age 15 with high accuracy in predicting aggression. CONCLUSIONS: Our findings highlight the potential role of DNAm in the development of aggressive behaviours. We observed pleiotropic genetic variants associated with identified DMPs, and various traits previously established to be relevant in shaping aggression in humans. The concordance of DNAm signatures in adolescents and young adults may have predictive value for inappropriate and maladaptive aggression later in life.


Assuntos
Metilação de DNA , Estudo de Associação Genômica Ampla , Criança , Adolescente , Adulto Jovem , Humanos , Adulto , Metilação de DNA/genética , Epigênese Genética , Predisposição Genética para Doença , Agressão
5.
Int J Mol Sci ; 24(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36674429

RESUMO

Aggression and deficient cognitive control problems are widespread in psychiatric disorders, including major depressive disorder (MDD). These abnormalities are known to contribute significantly to the accompanying functional impairment and the global burden of disease. Progress in the development of targeted treatments of excessive aggression and accompanying symptoms has been limited, and there exists a major unmet need to develop more efficacious treatments for depressed patients. Due to the complex nature and the clinical heterogeneity of MDD and the lack of precise knowledge regarding its pathophysiology, effective management is challenging. Nonetheless, the aetiology and pathophysiology of MDD has been the subject of extensive research and there is a vast body of the latest literature that points to new mechanisms for this disorder. Here, we overview the key mechanisms, which include neuroinflammation, oxidative stress, insulin receptor signalling and abnormal myelination. We discuss the hypotheses that have been proposed to unify these processes, as many of these pathways are integrated for the neurobiology of MDD. We also describe the current translational approaches in modelling depression, including the recent advances in stress models of MDD, and emerging novel therapies, including novel approaches to management of excessive aggression, such as anti-diabetic drugs, antioxidant treatment and herbal compositions.


Assuntos
Transtorno Depressivo Maior , Humanos , Depressão , Doenças Neuroinflamatórias , Agressão/psicologia , Estresse Oxidativo
6.
Hum Brain Mapp ; 43(1): 37-55, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-32420680

RESUMO

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Encéfalo , Neuroimagem , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Humanos , Estudos Multicêntricos como Assunto , Neurociências
7.
Int J Mol Sci ; 23(4)2022 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-35216176

RESUMO

The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram.


Assuntos
Anedonia/fisiologia , Ciclo-Oxigenase 2/metabolismo , Hipocampo/metabolismo , Estresse Psicológico/metabolismo , Anedonia/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Celecoxib/farmacologia , Citalopram/farmacologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Elevação dos Membros Posteriores/fisiologia , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Wistar , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estresse Psicológico/tratamento farmacológico , Natação/fisiologia
8.
Mol Psychiatry ; 25(9): 2047-2057, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-30116028

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (Ntotal = 70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those. Linkage analysis was performed using multi-point analysis in Superlink Online SNP 1.1. From prioritized linkage regions with a LOD score ≥ 2, a total of 24 genes harboring rare variants were selected. Those genes were taken forward and were jointly analyzed in gene-set analyses of exome-chip data using the MAGMA software in an independent sample of patients with persistent ADHD and healthy controls (N = 9365). The gene-set including all 24 genes together, and particularly the gene-set from one of the three families (12 genes), were significantly associated with persistent ADHD in this sample. Among the latter, gene-wide analysis for the AAED1 gene reached significance. A rare variant (rs151326868) within AAED1 segregated with ADHD in one of the families. The analytic strategy followed here is an effective approach for identifying novel ADHD risk genes. Additionally, this study suggests that both rare and more frequent variants in multiple genes act together in contributing to ADHD risk, even in individual multi-case families.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Deficit de Atenção com Hiperatividade/genética , Exoma/genética , Ligação Genética/genética , Predisposição Genética para Doença/genética , Humanos , Linhagem , Sequenciamento do Exoma
9.
J Neural Transm (Vienna) ; 128(2): 225-241, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33560471

RESUMO

Human induced pluripotent stem cells (hiPSCs) have revolutionized the generation of experimental disease models, but the development of protocols for the differentiation of functionally active neuronal subtypes with defined specification is still in its infancy. While dysfunction of the brain serotonin (5-HT) system has been implicated in the etiology of various neuropsychiatric disorders, investigation of functional human 5-HT specific neurons in vitro has been restricted by technical limitations. We describe an efficient generation of functionally active neurons from hiPSCs displaying 5-HT specification by modification of a previously reported protocol. Furthermore, 5-HT specific neurons were characterized using high-end fluorescence imaging including super-resolution microscopy in combination with electrophysiological techniques. Differentiated hiPSCs synthesize 5-HT, express specific markers, such as tryptophan hydroxylase 2 and 5-HT transporter, and exhibit an electrophysiological signature characteristic of serotonergic neurons, with spontaneous rhythmic activities, broad action potentials and large afterhyperpolarization potentials. 5-HT specific neurons form synapses reflected by the expression of pre- and postsynaptic proteins, such as Bassoon and Homer. The distribution pattern of Bassoon, a marker of the active zone along the soma and extensions of neurons, indicates functionality via volume transmission. Among the high percentage of 5-HT specific neurons (~ 42%), a subpopulation of CDH13 + cells presumably designates dorsal raphe neurons. hiPSC-derived 5-HT specific neuronal cell cultures reflect the heterogeneous nature of dorsal and median raphe nuclei and may facilitate examining the association of serotonergic neuron subpopulations with neuropsychiatric disorders.


Assuntos
Células-Tronco Pluripotentes Induzidas , Serotonina , Diferenciação Celular , Humanos , Núcleos da Rafe , Neurônios Serotoninérgicos
10.
Dev Sci ; 24(5): e13100, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33666309

RESUMO

Genetic variability is being discussed as a source of inter-individual differences in Theory of Mind development. Previous studies documented an association between variations in DRD4 VNTR 48 bp, OXTR rs53576, COMT rs4680, and Theory of Mind task performance. As empirical evidence on these associations is sparse, we conducted a preregistered replication attempt of a study reporting a link between DRD4 VNTR 48 bp and false belief understanding in 50-month-old children [Lackner, C., Sabbagh, M. A., Hallinan, E., Liu, X., & Holden, J. J. (2012). Developmental Science, 15(2), 272-280.]. Additionally, we attempted a replication of studies on the role of OXTR rs53576 and COMT rs4680 in Theory of Mind. In both replication attempts, we did not find any evidence for associations between the sampled genetic markers and Theory of Mind ability in a series of analyses. Extending the replication attempt of Lackner et al., we employed longitudinal data from several tasks and measurement points, which allowed us to run follow-up robustness checks with more reliable scores. These extensive analyses corroborated our null finding. This comprehensive non-replication is important to balance current research on genetic markers of Theory of Mind. In a combined evaluation of our own and previous studies, we point to substantial methodological issues that research on the genetic basis of Theory of Mind development faces. We conclude that these limitations currently prevent firm conclusions on genetic influences on Theory of Mind development.


Assuntos
Catecol O-Metiltransferase/genética , Receptores de Dopamina D4/genética , Receptores de Ocitocina/genética , Teoria da Mente , Pré-Escolar , Variação Genética , Humanos
11.
J Cell Mol Med ; 24(17): 10251-10257, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32667139

RESUMO

Genetic mutations in FUS, a DNA/RNA-binding protein, are associated with inherited forms of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A novel transgenic FUS[1-359]-tg mouse line recapitulates core hallmarks of human ALS in the spinal cord, including neuroinflammation and neurodegeneration, ensuing muscle atrophy and paralysis, as well as brain pathomorphological signs of FTLD. However, a question whether FUS[1-359]-tg mouse displays behavioural and brain pro-inflammatory changes characteristic for the FTLD syndrome was not addressed. Here, we studied emotional, social and cognitive behaviours, brain markers of inflammation and plasticity of pre-symptomatic FUS[1-359]-tg male mice, a potential FTLD model. These animals displayed aberrant behaviours and altered brain expression of inflammatory markers and related pathways that are reminiscent to the FTLD-like syndrome. FTLD-related behavioural and molecular Journal of Cellular and Molecular Medicine features were studied in the pre-symptomatic FUS[1-359]-tg mice that received standard or new ALS treatments, which have been reported to counteract the ALS-like syndrome in the mutants. We used anti-ALS drug riluzole (8 mg/kg/d), or anti-inflammatory drug, a selective blocker of cyclooxygenase-2 (celecoxib, 30 mg/kg/d) for 3 weeks, or a single intracerebroventricular (i.c.v.) infusion of human stem cells (Neuro-Cells, 500 000-CD34+ ), which showed anti-inflammatory properties. Signs of elevated anxiety, depressive-like behaviour, cognitive deficits and abnormal social behaviour were less marked in FUS-tg-treated animals. Applied treatments have normalized protein expression of interleukin-1ß (IL-1ß) in the prefrontal cortex and the hippocampus, and of Iba-1 and GSK-3ß in the hippocampus. Thus, the pre-symptomatic FUS[1-359]-tg mice demonstrate FTLD-like abnormalities that are attenuated by standard and new ALS treatments, including Neuro-Cell preparation.


Assuntos
Anti-Inflamatórios/farmacologia , Encéfalo/efeitos dos fármacos , Degeneração Lobar Frontotemporal/tratamento farmacológico , Degeneração Lobar Frontotemporal/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Ciclo-Oxigenase 2/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Mutação/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Comportamento Social , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
12.
J Cell Physiol ; 235(12): 9021-9036, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32372501

RESUMO

SLC2A3 encodes the predominantly neuronal glucose transporter 3 (GLUT3), which facilitates diffusion of glucose across plasma membranes. The human brain depends on a steady glucose supply for ATP generation, which consequently fuels critical biochemical processes, such as axonal transport and neurotransmitter release. Besides its role in the central nervous system, GLUT3 is also expressed in nonneural organs, such as the heart and white blood cells, where it is equally involved in energy metabolism. In cancer cells, GLUT3 overexpression contributes to the Warburg effect by answering the cell's increased glycolytic demands. The SLC2A3 gene locus at chromosome 12p13.31 is unstable and prone to non-allelic homologous recombination events, generating multiple copy number variants (CNVs) of SLC2A3 which account for alterations in SLC2A3 expression. Recent associations of SLC2A3 CNVs with different clinical phenotypes warrant investigation of the potential influence of these structural variants on pathomechanisms of neuropsychiatric, cardiovascular, and immune diseases. In this review, we accumulate and discuss the evidence how SLC2A3 gene dosage may exert diverse protective or detrimental effects depending on the pathological condition. Cellular states which lead to increased energetic demand, such as organ development, proliferation, and cellular degeneration, appear particularly susceptible to alterations in SLC2A3 copy number. We conclude that better understanding of the impact of SLC2A3 variation on disease etiology may potentially provide novel therapeutic approaches specifically targeting this GLUT.


Assuntos
Encéfalo/metabolismo , Variações do Número de Cópias de DNA/genética , Metabolismo Energético/fisiologia , Transportador de Glucose Tipo 3/metabolismo , Animais , Metabolismo Energético/genética , Dosagem de Genes/genética , Transportador de Glucose Tipo 3/genética , Humanos , Neurônios/metabolismo
13.
Cogn Affect Behav Neurosci ; 20(1): 59-75, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31802408

RESUMO

Functional genetic polymorphisms in the brain dopamine (DA) system have been suggested to underlie individual differences in response inhibition, namely the suppression of a prepotent or inappropriate action. However, findings on associations between single DA polymorphisms and inhibitory control often are mixed, partly due to their small effect sizes. In the present study, a cumulative genetic score (CGS) was used: alleles previously associated with both impulsive behavior and lower baseline DA level, precisely the DRD4 Exon III 7-repeat, DAT1 VNTR 10-repeat and the COMT 158val allele, each added a point to the DA-CGS. Participants (N = 128) completed a Go/No-Go task varying in difficulty and EEG recordings were made with focus on the NoGo-P3, an ERP that reflects inhibitory response processes. We found a higher DA-CGS (lower basal/tonic DA level) to be associated with better performance (lower %FA and more adaptive responding) in the very demanding/rapid than in the less demanding/rapid condition, whereas the reverse pattern was true for individuals with a lower DA-CGS. A similar interaction pattern of DA-CGS and task condition was found for NoGo-P3 amplitude. In line with assumptions of distinct optimum DA levels for different cognitive demands, a DA-CGS-dependent variation of tonic DA levels could have modulated the balance between cognitive stability and flexibility, thereby affecting the optimal DA level required for the specific task condition. Moreover, a task demand-dependent phasic DA release might have added to the DA-CGS-related basal/tonic DA levels, thereby additionally affecting the balance between flexibility and stability, in turn influencing performance and NoGo-P3.


Assuntos
Encéfalo/fisiologia , Dopamina/metabolismo , Comportamento Impulsivo/fisiologia , Inibição Psicológica , Adolescente , Adulto , Eletroencefalografia/métodos , Potenciais Evocados/fisiologia , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Tempo de Reação/fisiologia , Adulto Jovem
14.
J Neural Transm (Vienna) ; 127(11): 1547-1568, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32377792

RESUMO

Genetic and molecular mechanisms that play a causal role in mental illnesses are challenging to elucidate, particularly as there is a lack of relevant in vitro and in vivo models. However, the advent of induced pluripotent stem cell (iPSC) technology has provided researchers with a novel toolbox. We conducted a systematic review using the PRISMA statement. A PubMed and Web of Science online search was performed (studies published between 2006-2020) using the following search strategy: hiPSC OR iPSC OR iPS OR stem cells AND schizophrenia disorder OR personality disorder OR antisocial personality disorder OR psychopathy OR bipolar disorder OR major depressive disorder OR obsessive compulsive disorder OR anxiety disorder OR substance use disorder OR alcohol use disorder OR nicotine use disorder OR opioid use disorder OR eating disorder OR anorexia nervosa OR attention-deficit/hyperactivity disorder OR gaming disorder. Using the above search criteria, a total of 3515 studies were found. After screening, a final total of 56 studies were deemed eligible for inclusion in our study. Using iPSC technology, psychiatric disease can be studied in the context of a patient's own unique genetic background. This has allowed great strides to be made into uncovering the etiology of psychiatric disease, as well as providing a unique paradigm for drug testing. However, there is a lack of data for certain psychiatric disorders and several limitations to present iPSC-based studies, leading us to discuss how this field may progress in the next years to increase its utility in the battle to understand psychiatric disease.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno Bipolar , Transtorno Depressivo Maior , Células-Tronco Pluripotentes Induzidas , Transtornos Mentais , Transtorno Obsessivo-Compulsivo , Humanos , Saúde Mental
15.
Am J Med Genet B Neuropsychiatr Genet ; 183(5): 247-257, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31099984

RESUMO

KCNJ6, encoding a potassium channel subunit, regulates the excitability of dopaminergic neurons and is expressed in attention-deficit/hyperactivity disorder (ADHD)-relevant brain regions. As a potential ADHD risk gene, KCNJ6, therefore, may contribute to the endophenotypic variation of the disorder. The impact of two SNPs, rs7275707 and rs6517442, both located in the transcriptional control region of KCNJ6, on reporter gene expression was explored in cultured cells. The KCNJ6 variants were then tested for association with ADHD and personality traits in a family-based sample (165 affected children) and an adult case-control sample (450 patients, 426 controls). Furthermore, the genotypic influence on performance in an n-back task and a cued continuous performance test (cCPT) was investigated by electroencephalography recordings. Finally, rs6517442 function was assessed by a reward anticipation paradigm using functional magnetic resonance imaging. Different haplotypes of rs7275707 and rs6517442 significantly influenced KCNJ6 gene expression proving their functional relevance on the molecular level. In the family-based children sample rs7275707 was associated with ADHD (p = .038). Moreover, rs7275707 showed association with the personality trait of Reward Dependence (p = .031). In the ADHD group, both rs7275707 and rs6517442 influenced the Go-centroid location in the cCPT and the N200 amplitude in the n-back task. Furthermore, ventral striatal activation was impacted by rs6517442 during reward anticipation. Our data indicate that functional variants of KCNJ6 influence brain activity during reward-related and executive processes supporting the view of a differential, age-dependent modulatory impact of dopamine-related brain processes in ADHD risk.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Encéfalo/fisiopatologia , Função Executiva/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Recompensa , Regiões 5' não Traduzidas , Adulto , Mapeamento Encefálico , Estudos de Casos e Controles , Dopamina/metabolismo , Eletroencefalografia , Saúde da Família , Feminino , Haplótipos , Humanos , Imageamento por Ressonância Magnética , Masculino , Mutagênese , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
16.
Stroke ; 50(11): 3238-3245, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31551038

RESUMO

Background and Purpose- Ischemic stroke is one of the leading causes of disability and death. The principal goal of acute stroke treatment is the recanalization of the occluded cerebral arteries, which is, however, only effective in a very narrow time window. Therefore, neuroprotective treatments that can be combined with recanalization strategies are needed. Calcium overload is one of the major triggers of neuronal cell death. We have previously shown that capacitative Ca2+ entry, which is triggered by the depletion of intracellular calcium stores, contributes to ischemia-induced calcium influx in neurons, but the responsible Ca2+ channel is not known. Methods- Here, we have generated mice lacking the calcium channel subunit Orai2 and analyzed them in experimental stroke. Results- Orai2-deficient mice were protected from ischemic neuronal death both during acute ischemia under vessel occlusion and during ischemia/reperfusion upon successful recanalization. Calcium signals induced by calcium store depletion or oxygen/glucose deprivation were significantly diminished in Orai2-deficient neurons demonstrating that Orai2 is a central mediator of neuronal capacitative Ca2+ entry and is involved in calcium overload during ischemia. Conclusions- Our experimental data identify Orai2 as an attractive target for pharmaceutical intervention in acute stroke.


Assuntos
Isquemia Encefálica , Sinalização do Cálcio , Cálcio/metabolismo , Neuroproteção , Proteína ORAI2/deficiência , Acidente Vascular Cerebral , Doença Aguda , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Isquemia Encefálica/prevenção & controle , Morte Celular , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Proteína ORAI2/metabolismo , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/prevenção & controle
17.
J Child Psychol Psychiatry ; 60(3): 229-231, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30786021

RESUMO

Converging evidence from new epidemiologic, genetic, epigenetic, neuroimaging, and experimental model findings are further refining a long-standing concept, regarding the underlying neurobiology of attention-deficit/hyperactivity disorder (ADHD): that ADHD onset and its persistence into adulthood are the result of dysregulated myelination and associated alterations in neuronal plasticity - linked to disrupted brain maturation and the persistence of cognitive and emotional impairments across the life span. If supported by further work, this concept represents a pathophysiologic mechanism amenable to therapeutic intervention.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Adulto , Encéfalo , Criança , Humanos , Neurobiologia , Neuroimagem
18.
Acta Neuropsychiatr ; 31(2): 84-92, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30472966

RESUMO

OBJECTIVE: Individual biological predispositions should play a role in risky driving behaviour. Platelet monoamine oxidase (MAO) activity, dopamine transporter gene (DAT1) and neuropeptide S receptor 1 (NPSR1) gene polymorphisms have been identified as markers of impulsivity, alcohol use and excessive risk-taking. We aimed to find out how this knowledge on neurobiology of impulsivity applies to drunk driving and traffic behaviour in general. METHODS: We have longitudinally examined the behaviour of drunk drivers (n = 203) and controls (n = 211) in traffic, in association with their alcohol-related problems, personality measures and the three biomarkers. We analysed differences between the subjects based on whether they had committed driving while impaired by alcohol (DWI) violation in a 10-year time period after recruitment or not and investigated further, what kind of predictive value do the different biomarkers have in committing DWI and other traffic violations and accidents. RESULTS: The original drunk drivers group had lower platelet MAO activity but further DWI was not significantly associated with this measure. Being a NPSR1 T-allele carrier contributed to the risk of repeatedly committing DWI. DAT1 9R carriers in contrast were involved in more traffic accidents by their own fault (active accidents), compared to 10R homozygotes in the whole sample. All groups with DWI also had significantly more alcohol-related problems and higher scores in maladaptive impulsivity compared to controls without DWI. CONCLUSIONS: Established biological markers of alcohol use and impulsivity can be reliably associated with everyday traffic behaviour and help in contributing to the understanding of the need for more personalized prevention activities.


Assuntos
Acidentes de Trânsito/estatística & dados numéricos , Transtornos Relacionados ao Uso de Álcool , Plaquetas/enzimologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Dirigir sob a Influência/estatística & dados numéricos , Comportamento Impulsivo/fisiologia , Monoaminoxidase/metabolismo , Receptores Acoplados a Proteínas G/genética , Adulto , Transtornos Relacionados ao Uso de Álcool/epidemiologia , Transtornos Relacionados ao Uso de Álcool/genética , Transtornos Relacionados ao Uso de Álcool/metabolismo , Biomarcadores , Estônia/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade
19.
Am J Med Genet B Neuropsychiatr Genet ; 180(6): 365-376, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30474181

RESUMO

Wnt-signaling is one of the most abundant pathways involved in processes such as cell-proliferation, -polarity, and -differentiation. Altered Wnt-signaling has been linked with several neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) as well as with cognitive functions, learning and memory. Particularly, lipoprotein receptor-related protein 5 (LRP5) or LRP6 coreceptors, responsible in the activation of the canonical Wnt-pathway, were associated with cognitive alterations in psychiatric disorders. Following the hypothesis of Wnt involvement in ADHD, we investigated the association of genetic variations in LRP5 and LRP6 genes with three independent child and adolescent ADHD (cADHD) samples (total 2,917 participants), followed by a meta-analysis including previously published data. As ADHD is more prevalent in males, we stratified the analysis according to sex and compared the results with the recent ADHD Psychiatric Genomic Consortium (PGC) GWAS. Meta-analyzing our data including previously published cADHD studies, association of LRP5 intronic rs4988319 and rs3736228 (Ala1330Val) with cADHD was observed among girls (OR = 1.80 with 95% CI = 1.07-3.02, p = .0259; and OR = 2.08 with 95% CI = 1.01-4.46, p = .0026, respectively), whereas in boys association between LRP6 rs2302685 (Val1062Ile) and cADHD was present (OR = 1.66, CI = 1.20-2.31, p = .0024). In the PGC-ADHD dataset (using pooled data of cADHD and adults) tendency of associations were observed only among females with OR = 1.09 (1.02-1.17) for LRP5 rs3736228 and OR = 1.18 (1.09-1.25) for LRP6 rs2302685. Together, our findings suggest a potential sex-specific link of cADHD with LRP5 and LRP6 gene variants, which could contribute to the differences in brain maturation alterations in ADHD affected boys and girls, and suggest possible therapy targets.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Criança , Feminino , Variação Genética/genética , Humanos , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Caracteres Sexuais , Fatores Sexuais , Via de Sinalização Wnt/genética , Via de Sinalização Wnt/fisiologia
20.
J Neural Transm (Vienna) ; 125(6): 913-923, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29488099

RESUMO

The distinct subgroup of the Ras family member 2 (DIRAS2) gene has been found to be associated with attention-deficit/hyperactivity disorder (ADHD) in one of our previous studies. This gene is coding for a small Ras GTPase with unknown function. DIRAS2 is highly expressed in the brain. However, the exact neural expression pattern of this gene was unknown so far. Therefore, we investigated the expressional profile of DIRAS2 in the human and murine brain. In the present study, qPCR analyses in the human and in the developing mouse brain, immunocytological double staining on murine hippocampal primary cells and RNA in situ hybridization (ISH) on brain sections of C57BL/6J wild-type mice, have been used to reveal the expression pattern of DIRAS2 in the brain. We could show that DIRAS2 expression in the human brain is the highest in the hippocampus and the cerebral cortex, which is in line with the ISH results in the mouse brain. During mouse brain development, Diras2 levels strongly increase from prenatal to late postnatal stages. Co-expression studies indicate Diras2 expression in glutamatergic and catecholaminergic neurons. Our findings support the idea of DIRAS2 as a candidate gene for ADHD as the timeline of its expression as well as the brain regions and cell types that show Diras2 expression correspond to those assumed to underlie the pathomechanisms of the disease.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Encéfalo/metabolismo , Proteínas ras/biossíntese , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Transcriptoma , Proteínas ras/genética
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