Biological Characterization of Genetic Mechanisms in Neuropsychiatric Disorders

神经精神疾病遗传机制的生物学特征

• 批准号: 8342173
• 负责人: Daniel Weinberger
• 金额: $ 173.02万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8342173
• 关键词: Adult; Adverse event; Affect; African American; Alleles; Amygdaloid structure; Animal Model; Anorexia; Anorexia Nervosa; Anxiety; Autopsy; Behavior; Behavior Therapy; Biological; Biological Assay; Biology; Blood; Brain; Brain imaging; Brain-Derived Neurotrophic Factor; CYP3A4 gene; Calcium Channel; Cell model; Cells; Cerebral cortex; Characteristics; Chromosome Mapping; Clinical; Cognition; Cognitive; Collaborations; Coupling; Cues; Data; Delusions; Dependence; Development; Diagnosis; Disease; Dose; Down-Regulation; Drug Kinetics; Emotional; Enzymes; Europe; Event; Exploratory Behavior; Family; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genotype; Hippocampus (Brain); Homeostasis; Human; Hypothalamic structure; Image; Impairment; Incidence; Individual Differences; Institutes; Interneurons; Knowledge; Lead; Learning; Life; Link; Liver; Measures; Mediating; Mediator of activation protein; Messenger RNA; Mission; Modeling; Molecular; Molecular Target; Monitor; Mus; Neurobiology; Neurologic; Neuropeptides; Neurosciences; Other Genetics; Outcome; Oxytocin; Oxytocin Receptor; Pathway interactions; Patients; Perception; Pharmaceutical Preparations; Phase; Phenotype; Prevention; Process; Protein Isoforms; Proteins; Psychotic Disorders; Race; Reaction; Receptor Gene; Regulation; Relative (related person); Reporting; Research; Research Personnel; Resources; Rest; Rewards; Risk; Rosa; Schizophrenia; Scientist; Severities; Shapes; Signal Pathway; Signal Transduction; Sleep; Sleep Deprivation; Social Behavior; Social Interaction; Social status; Starvation; Stimulus; Structure; Susceptibility Gene; Symptoms; Synaptic plasticity; System; Temperament; Therapeutic; Time; Tissues; Transcript; Translating; United States National Institutes of Health; Variant; Ventral Striatum; Wakefulness; Work; base; clinical Diagnosis; cortistatin; disorder risk; disturbance in affect; dopaminergic neuron; gamma-Aminobutyric Acid; gene function; genetic association; genetic variant; inhibitor/antagonist; insight; mRNA Expression; male; molecular pathology; neurobiological mechanism; neuroimaging; neuromechanism; neuronal survival; neuropsychiatry; neuropsychological; novel; olanzapine; pressure; programs; promoter; relating to nervous system; response; sex; sleep regulation; social; socioeconomics; voltage

Our group explored neurobiological mechanisms related to risk genes for SZ in Bigos, Arch Gen Psych 2010 and Kao, PNAS 2010. We studied the association of CACNA1C gene, voltage-gated calcium channel, and the clinical implication of potential brain-related phenotypes. A genetic variant of CACNA1C increased hippocampal (HP) and prefrontal activity during emotional processing and executive cognition. This variant increased expression of mRNA and was associated with SZ. Increased expression of the CACNA1C transcript suggests that calcium channel inhibitors may have clinical value in treating psychiatric illness. Genotype or brain imaging-based phenotypes might be predictors of response to these agents. Studies are needed to fully characterize the mechanism by which alterations in CACNA1C expression results in brain function changes. We also scrutinized SZ and several genes in the NRG-ErbB signaling pathway, implicated in disease risk and suggestive of a pathogenic network. Kao identified association of neuregulin3 (NRG3) genetic variants with increased risk for SZ and confirmed association to patient delusion and positive symptom severity. NRG3 produces 15 distinct tissue-specific and developmentally regulated isoforms that are not characterized. Future studies will determine their significance and functionality. Martinowich, Mol Brain 2011, studied the neurobiology mechanism of brain-derived neurotrophic factor (BDNF) and cortistatin (Cort) in sleep homeostasis. There is a link between synaptic plasticity in cerebral cortex and sleep homeostasis. The degree of BDNF expression during wakefulness is linked to the extent of slow wave activity during the rest period. BDNF is expressed in developing and adult brain and impacts neuronal survival, differentiation, and synaptic plasticity. Cort is a neuropeptide expressed in gamma-aminobutyric acid interneurons in the cerebral cortex and HP. There is a positive correlation between exploratory behaviors during wakefulness, induction of plasticity genes like BDNF, and the extent of sleep pressure/need. Sleep deprivation (SD) led to an increase in cortical Cort mRNA expression. Disruption of activity-dependent BDNF expression in modified mouse (BDNF-KIV) impaired levels of Cort mRNA at baseline and after SD, which also led to decreased sleep time in the active phase. BDNF-KIV mice slept less overall than normal mice. Progression of the active cycle or in response to SD, BDNF and Cort expression increased as sleep pressure rose. In BDNF-KIV the levels of BDNF mRNA and Cort gene expression were impaired. Modified mice showed complete disruption of BDNF promoter IV and down regulation of other BDNF transcripts, which led to complete loss of SD. Our results raise the possibility that BDNF regulation of SD may be mediated via activity-dependent BDNF regulation of Cort-positive interneurons. Our studies suggest that regulation of Cort-expressing interneurons by activity-dependent BDNF expression may contribute to regulation of sleep behavior consistent with sleep homeostasis. We examined clearance of olanzapine, a drug widely used in treatment of SZ known for its high rate of discontinuation due to inefficiency and adverse events. Bigos, Mol Psych 2011 identified a SNP in the drug metabolizing enzyme, CYP3A43 which predicted olanzapine clearance. Half of all drugs are metabolized by the CYP3A family of enzymes which includes CYP3A43. CYP3A43 is expressed at much lower levels in liver than other metabolizing enzymes. This suggests genetic variability in olanzapine pharmacokinetics and, may result in differences in clinical response. The CYP3A43 SNP in this study is not functional. Additional studies will discover functional variants that may be monitored by this SNP. At standard dose, 50% of subjects with high clearance genotype (AA) had blood levels below therapeutic range. In our data, 50% of AA carriers (primarily African Americans) had predicted concentrations <20ngml, less than the target of 20-50ngml. Removing the AA genotype, race was no longer a predictor of olanzapine clearance. Patients with greater clearance had higher symptom ratings and incidence of discontinuation. While genotype alone does not predict clinical outcome, using CYP 3A43 genotype significantly predicted symptom severity, and was associated with discontinuation. It may be important to take CYP3A43 genotype and other contributors to pharmacokinetics variability into consideration when dosing. Tost, PNAS 2011 studied the evolutionally highly conserved neuropeptide oxytocin as a mediator of social and emotional behavior. A genetic variant in the oxytocin receptor gene (OXTR) has been implicated in social-behavior phenotypes and neuropsychiatric disorders associated with social impairment, but the neural mechanisms are unknown. Activation and interregional coupling of the amygdala during the processing of emotionally salient social cues were affected by genotype and neural characteristics predicted lower levels of reward dependence in male risk allele carriers. We identified sex-dependent mechanisms impacted the structure and function of hypothalamic-limbic circuits that are of potential clinical and translational significance. We provided evidence for a neural mechanism linking structural and neural signaling alterations in the OXTR system to individual differences in emotional reactivity and prosocial temperament. Our findings support the idea that risk for social dysfunction in males has a sex-related neural basis. Our study extends prior knowledge on neuropeptide function in the human brain and provides further insight into the neural mechanisms that shape our capacity to develop successful social relationships. The impact of a common genetic variant in RELN on the level of brain structure and function was investigated in Tost, Biol Psych 2010. Results did not identify a biological effect of this variant in RELN. This is a true negative result. We covered an extended spectrum of intermediate phenotype measures, analyzed a copious amount of data, and increased sensibility of our models to reduce the lack of statistical power, as confirmed by our post hoc analysis. These findings did not disprove an association of RELN with SZ but imply that a comprehensive attempt to validate the neurobiological impact of a specific allelic variant in RELN was unsuccessful. This work invites research on other genetic variants in RELN that could underlie some of the neurobiological abnormalities reported in schizophrenia. In Ly, Cur Biol 2011, studied the ventral striatum (VS) and showed that viewing higher-ranked subjects evoked a VS response indicative of a greater assignment of value/salience to higher status. We concluded that ones subjective socio-economic rank influences VS response to social status information which suggested that value attributed to social status in humans is dependent on rank. These data provided a human neurobiological correlate underlying the modulation of social status related to value by ones own relative social rank, thus bettering our understanding of neural mechanisms involved in the perception of status-related cues used to guide appropriate social interactions. Lastly Zink, Nat Med 2010 discussed the basis of mood alterations and how our reaction can provide clues for new therapies to target these neurological events. People with anorexia nervosa show a connection between self starvation and motivational value, opposite to the traditional idea linking the absence of joy to the symptoms. A new view of anorexia may lead to development of more effective pharmacological and psychotherapeutic treatment that could focus on the regulation of motivational salience not avoidance of anxiety. This drug might modulate the response of dopamine neurons to external stimuli, suggesting new behavioral intervention paradigms.

我们的团队在Bigos， Arch Gen Psych 2010和Kao， PNAS 2010上探讨了与SZ风险基因相关的神经生物学机制。我们研究了CACNA1C基因与电压门控钙通道的关系，以及潜在的脑相关表型的临床意义。在情绪加工和执行认知过程中，CACNA1C的遗传变异增加了海马（HP）和前额叶活动。该变异增加了mRNA的表达，与SZ相关。CACNA1C转录物表达的增加表明钙通道抑制剂可能在治疗精神疾病方面具有临床价值。基因型或基于脑成像的表型可能是对这些药物反应的预测因子。CACNA1C表达改变导致脑功能改变的机制尚需进一步研究。我们还仔细研究了SZ和NRG-ErbB信号通路中的几个基因，这些基因与疾病风险有关，并暗示了一个致病网络。Kao发现神经调节蛋白3 （NRG3）遗传变异与SZ风险增加有关，并证实与患者妄想和阳性症状严重程度有关。NRG3产生15种不同的组织特异性和发育调节异构体，这些异构体尚未被表征。未来的研究将确定它们的意义和功能。Martinowich， Mol Brain 2011研究了脑源性神经营养因子（BDNF）和皮质抑素（Cort）在睡眠稳态中的神经生物学机制。大脑皮层突触可塑性与睡眠稳态之间存在联系。清醒时BDNF的表达程度与休息时慢波活动的程度有关。BDNF在发育和成人大脑中表达，影响神经元的存活、分化和突触可塑性。Cort是一种在大脑皮层和HP的-氨基丁酸中间神经元中表达的神经肽。清醒时的探索性行为、BDNF等可塑性基因的诱导与睡眠压力/需求程度呈正相关。睡眠剥夺（SD）导致皮质Cort mRNA表达增加。活动依赖性BDNF表达的破坏修饰小鼠（BDNF- kiv）在基线和SD后的Cort mRNA水平受损，这也导致活动期睡眠时间减少。BDNF-KIV小鼠总体睡眠时间少于正常小鼠。活跃周期的进展或对SD的反应，BDNF和Cort的表达随着睡眠压力的升高而增加。在BDNF- kiv中，BDNF mRNA和Cort基因表达水平受损。修饰小鼠显示BDNF启动子IV完全破坏，其他BDNF转录物下调，导致SD完全丧失。我们的研究结果提出了BDNF对SD的调节可能是通过cort阳性中间神经元的活性依赖性BDNF调节来介导的。我们的研究表明，活动依赖性BDNF表达对表达cort的中间神经元的调节可能有助于调节与睡眠稳态一致的睡眠行为。