RESUMO
Mapping the neural patterns that drive human behavior is a key challenge in neuroscience. Even the simplest of our everyday actions stem from the dynamic and complex interplay of multiple neural structures across the central nervous system (CNS). Yet, most neuroimaging research has focused on investigating cerebral mechanisms, while the way the spinal cord accompanies the brain in shaping human behavior has been largely overlooked. Although the recent advent of functional magnetic resonance imaging (fMRI) sequences that can simultaneously target the brain and spinal cord has opened up new avenues for studying these mechanisms at multiple levels of the CNS, research to date has been limited to inferential univariate techniques that cannot fully unveil the intricacies of the underlying neural states. To address this, we propose to go beyond traditional analyses and instead use a data-driven multivariate approach leveraging the dynamic content of cerebro-spinal signals using innovation-driven coactivation patterns (iCAPs). We demonstrate the relevance of this approach in a simultaneous brain-spinal cord fMRI dataset acquired during motor sequence learning (MSL), to highlight how large-scale CNS plasticity underpins rapid improvements in early skill acquisition and slower consolidation after extended practice. Specifically, we uncovered cortical, subcortical and spinal functional networks, which were used to decode the different stages of learning with a high accuracy and, thus, delineate meaningful cerebro-spinal signatures of learning progression. Our results provide compelling evidence that the dynamics of neural signals, paired with a data-driven approach, can be used to disentangle the modular organization of the CNS. While we outline the potential of this framework to probe the neural correlates of motor learning, its versatility makes it broadly applicable to explore the functioning of cerebro-spinal networks in other experimental or pathological conditions.
Assuntos
Encéfalo , Medula Espinal , Humanos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Medula Espinal/diagnóstico por imagem , Medula Espinal/fisiologia , Aprendizagem/fisiologia , Imageamento por Ressonância Magnética/métodos , NeuroimagemRESUMO
There is considerable inter-individual variability in the rate at which working memory (WM) develops during childhood and adolescence, but the neural and genetic basis for these differences are poorly understood. Dopamine-related genes, striatal activation and morphology have been associated with increased WM capacity after training. Here we tested the hypothesis that these factors would also explain some of the inter-individual differences in the rate of WM development. We measured WM performance in 487 healthy subjects twice: at age 14 and 19. At age 14 subjects underwent a structural MRI scan, and genotyping of five single nucleotide polymorphisms (SNPs) in or close to the dopamine genes DRD2, DAT-1 and COMT, which have previously been associated with gains in WM after WM training. We then analyzed which biological factors predicted the rate of increase in WM between ages 14 and 19. We found a significant interaction between putamen size and DAT1/SLC6A3 rs40184 polymorphism, such that TC heterozygotes with a larger putamen at age 14 showed greater WM improvement at age 19. The effect of the DAT1 polymorphism on WM development was exerted in interaction with striatal morphology. These results suggest that development of WM partially share neuro-physiological mechanism with training-induced plasticity.
Assuntos
Corpo Estriado/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Memória de Curto Prazo/fisiologia , Adolescente , Adulto , Feminino , Humanos , Aprendizagem , Masculino , Polimorfismo Genético , Adulto JovemRESUMO
In many societies, the majority of adults regularly consume alcohol. However, only a small proportion develops alcohol addiction. Individuals at risk often show a high sensation-seeking/low-anxiety behavioural phenotype. Here we asked which role EF hand domain containing 2 (EFhd2; Swiprosin-1) plays in the control of alcohol addiction-associated behaviours. EFhd2 knockout (KO) mice drink more alcohol than controls and spontaneously escalate their consumption. This coincided with a sensation-seeking and low-anxiety phenotype. A reversal of the behavioural phenotype with ß-carboline, an anxiogenic inverse benzodiazepine receptor agonist, normalized alcohol preference in EFhd2 KO mice, demonstrating an EFhd2-driven relationship between personality traits and alcohol preference. These findings were confirmed in a human sample where we observed a positive association of the EFhd2 single-nucleotide polymorphism rs112146896 with lifetime drinking and a negative association with anxiety in healthy adolescents. The lack of EFhd2 reduced extracellular dopamine levels in the brain, but enhanced responses to alcohol. In confirmation, gene expression analysis revealed reduced tyrosine hydroxylase expression and the regulation of genes involved in cortex development, Eomes and Pax6, in EFhd2 KO cortices. These findings were corroborated in Xenopus tadpoles by EFhd2 knockdown. Magnetic resonance imaging (MRI) in mice showed that a lack of EFhd2 reduces cortical volume in adults. Moreover, human MRI confirmed the negative association between lifetime alcohol drinking and superior frontal gyrus volume. We propose that EFhd2 is a conserved resilience factor against alcohol consumption and its escalation, working through Pax6/Eomes. Reduced EFhd2 function induces high-risk personality traits of sensation-seeking/low anxiety associated with enhanced alcohol consumption, which may be related to cortex function.
Assuntos
Alcoolismo/genética , Ansiedade/genética , Proteínas de Ligação ao Cálcio/genética , Adolescente , Adulto , Consumo de Bebidas Alcoólicas/genética , Animais , Transtornos de Ansiedade/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Polimorfismo de Nucleotídeo Único , Assunção de Riscos , Xenopus laevisRESUMO
Ubiquitously expressed genes have been implicated in a variety of specific behaviors, including responses to ethanol. However, the mechanisms that confer this behavioral specificity have remained elusive. Previously, we showed that the ubiquitously expressed small GTPase Arf6 is required for normal ethanol-induced sedation in adult Drosophila. Here, we show that this behavioral response also requires Efa6, one of (at least) three Drosophila Arf6 guanine exchange factors. Ethanol-naive Arf6 and Efa6 mutants were sensitive to ethanol-induced sedation and lacked rapid tolerance upon re-exposure to ethanol, when compared with wild-type flies. In contrast to wild-type flies, both Arf6 and Efa6 mutants preferred alcohol-containing food without prior ethanol experience. An analysis of the human ortholog of Arf6 and orthologs of Efa6 (PSD1-4) revealed that the minor G allele of single nucleotide polymorphism (SNP) rs13265422 in PSD3, as well as a haplotype containing rs13265422, was associated with an increased frequency of drinking and binge drinking episodes in adolescents. The same haplotype was also associated with increased alcohol dependence in an independent European cohort. Unlike the ubiquitously expressed human Arf6 GTPase, PSD3 localization is restricted to the brain, particularly the prefrontal cortex (PFC). Functional magnetic resonance imaging revealed that the same PSD3 haplotype was also associated with a differential functional magnetic resonance imaging signal in the PFC during a Go/No-Go task, which engages PFC-mediated executive control. Our translational analysis, therefore, suggests that PSD3 confers regional specificity to ubiquitous Arf6 in the PFC to modulate human alcohol-drinking behaviors.
Assuntos
Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fator 6 de Ribosilação do ADP , Fatores de Ribosilação do ADP/metabolismo , Animais , Drosophila , Proteínas de Drosophila/metabolismo , Etanol/metabolismo , Etanol/farmacologia , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Masculino , Proteínas do Tecido Nervoso/genéticaRESUMO
Value information about a drug, such as the price tag, can strongly affect its therapeutic effect. We discovered that value information influences adverse treatment outcomes in humans even in the absence of an active substance. Labeling an inert treatment as expensive medication led to stronger nocebo hyperalgesia than labeling it as cheap medication. This effect was mediated by neural interactions between cortex, brainstem, and spinal cord. In particular, activity in the prefrontal cortex mediated the effect of value on nocebo hyperalgesia. Value furthermore modulated coupling between prefrontal areas, brainstem, and spinal cord, which might represent a flexible mechanism through which higher-cognitive representations, such as value, can modulate early pain processing.
Assuntos
Tronco Encefálico/fisiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/psicologia , Hiperalgesia/psicologia , Efeito Nocebo , Percepção da Dor/fisiologia , Placebos/efeitos adversos , Córtex Pré-Frontal/fisiologia , Medula Espinal/fisiologia , Adulto , Feminino , Neuroimagem Funcional , Humanos , Masculino , Medição da Dor , Percepção da Dor/efeitos dos fármacos , Preparações Farmacêuticas/economia , Creme para a Pele/administração & dosagem , Adulto JovemRESUMO
The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 × 10-8; rs191260602, P=3.9 × 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 × 10-4) and rs7688285 (P=7.6 × 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.
Assuntos
Agorafobia/genética , Agorafobia/metabolismo , Receptores de Glicina/genética , Adulto , Alelos , Ansiedade/complicações , Transtornos de Ansiedade/genética , Encéfalo/metabolismo , Encéfalo/fisiologia , Estudos de Casos e Controles , Cognição/fisiologia , Medo/fisiologia , Medo/psicologia , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Alemanha , Humanos , Masculino , Mutação/genética , Transtorno de Pânico/genética , Receptores de Glicina/metabolismo , Reflexo de Sobressalto/genéticaRESUMO
Up to 40% of youth with autism spectrum disorder (ASD) also suffer from anxiety, and this comorbidity is linked with significant functional impairment. However, the mechanisms of this overlap are poorly understood. We investigated the interplay between ASD traits and anxiety during reward processing, known to be affected in ASD, in a community sample of 1472 adolescents (mean age=14.4 years) who performed a modified monetary incentive delay task as part of the Imagen project. Blood-oxygen-level dependent (BOLD) responses to reward anticipation and feedback were compared using a 2x2 analysis of variance test (ASD traits: low/high; anxiety symptoms: low/high), controlling for plausible covariates. In addition, we used a longitudinal design to assess whether neural responses during reward processing predicted anxiety at 2-year follow-up. High ASD traits were associated with reduced BOLD responses in dorsal prefrontal regions during reward anticipation and negative feedback. Participants with high anxiety symptoms showed increased lateral prefrontal responses during anticipation, but decreased responses following feedback. Interaction effects revealed that youth with combined ASD traits and anxiety, relative to other youth, showed high right insula activation when anticipating reward, and low right-sided caudate, putamen, medial and lateral prefrontal activations during negative feedback (all clusters PFWE<0.05). BOLD activation patterns in the right dorsal cingulate and right medial frontal gyrus predicted new-onset anxiety in participants with high but not low ASD traits. Our results reveal both quantitatively enhanced and qualitatively distinct neural correlates underlying the comorbidity between ASD traits and anxiety. Specific neural responses during reward processing may represent a risk factor for developing anxiety in ASD youth.
Assuntos
Transtornos de Ansiedade/diagnóstico por imagem , Transtorno do Espectro Autista/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Imageamento por Ressonância Magnética , Recompensa , Adolescente , Antecipação Psicológica/fisiologia , Transtornos de Ansiedade/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiopatologia , Comorbidade , Dominância Cerebral/fisiologia , Retroalimentação , Feminino , Seguimentos , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Humanos , Estudos Longitudinais , Masculino , Oxigênio/sangue , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologiaRESUMO
BACKGROUND: Resilience is the capacity of individuals to resist mental disorders despite exposure to stress. Little is known about its neural underpinnings. The putative variation of white-matter microstructure with resilience in adolescence, a critical period for brain maturation and onset of high-prevalence mental disorders, has not been assessed by diffusion tensor imaging (DTI). Lower fractional anisotropy (FA) though, has been reported in the corpus callosum (CC), the brain's largest white-matter structure, in psychiatric and stress-related conditions. We hypothesized that higher FA in the CC would characterize stress-resilient adolescents. METHOD: Three groups of adolescents recruited from the community were compared: resilient with low risk of mental disorder despite high exposure to lifetime stress (n = 55), at-risk of mental disorder exposed to the same level of stress (n = 68), and controls (n = 123). Personality was assessed by the NEO-Five Factor Inventory (NEO-FFI). Voxelwise statistics of DTI values in CC were obtained using tract-based spatial statistics. Regional projections were identified by probabilistic tractography. RESULTS: Higher FA values were detected in the anterior CC of resilient compared to both non-resilient and control adolescents. FA values varied according to resilience capacity. Seed regional changes in anterior CC projected onto anterior cingulate and frontal cortex. Neuroticism and three other NEO-FFI factor scores differentiated non-resilient participants from the other two groups. CONCLUSION: High FA was detected in resilient adolescents in an anterior CC region projecting to frontal areas subserving cognitive resources. Psychiatric risk was associated with personality characteristics. Resilience in adolescence may be related to white-matter microstructure.
Assuntos
Corpo Caloso/ultraestrutura , Imagem de Tensor de Difusão , Resiliência Psicológica , Estresse Psicológico , Substância Branca/ultraestrutura , Adolescente , Anisotropia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Determinação da PersonalidadeRESUMO
Changes in reward processing have been identified as one important pathogenetic mechanism in alcohol addiction. The nonsynonymous single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene (rs6265/Val66Met) modulates the central nervous system activity of neurotransmitters involved in reward processing such as serotonin, dopamine, and glutamate. It was identified as crucial for alcohol consumption in healthy adults and, in rats, specifically related to the function in the striatum, a region that is commonly involved in reward processing. However, studies in humans on the association of BDNF Val66Met and reward-related brain functions and its role for alcohol consumption, a significant predictor of later alcohol addiction, are missing. Based on an intermediate phenotype approach, we assessed the early orientation toward alcohol and alcohol consumption in 530 healthy adolescents that underwent a monetary incentive delay task during functional magnetic resonance imaging. We found a significantly lower response in the putamen to reward anticipation in adolescent Met carriers with high versus low levels of alcohol consumption. During reward feedback, Met carriers with low putamen reactivity were significantly more likely to orient toward alcohol and to drink alcohol 2 years later. This study indicates a possible effect of BDNF Val66Met on alcohol addiction-related phenotypes in adolescence.
Assuntos
Comportamento do Adolescente/fisiologia , Consumo de Bebidas Alcoólicas/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Encéfalo/fisiologia , Recompensa , Adolescente , Comportamento do Adolescente/psicologia , Consumo de Bebidas Alcoólicas/psicologia , Feminino , Seguimentos , Humanos , Masculino , Metionina/genética , Valina/genéticaRESUMO
Despite the recognition that cortical thickness is heritable and correlates with intellectual ability in children and adolescents, the genes contributing to individual differences in these traits remain unknown. We conducted a large-scale association study in 1583 adolescents to identify genes affecting cortical thickness. Single-nucleotide polymorphisms (SNPs; n=54,837) within genes whose expression changed between stages of growth and differentiation of a human neural stem cell line were selected for association analyses with average cortical thickness. We identified a variant, rs7171755, associating with thinner cortex in the left hemisphere (P=1.12 × 10(-)(7)), particularly in the frontal and temporal lobes. Localized effects of this SNP on cortical thickness differently affected verbal and nonverbal intellectual abilities. The rs7171755 polymorphism acted in cis to affect expression in the human brain of the synaptic cell adhesion glycoprotein-encoding gene NPTN. We also found that cortical thickness and NPTN expression were on average higher in the right hemisphere, suggesting that asymmetric NPTN expression may render the left hemisphere more sensitive to the effects of NPTN mutations, accounting for the lateralized effect of rs7171755 found in our study. Altogether, our findings support a potential role for regional synaptic dysfunctions in forms of intellectual deficits.
Assuntos
Encéfalo/anatomia & histologia , Cognição/fisiologia , Inteligência/fisiologia , Glicoproteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Animais , Células Cultivadas , Feminino , Estudos de Associação Genética , Humanos , Processamento de Imagem Assistida por Computador , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Metanálise como Assunto , Camundongos , Camundongos Transgênicos , Análise em Microsséries , Células-Tronco Neurais/fisiologia , Testes NeuropsicológicosRESUMO
Human brain anatomy is strikingly diverse and highly inheritable: genetic factors may explain up to 80% of its variability. Prior studies have tried to detect genetic variants with a large effect on neuroanatomical diversity, but those currently identified account for <5% of the variance. Here, based on our analyses of neuroimaging and whole-genome genotyping data from 1765 subjects, we show that up to 54% of this heritability is captured by large numbers of single-nucleotide polymorphisms of small-effect spread throughout the genome, especially within genes and close regulatory regions. The genetic bases of neuroanatomical diversity appear to be relatively independent of those of body size (height), but shared with those of verbal intelligence scores. The study of this genomic architecture should help us better understand brain evolution and disease.
Assuntos
Encéfalo/anatomia & histologia , Genoma , Fenótipo , Adolescente , Estudos de Coortes , Simulação por Computador , Feminino , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Modelos Genéticos , Tamanho do Órgão , Polimorfismo de Nucleotídeo ÚnicoRESUMO
A well-characterized potential marker for addiction is impulsive choice, stably measured by delay discounting (DD) paradigms. While genetic influences partly account for inter-individual variance in impulsivity, environmental factors such as parenting practices may have an important role. The present study investigates how inconsistent fulfillment of delayed reward promises impacts on DD. A combined correlational and experimental functional magnetic resonance imaging (fMRI) design was performed in a sample of 48 healthy adolescents (13-15 years). More specifically, neural activation during a DD task was investigated at two assessment points (T0 and T1). Adolescents' self-reports of parenting and substance use were assessed at T0. Between assessment points, we experimentally varied the reliability of delayed reward promises, measuring the impact of this intervention on DD and neural value processing at T1. In the correlational part, same-sex parent reward inconsistency was associated with steeper DD and an attenuated subjective value (SV) representation in the nucleus accumbens (NAcc) and ventromedial prefrontal cortex (vmPFC). Steeper DD was in turn associated with alcohol use during the past year. In the experimental part, the reward inconsistency manipulation resulted in an attenuation of the NAcc SV representation, similar to the parental inconsistency effect. Together, our correlational and experimental findings raise new light on how parents may influence their children's degree of impulsivity, making parenting a potential target in addiction prevention.
Assuntos
Desvalorização pelo Atraso/fisiologia , Comportamento Impulsivo/fisiologia , Núcleo Accumbens/fisiologia , Poder Familiar/psicologia , Córtex Pré-Frontal/fisiologia , Recompensa , Adolescente , Mapeamento Encefálico , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Fatores SexuaisRESUMO
Abnormalities in white-matter (WM) microstructure, as lower fractional anisotropy (FA), have been reported in adolescent-onset bipolar disorder and in youth at familial risk for bipolarity. We sought to determine whether healthy adolescents with subthreshold bipolar symptoms (SBP) would have early WM microstructural alterations and whether those alterations would be associated with differences in gray-matter (GM) volumes. Forty-two adolescents with three core manic symptoms and no psychiatric diagnosis, and 126 adolescents matched by age and sex, with no psychiatric diagnosis or symptoms, were identified after screening the IMAGEN database of 2223 young adolescents recruited from the general population. After image quality control, voxel-wise statistics were performed on the diffusion parameters using tract-based spatial statistics in 25 SBP adolescents and 77 controls, and on GM and WM images using voxel-based morphometry in 30 SBP adolescents and 106 controls. As compared with healthy controls, adolescents with SBP displayed lower FA values in a number of WM tracts, particularly in the corpus callosum, cingulum, bilateral superior and inferior longitudinal fasciculi, uncinate fasciculi and corticospinal tracts. Radial diffusivity was mainly higher in posterior parts of bilateral superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi and right cingulum. As compared with controls, SBP adolescents had lower GM volume in the left anterior cingulate region. This is the first study to investigate WM microstructure and GM morphometric variations in adolescents with SBP. The widespread FA alterations in association and projection tracts, associated with GM changes in regions involved in mood disorders, suggest altered structural connectivity in those adolescents.
Assuntos
Transtorno Bipolar/patologia , Encéfalo/patologia , Fibras Nervosas Mielinizadas/patologia , Adolescente , Anisotropia , Distribuição de Qui-Quadrado , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Escalas de Graduação Psiquiátrica , AutorrelatoRESUMO
The purpose of this experiment was to test a computational model of reinforcement learning with and without fictive prediction error (FPE) signals to investigate how counterfactual consequences contribute to acquired representations of action-specific expected value, and to determine the functional neuroanatomy and neuromodulator systems that are involved. 80 male participants underwent dietary depletion of either tryptophan or tyrosine/phenylalanine to manipulate serotonin (5HT) and dopamine (DA), respectively. They completed 80 rounds (240 trials) of a strategic sequential investment task that required accepting interim losses in order to access a lucrative state and maximize long-term gains, while being scanned. We extended the standard Q-learning model by incorporating both counterfactual gains and losses into separate error signals. The FPE model explained the participants' data significantly better than a model that did not include counterfactual learning signals. Expected value from the FPE model was significantly correlated with BOLD signal change in the ventromedial prefrontal cortex (vmPFC) and posterior orbitofrontal cortex (OFC), whereas expected value from the standard model did not predict changes in neural activity. The depletion procedure revealed significantly different neural responses to expected value in the vmPFC, caudate, and dopaminergic midbrain in the vicinity of the substantia nigra (SN). Differences in neural activity were not evident in the standard Q-learning computational model. These findings demonstrate that FPE signals are an important component of valuation for decision making, and that the neural representation of expected value incorporates cortical and subcortical structures via interactions among serotonergic and dopaminergic modulator systems.
Assuntos
Encéfalo/fisiologia , Comportamento de Escolha/fisiologia , Recompensa , Adolescente , Adulto , Mapeamento Encefálico , Dopamina/fisiologia , Humanos , Imaginação/fisiologia , Imageamento por Ressonância Magnética , Masculino , Modelos Teóricos , Punição , Serotonina/fisiologia , Pensamento/fisiologia , Adulto JovemRESUMO
Animal models and human functional imaging data implicate the dopamine system in mediating enhanced encoding of novel stimuli into human memory. A separate line of investigation suggests an association between a functional polymorphism in the promoter region for the human dopamine 4 receptor gene (DRD4) and sensitivity to novelty. We demonstrate, in two independent samples, that the -521C>T DRD4 promoter polymorphism determines the magnitude of human memory enhancement for contextually novel, perceptual oddball stimuli in an allele dose-dependent manner. The genotype-dependent memory enhancement conferred by the C allele is associated with increased neuronal responses during successful encoding of perceptual oddballs in the ventral striatum, an effect which is again allele dose-dependent. Furthermore, with repeated presentations of oddball stimuli, this memory advantage decreases, an effect mirrored by adaptation of activation in the hippocampus and substantia nigra/ventral tegmental area in C carriers only. Thus, a dynamic modulation of human memory enhancement for perceptually salient stimuli is associated with activation of a dopaminergic-hippocampal system, which is critically dependent on a functional polymorphism in the DRD4 promoter region.
Assuntos
Encéfalo/fisiologia , Memória/fisiologia , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Receptores de Dopamina D4/genética , Adulto , Dopamina/genética , Dopamina/metabolismo , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Adulto JovemRESUMO
Genetic variation in a genomic region on chromosome 15q25.1, which encodes the alpha5, alpha3, and beta4 subunits of the cholinergic nicotinic receptor genes, confers risk to smoking and nicotine dependence (ND). Neural reward-related responses have previously been identified as important factors in the development of drug dependence involving ND. Applying an imaging genetics approach in two cohorts (N=487; N=478) of healthy non-smoking adolescents, we aimed to elucidate the impact of genome-wide significant smoking-associated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on reward-related neural responses in central regions such as the striatum, orbitofrontal and anterior cingulate cortex (ACC), and personality traits related to addiction. In both samples, carriers of the rs578776 GG compared with AG/AA genotype showed a significantly lower neural response to reward outcomes in the right ventral and dorsal ACC but not the striatum or the orbitofrontal cortex. Rs578776 was unrelated to neural reward anticipation or reward magnitude. Significantly higher scores of anxiety sensitivity in GG compared with AG/AA carriers were found only in sample 1. Associations with other personality traits were not observed. Our findings suggest that the rs578776 risk variant influences susceptibility to ND by dampening the response of the ACC to reward feedback, without recruiting the striatum or orbitofrontal cortex during feedback or anticipation. Thus, it seems to have a major role in the processing of and behavioral adaptation to changing reward outcomes.
Assuntos
Comportamento do Adolescente/psicologia , Predisposição Genética para Doença/genética , Proteínas do Tecido Nervoso/genética , Receptores Nicotínicos/genética , Recompensa , Tabagismo/genética , Adolescente , Corpo Estriado/fisiologia , Feminino , Lobo Frontal/fisiologia , Neuroimagem Funcional , Genótipo , Giro do Cíngulo/fisiologia , Saúde , Humanos , Masculino , Família Multigênica/genética , Personalidade/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Tabagismo/fisiopatologia , Tabagismo/psicologia , População Branca/genéticaRESUMO
Sleep, in particular REM sleep, has been shown to improve the consolidation of emotional memories. Here, we investigated the role of sleep and sleep deprivation on the consolidation of fear memories and underlying neuronal mechanisms. We employed a Pavlovian fear conditioning paradigm either followed by a night of polysomnographically monitored sleep, or wakefulness in forty healthy participants. Recall of learned fear was better after sleep, as indicated by stronger explicitly perceived anxiety and autonomous nervous responses. These effects were positively correlated with the preceding time spent in REM sleep and paralleled by activation of the basolateral amygdala. These findings suggest REM sleep-associated consolidation of fear memory in the human amygdala. In view of the critical participation of fear learning mechanisms in the etiology of anxiety and post-traumatic stress disorder, deprivation of REM sleep after exposure to distressing events is an interesting target for further investigation.
Assuntos
Medo/fisiologia , Memória/fisiologia , Privação do Sono , Sono REM/fisiologia , Adulto , Condicionamento Clássico , Humanos , Masculino , Polissonografia , Sono/fisiologia , Adulto JovemRESUMO
Impulsiveness is a pivotal personality trait representing a core domain in all major personality inventories. Recently, impulsiveness has been identified as an important modulator of cognitive processing, particularly in tasks that require the processing of large amounts of information. Although brain imaging studies have implicated the prefrontal cortex to be a common underlying representation of impulsiveness and related cognitive functioning, to date a fine-grain and detailed morphometric analysis has not been carried out. On the basis of ahigh-resolution magnetic resonance scans acquired in 1620 healthy adolescents (IMAGEN), the individual cortical thickness (CT) was estimated. Correlations between Cloninger's impulsiveness and CT were studied in an entire cortex analysis. The cluster identified was tested for associations with performance in perceptual reasoning tasks of the Wechsler Intelligence Scale for Children (WISC IV). We observed a significant inverse correlation between trait impulsiveness and CT of the left superior frontal cortex (SFC; Monte Carlo Simulation P<0.01). CT within this cluster correlated with perceptual reasoning scores (Bonferroni corrected) of the WISC IV. On the basis of a large sample of adolescents, we identified an extended area in the SFC as a correlate of impulsiveness, which appears to be in line with the trait character of this prominent personality facet. The association of SFC thickness with perceptual reasoning argues for a common neurobiological basis of personality and specific cognitive domains comprising attention, spatial reasoning and response selection. The results may facilitate the understanding of the role of impulsiveness in several psychiatric disorders associated with prefrontal dysfunctions and cognitive deficits.
Assuntos
Mapeamento Encefálico , Comportamento Impulsivo/diagnóstico , Processos Mentais/fisiologia , Percepção , Córtex Pré-Frontal/anatomia & histologia , Adolescente , Europa (Continente) , Feminino , Lateralidade Funcional , Humanos , Processamento de Imagem Assistida por Computador , Classificação Internacional de Doenças , Masculino , Testes Neuropsicológicos , Testes de Personalidade , Escalas de Graduação PsiquiátricaRESUMO
In this work we have applied picosecond and steady-state fluorescence measurements to study excitation energy transfer and trapping in intact Cyclotella meneghiniana diatom cells grown at different light intensities. Different excitation and detection wavelengths were used to discriminate between Photosystem I and II (PSI and PSII) kinetics and to study excitation energy transfer from the outer antenna to the core of PSI and PSII. It is found that the light-harvesting fucoxanthin chlorophyll proteins (FCPs) transfer their excitation energy predominantly to PSII. It is also observed that the PSII antenna is slightly richer in red-absorbing fucoxanthin than the FCPs associated with PSI. The average excitation trapping time in PSI is around 75 ps whereas this time is around 450 ps for PSII in cells grown in 20 µmol of photons per m(2) per s. The latter time decreases to 425 ps for 50 µmol of photons and 360 ps for 140 µmol of photons. It is concluded that cells grown under higher photon flux densities have a smaller antenna size than the ones grown in low light. At the same time, the increase of growth light intensity leads to a decrease of the relative amount of PSI. This effect is accompanied by a substantial increase in the amount of chlorophyll a that is not active in excitation energy transfer and most probably attached to inactivated/disassembled PSII units.
Assuntos
Diatomáceas/metabolismo , Diatomáceas/efeitos da radiação , Luz , Fotossíntese/efeitos da radiação , Clorofila/metabolismo , Clorofila/efeitos da radiação , Clorofila A , Proteínas de Ligação à Clorofila/metabolismo , Proteínas de Ligação à Clorofila/efeitos da radiação , Diatomáceas/crescimento & desenvolvimento , Transferência de Energia , Cinética , Complexos de Proteínas Captadores de Luz/metabolismo , Complexos de Proteínas Captadores de Luz/efeitos da radiação , Complexo de Proteína do Fotossistema I/metabolismo , Complexo de Proteína do Fotossistema I/efeitos da radiação , Complexo de Proteína do Fotossistema II/metabolismo , Complexo de Proteína do Fotossistema II/efeitos da radiação , Multimerização Proteica , Espectrometria de FluorescênciaRESUMO
Considerable animal and human research has been dedicated to the effects of parenting on structural brain development, focusing on hippocampal and prefrontal areas. Conversely, although functional imaging studies suggest that the neural reward circuitry is involved in parental affection, little is known about mothers' interpersonal qualities in relation to their children's brain structure and function. Moreover, gender differences concerning the effect of maternal qualities have rarely been investigated systematically. In 63 adolescents, we assessed structural and functional magnetic resonance imaging as well as interpersonal affiliation in their mothers. This allowed us to associate maternal affiliation with gray matter density and neural responses during different phases of the well-established Monetary Incentive Delay task. Maternal affiliation was positively associated with hippocampal and orbitofrontal gray matter density. Moreover, in the feedback of reward hit as compared with reward miss, an association with caudate activation was found. Although no significant gender effects were observed in these associations, during reward feedback as compared with baseline, maternal affiliation was significantly associated with ventral striatal and caudate activation only in females. Our findings demonstrate that maternal interpersonal affiliation is related to alterations in both the brain structure and reward-related activation in healthy adolescents. Importantly, the pattern is in line with typical findings in depression and post-traumatic stress disorder, suggesting that a lack of maternal affiliation might have a role in the genesis of mental disorders.