Genetic Basis Of Cortical Malfunction In Schizophrenia

精神分裂症皮质功能障碍的遗传基础

• 批准号: 8342119
• 负责人: Daniel Weinberger
• 金额: $ 429.34万
• 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/8342119
• 关键词: AKT1 gene; Adverse effects; Adverse event; Affect; Agreement; Alleles; Amphetamines; Amygdaloid structure; Anger; Animals; Anterior; Anxiety; Arousal; Attention; Back; Basic Science; Behavior; Biological; Biological Assay; Biology; Blood Pressure; Blood specimen; Brain; Brain Diseases; Brain region; Brain-Derived Neurotrophic Factor; Cardiovascular system; Catechols; Cell Line; Chemical Structure; Chronic; Chronic Schizophrenia; Clinical; Clinical assessments; Cognition; Cognitive; Cognitive deficits; Collaborations; Complex; Coupling; Data; Development; Diagnosis; Diagnostic; Dopamine; Dose; Double-Blind Method; Emotional; Evaluation; Event; Exclusion; Face; Family; Fatigue; Fright; Functional Imaging; Functional Magnetic Resonance Imaging; Future; Generations; Genes; Genetic; Genetic Epistasis; Heart Rate; Hippocampus (Brain); Human; Human Cell Line; Image; Impaired cognition; Interview; Lead; Lithium; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Medial; Memory; Mental disorders; Methods; Methyltransferase; Mission; Modafinil; Molecular; Molecular Models; Mood stabilizers; Moods; Neuronal Plasticity; Neurons; Neuropsychological Tests; Neurotransmitters; Norepinephrine; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacologic Substance; Placebos; Predisposition; Prefrontal Cortex; Procedures; Process; Publishing; Reaction; Reaction Time; Records; Recruitment Activity; Regulation; Reporting; Risk; Sample Size; Sampling; Schizophrenia; Series; Serotonin; Short-Term Memory; Siblings; Signal Transduction; Single Nucleotide Polymorphism; Source; Stimulus; Structure; System; Task Performances; Temporal Lobe; Testing; Validation; Valproate Sodium; Variant; base; blood oxygen level dependent; brain volume; case control; gamma-Aminobutyric Acid; gene interaction; genetic analysis; genetic association; gray matter; improved; in vivo; information processing; molecular modeling; neurochemistry; neuroimaging; neuropathology; neuropsychiatry; new therapeutic target; novel strategies; placebo controlled study; proband; protein expression; psychostimulant; relating to nervous system; response; trait; trend

Potential treatments in neuropsychiatry (cognitive dysfunction) are the targets of psychostimulants. Cognitive dysfunction is a core feature of complex mental disorders like schizophrenia. Modafinil, a psychostimulant, differs from other arousal-enhancing agents in chemical structure, neurochemical profile, and behavior effects. It has a lower liability for abuse and lower risk for adverse events on the cardiovascular system. Amphetamine, another psychostimulant has pronounced effects on generation of anxiety and fear as shown by increased amygdala reaction for fearful faces tasks. Previous fMRI studies examined the effect of Modafinil only on information processing which supports executive cognition, but also has been shown to have pronounced effects on emotional behavior. In this study we used cognitive, imaging and basic science methods to test our hypothesis and identify a possible treatment approach for cognitive dysfunction. We examined healthy subjects in a double-blind, placebo controlled study using BOLD fMRI. Subjects performed emotional information processing task (face matching) to activate the amygdala, and cognitive tasks: working memory (2-Back) and the Variable Attentional Control to activate the prefrontal region. They also underwent clinical assessments which included: blood pressure, heart rate, Hamilton anxiety scale, POMS (profile of mood state). We hypothesized there would be no change in amygdala reaction or decreased reaction and improved cortical efficiency defined as engaging less cortical activity or more focused cortical activity for a similar level of task performance vs. placebo. Our result on the effects of chronic low dose Modafinil was significantly decreased amygdala activation to anxiety and fearful stimuli on drug vs. placebo, which is in stark contrast to other psychostimulants, like low-dose amphetamine. In addition, we observed an increase in negative coupling between the supragenual cingulate and the amygdala in a functional connectivity analysis. The molecular mechanism of the Modafinil effect on amygdala reactivity is unknown. It is possible that the increase in negative coupling between the supragenual cingulate and amygdala suggest a top-down control mechanism may be responsible at the neural systems level for the dampening effect on amygdala reactivity. Reduced amygdala reactivity may then lead to the reduction in positive coupling with the supragenual cingulate. Additional studies will be needed to determine the functional directionality and to confirm our hypothesis. Alternatively, the reduction in amygdala reactivity on Modafinil could result from alterations in intra-amygdalar signaling due to changes in any one or a combination of norepinephrine, dopamine, serotonin, or gamma-Aminobutyric acid levels. It has been previously reported that reduction of amygdala reactivity is observed after administration of drugs that act on noradrengic system and the serotonin system. Because Modafinil acts on both systems as well as other neurotransmitter pathways, makes it difficult to determine the mechanism through which Modafinil affects amygdala reactivity. Additional studies will be needed to identify the mechanism on which Modafinil acts to modulate amygdala reactivity. Executive cognitive tasks comparing the same level of task performance, Modafinil reduced BOLD signal in prefrontal cortex and anterior cingulate. These results are in agreement with previously published reports which suggest improvement in the efficiency of information processing in brain regions highly populated with catecholaminergic neurons. Although not significant, there was a trend for reduced anxiety, decreased fatigue, increased activity, and decreased anger while taking Modafinil. In our study, improved cortical efficiency meant engaging less cortical activity or having more focused cortical activity on a similar level of task performance vs. placebo. These changes in BOLD signal were observed in the absence of any difference in accuracy, reaction time during 2-Back working memory task, and therefore reflected an improvement in prefrontal cortex efficiency while taking Modafinil. The variable attention control task showed an increase in demand on the level (low-intermediate-high) of attentional control with a significant drug-effect in the anterior cingulate activation in placebo vs. Modafinil. Future studies will implore event-related working memory paradigms to define subprocesses that are modulated by the drug. Using a larger sample size following imaging quality exclusion and examining a within subject dose-response effects will strengthen our analyses. Additional studies will also be needed on the circuit underlying anxiety to other drugs to elucidate the neurotransmitter systems implicated in Modafinil effect on amygdala. This is the first in vivo study in humans of multiple effects of Modafinil. In summary, low doses of Modafinil appears to show no adverse effect on the cardiovascular system, improves the efficiency of cognitive information processing, and reduces amygdala reactivity for anxiety to fearful stimuli. In another study that used genes associated with schizophrenia, we looked at gene-gene interactions to better characterize the impact of a single nucleotide polymorphism (SNP) rs1130233 in AKT1 on human medial temporal lobe (MTL) development and plasticity. This specific AKT1 SNP was previously reported to impact protein expression, prefrontal function and increases risk for schizophrenia, also affects MTL structure and memory function. We found interactions between the AKT1 SNP with BDNF (brain-derived neurotrophic factor) and COMT (catechol-o-methyltransferase) SNPs (Val66Met and Val158Met respectively). BDNF and COMT also impact MTL biology, as related to AKT1. We found epistasis between functional variants in all three genes on schizophrenia risk and pharmacogenetics interactions of AKT1 with effects on cognition and brain volume as measured by AKT1 activators, lithium and sodium valproate. Our findings suggest that AKT1 affects risk and cognitive deficits in part thru genetic interactions related to brain neuroplasticity and development, and these AKT1 effects may be modulated with pharmaceuticals. AKT1 influences memory-dependent hippocampal activity, gray matter volume for patients on mood stabilizers, has epistatic interactions with BDNF and COMT on risk for schizophrenia (as seen in casecontrol sample), and pharmacogenetics effects on cognition and brain structure in schizophrenia. A convergent series of human studies identified effects of an AKT1 allelic variation in memory-dependent neuroplasticity and structural brain processes related to normal brain development as well as to schizophrenia, and epistatic interactions with neurotrophic and dopaminergic processes that modulate these AKT1 effects. AKT1 regulation through pharmacologic was further associated with effects on schizophrenia-related cognition and the corresponding prefrontal-MTL brain structure in schizophrenia patients. AKT1 and related neuroplasticity and developmental pathways may, therefore, genetically influence cognition and risk for schizophrenia through effects that may be pharmacologically manipulated.

神经精神病学的潜在治疗（认知功能障碍）是精神刺激药的靶标。认知功能障碍是精神分裂症等复杂精神障碍的核心特征。莫达非尼是一种心理刺激剂，与其他唤醒的剂在化学结构，神经化学谱和行为效应方面有所不同。它对心血管系统上的滥用责任和较低的不良事件风险负有较低的责任。苯丙胺是另一种心理刺激剂对焦虑和恐惧产生的明显影响，如杏仁核反应增加而对恐惧面孔的任务增加。以前的fMRI研究仅研究了莫达非尼对支持执行认知的信息处理的影响，但也证明对情绪行为有明显的影响。在这项研究中，我们使用认知，成像和基础科学方法来检验我们的假设并确定一种可能的认知功能障碍方法。我们在使用BOLD FMRI的双盲，安慰剂对照研究中检查了健康受试者。受试者执行了情感信息处理任务（面部匹配）以激活杏仁核和认知任务：工作记忆（2-back）和可变注意力控制以激活前额叶区域。他们还接受了临床评估，其中包括：血压，心率，汉密尔顿焦虑量表，POMS（情绪状态）。我们假设杏仁核反应或反应降低不会发生变化，并提高了皮质效率，定义为具有较少的皮质活性或更集中的皮质活性，而皮质活性与安慰剂相似。我们对慢性低剂量莫达非尼影响的结果显着降低了杏仁核激活焦虑和可怕的刺激对药物与安慰剂的影响，该药物与安慰剂相比，与其他精神刺激剂形成鲜明对比，例如低剂量的苯丙胺。此外，我们观察到在功能连通性分析中，上扣带回和杏仁核之间负耦合的增加。莫达非尼对杏仁核反应性的分子机制尚不清楚。上扣带回和杏仁核之间负耦合的增加可能表明，自上而下的控制机制可能是在神经系统水平上负责的，从而导致对杏仁核反应性的抑制作用。然后，杏仁核反应性的降低可能导致阳性耦合与上扣扣带回的降低。需要进行其他研究来确定功能方向性并确认我们的假设。另外，由于任何一种或脱甲肾上腺素，多巴胺，5-羟色胺或γ-氨基氨基丁酸水平的变化，杏仁核对莫法拉反应性的降低可能导致杏仁核内信号传导的改变。先前据报道，在对Noradrengic System和5-羟色胺系统作用的药物后，观察到杏仁核反应性的降低。因为莫达非尼在两个系统以及其他神经递质途径上起作用，因此很难确定莫达非尼影响杏仁核反应性的机制。需要进行其他研究来确定莫达非尼起作用以调节杏仁核反应性的机制。比较相同级别的任务性能的执行认知任务，莫达非尼减少了前额叶皮层和前扣带回中的大胆信号。这些结果与先前发表的报告一致，这些报告表明在大脑区域的信息处理效率提高了高度占Catecholamin能神经元的效率。尽管不重要，但在服用莫达非尼时，焦虑症减轻，疲劳，活动增加和愤怒的趋势存在趋势。在我们的研究中，提高的皮质效率意味着减少皮质活动或在类似的任务绩效与安慰剂的水平上具有更专注的皮质活动。在没有任何差异的准确性，2个背包工作记忆任务中的反应时间差异的情况下，观察到了大胆信号的这些变化，因此在服用莫达非尼时反映了前额叶皮层效率的提高。可变的注意力控制任务显示，注意力控制水平（低接口高）的需求增加，在安慰剂与莫达非尼的前扣带回激活中具有明显的药物效应。未来的研究将恳请与事件相关的工作记忆范例定义由药物调节的子过程。在成像质量排除后使用较大的样本量并检查受试者内部剂量反应效应将加强我们的分析。还需要在其他药物的焦虑症中进行其他研究，以阐明与莫达非尼对杏仁核有关的神经递质系统。 这是对莫达非尼多种影响的人类的第一项体内研究。 总而言之，低剂量的莫达非尼似乎对心血管系统没有不利影响，提高了认知信息处理的效率，并降低了杏仁核的反应性，使其焦虑对可怕的刺激。 在另一项使用与精神分裂症相关的基因的研究中，我们研究了基因 - 基因相互作用，以更好地表征单个核苷酸多态性（SNP）RS1130233对AKT1对人内侧颞叶（MTL）发育和可变性的影响。以前，这种特定的AKT1 SNP会影响蛋白质表达，前额叶功能并增加精神分裂症的风险，还会影响MTL的结构和记忆功能。我们发现AKT1 SNP与BDNF（脑衍生的神经营养因子）与COMT（Catechol-O-O-甲基转移酶）SNP（分别为Val66met和Val158met）之间的相互作用。 BDNF和COMT也影响了与AKT1相关的MTL生物学。我们发现，正如Akt1激活剂，锂和丙戊酸钠测量的，Akt1的所有三个基因的功能变异与精神分裂症风险的功能变异与对认知和脑体积的影响的相互作用之间的上毒。我们的发现表明，AKT1通过与脑神经可塑性和发育相关的部分遗传相互作用影响风险和认知缺陷，并且这些AKT1效应可能会通过药物调节。 AKT1影响了依赖记忆的海马活性，对情绪稳定剂的患者的灰质体积，与BDNF和COMT具有精神分裂症的风险（在Casecontrol样本中可以看到）以及对精神分裂症的认知和脑结构的影响。一系列收敛的人类研究确定了AKT1等位基因变异在记忆依赖性神经塑性和结构性大脑过程中与正常脑发育以及精神分裂症有关的作用，以及与神经营养和多巴胺能过程的上皮相互作用，从而调节这些AKT1效应。通过药理学的AKT1调节进一步与精神分裂症相关认知的影响以及精神分裂症患者的相应前额叶MTL脑结构有关。因此，AKT1及相关的神经塑性和发育途径可能会通过可能通过药理学操纵的作用来影响基因认知和精神分裂症的风险。