Neuroimaging of Brain Circuits and Neurogenetic Mechanisms in Normal Cognition

正常认知中的脑回路神经影像和神经发生机制

• 批准号: 7969328
• 负责人: Karen FAITH Berman
• 金额: $ 84.2万
• 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/7969328
• 关键词: Accounting; Adult; Affect; Aging; Alleles; Anxiety Disorders; Area; Autopsy; Biological; Brain; Brain region; Brain scan; COMT gene; Catabolism; Catechol O-Methyltransferase; Cerebrovascular Circulation; Cognition; Complex; Corpus striatum structure; Country; Data; Data Set; Dopamine; Enzymes; Event; Exhibits; Functional Magnetic Resonance Imaging; Functional disorder; General Population; Genes; Genetic; Genetic Polymorphism; Genotype; Gonadal Steroid Hormones; Hormones; Human; Individual; Knowledge; Lead; Life; Light; Link; Longevity; Measures; Mental disorders; Methionine; Methods; Midbrain structure; Minisatellite Repeats; Mood Disorders; Moods; Mutation; Neurobiology; Ovulation; Pattern; Persons; Pharmaceutical Preparations; Phase; Phenotype; Play; Positron-Emission Tomography; Prefrontal Cortex; Process; Regulation; Rewards; Risk; Role; Sample Size; Scanning; Schizophrenia; Short-Term Memory; Simulate; Specimen; System; Testing; Therapeutic Intervention; Time; Translating; United States; Valine; Variant; Woman; Work; age related; area striata; cost; dopamine system; dopamine transporter; frontal lobe; gene interaction; healthy aging; insight; interest; men; methionylmethionine; neural circuit; neurogenetics; neuroimaging; neuromechanism; neurotransmission; pleasure; presynaptic; radioligand; receptor; relating to nervous system; response; reward processing; tool; transmission process; uptake

We have used neuroimaging to explore the effects in the brain of gene allelic variation in the catechol-O-methyltransferase(COMT) gene, which has been identified as a gene of interest for schizophrenia. It is well-established that, particularly in prefrontal cortex, COMT is a prime determinant of dopamine catabolism, influencing intrasynaptic dopamine levels. A common polymorphism in the COMT gene (val158met) leads to significantly reduced catabolic activity in the COMT enzyme by methionine allele, with increased availability of dopamine in the prefrontal cortex (PFC). The valine allele has been associated with poor working memory and inefficient cortical processing. Postmortem studies have shown a direct correlation between valine-encoding alleles and increased dopamine synthesis in the midbrain. Building upon these findings, our group engaged in a study to demonstrate the specific interactions between PFC and midbrain dopamine synthesis in normal healthy people as a function of COMT genotype. We used positron emission tomography (PET) to measure both regional cerebral blood flow (rCBF) during working memory and 18FDPOA (18-Fluoro-dopamine) uptake to measure dopamine synthesis and presynaptic stores in the same individuals. We not only demonstrated that valine carriers have increased midbrain 18FDOPA uptake, confirming in living persons the findings in postmortem brain specimens, we also extended our knowledge of the implications of this gene-related alteration by demonstrating that the COMT genotype determines the direction of the relationship between midbrain FDOPA and prefrontal rCBF during working memory. This work substantiates the idea of strong interactions between PFC and dopamine and of genetic control of the PFC-midbrain tuning mechanism. It also provides for the first time important corroborative evidence in humans that supports current concepts about dopaminergic modulation of PFC function and its effect on subcortical dopamine regulation. Previous studies have also demonstrated that dopamine neurotransmission is dependent upon the COMT val158met functional mutation in conjunction with a functional mutation in the variable number of tandem repeats in the dopamine transporter (DAT1) gene. Currently, we are investigating the effect of COMT val158met and DAT1 functional mutations on specific components of the reward system in healthy subjects. This year, our study used event-related fMRI (functional magnetic resonance imaging) to exam the neurofunctional effects of val158met COMT and DAT1 mutations on specific components of the reward system. We showed a main effect of COMT genotype in one brain region during reward anticipation and in another brain region when the reward was delivered. COMT met/met had the highest activation. This same pattern of main effect in one brain region during reward anticipation and another brain region when the reward was delivered was observed in DAT1 genotype. The DAT1 9-repeat allele showed the most activity. Interaction between the two genes showed once again a similar pattern, with the highest activity exhibited from COMT met/met and DAT1-9-repeat. This suggests that variations in dopamine transmission is genetically influenced and can therefore modulate brain region responses involved in anticipation and reception of rewards. Very little is known about the neurofunctional consequences of this age-related dopamine decline. We examined how the dopamine system, which plays a crucial role in reward processing, affects aging individuals. There has been no direct demonstration of a link between midbrain dopamine and reward-related neural response. In this study, we directly characterize the interactions between midbrain dopamine function and the reward system in both healthy young and older subjects and identify changes in this regulatory circuit in healthy aging. Using both 18FDOPA PET and event-related functional magnetic resonance imaging in the same subjects directly demonstrates a link between midbrain dopamine synthesis and reward-related prefrontal activity. This shows that healthy aging induces functional alterations in the reward system, and identify an age-related change in the direction of the relationship between midbrain dopamine synthesis and prefrontal activity. These results indicate an age-dependent dopamine tuning mechanism for cortical reward processing and provide systems-level information about alteration of a key neural circuit in healthy aging. Our data provide characterization of the interactions between midbrain dopamine function and the reward system in healthy aging; and identifies changes in this regulatory circuit across the adult lifespan. These results may prompt additional studies in the identified circuit and may lead to studies of mechanistically targeted therapeutic interventions involving the dopamine system. We have also evaluated hormone effects on the reward circuit. We scanned the brain activity of women and men while they performed a task involving simulated slot machines. The women were scanned before and after ovulation. The fMRI data showed that the reward system responded differently when women anticipated a reward compared with when the reward was actually delivered, depending upon their menstrual phase. When they hit the jackpot and actually won a reward, women in the pre-ovulatory phase activated the striatum and circuit areas linked to pleasure and reward more than when in the post-ovulatory phase. The study confirmed that the reward-related brain activity was directly linked to levels of sex hormones. Men showed a different activation profile than women during both anticipation and delivery of rewards. Men had more activity in the striatum area during anticipation compared to women and women had more activity in the frontal cortex area at the time of reward delivery compared to men. This was the first study of how sex hormones influence reward-evoked brain activity, and provided insights into menstrual-related mood disorders, women's higher rates of mood and anxiety disorders, and their later onset and less severe course in schizophrenia. This study also shed light on the neural mechanism that renders women more vulnerable to addictive drugs during the pre-ovulation phase of the cycle.

我们使用神经影像学来探索儿茶酚-O-甲基转移酶（COMT）基因等位基因变异对大脑的影响，该基因已被确定为精神分裂症的相关基因。众所周知，特别是在前额皮质中，COMT 是多巴胺分解代谢的主要决定因素，影响突触内多巴胺水平。 COMT 基因 (val158met) 中常见的多态性导致蛋氨酸等位基因导致 COMT 酶的分解代谢活性显着降低，同时前额皮质 (PFC) 中多巴胺的可用性增加。缬氨酸等位基因与较差的工作记忆和低效的皮质处理有关。尸检研究表明，缬氨酸编码等位基因与中脑多巴胺合成增加之间存在直接相关性。基于这些发现，我们小组开展了一项研究，以证明正常健康人群中 PFC 和中脑多巴胺合成之间的特定相互作用是 COMT 基因型的函数。我们使用正电子发射断层扫描 (PET) 测量工作记忆期间的局部脑血流量 (rCBF)，并使用 18FDPOA（18-氟多巴胺）摄取来测量同一个体的多巴胺合成和突触前储存。我们不仅证明缬氨酸携带者增加了中脑 18FDOPA 的摄取，在活人中证实了死后大脑标本中的发现，而且还通过证明 COMT 基因型决定了工作记忆期间中脑 FDOPA 和前额叶 rCBF 之间关系的方向，扩展了我们对这种基因相关改变的影响的认识。这项工作证实了 PFC 和多巴胺之间的强烈相互作用以及 PFC-中脑调节机制的遗传控制的想法。它还首次在人类中提供了重要的确凿证据，支持当前关于 PFC 功能的多巴胺能调节及其对皮质下多巴胺调节的影响的概念。先前的研究还表明，多巴胺神经传递依赖于 COMT val158met 功能突变以及多巴胺转运蛋白 (DAT1) 基因中可变数量串联重复的功能突变。目前，我们正在研究 COMT val158met 和 DAT1 功能突变对健康受试者奖励系统特定组成部分的影响。 今年，我们的研究使用事件相关的 fMRI（功能磁共振成像）来检查 val158met COMT 和 DAT1 突变对奖励系统特定组成部分的神经功能影响。 我们展示了 COMT 基因型在奖励预期期间的一个大脑区域和奖励交付时的另一个大脑区域的主要影响。 COMT met/met 的激活度最高。 在 DAT1 基因型中，在奖励预期期间的一个大脑区域和奖励交付时的另一个大脑区域中观察到了相同的主效应模式。 DAT1 9 重复等位基因显示出最强的活性。 两个基因之间的相互作用再次显示出相似的模式，COMT met/met 和 DAT1-9-repeat 表现出最高的活性。这表明多巴胺传输的变化受到遗传影响，因此可以调节涉及预期和接受奖励的大脑区域反应。 人们对这种与年龄相关的多巴胺下降的神经功能后果知之甚少。我们研究了在奖励处理中发挥关键作用的多巴胺系统如何影响衰老个体。目前还没有直接证据表明中脑多巴胺与奖励相关的神经反应之间存在联系。在这项研究中，我们直接描述了健康年轻和老年受试者中脑多巴胺功能与奖励系统之间的相互作用，并确定了健康衰老过程中这一调节回路的变化。在同一受试者中使用 18FDOPA PET 和事件相关功能磁共振成像直接证明了中脑多巴胺合成与奖励相关前额叶活动之间的联系。这表明健康的衰老会引起奖励系统的功能改变，并确定中脑多巴胺合成和前额叶活动之间关系方向的与年龄相关的变化。这些结果表明了皮质奖励处理的年龄依赖性多巴胺调节机制，并提供了有关健康衰老过程中关键神经回路改变的系统级信息。我们的数据提供了健康老龄化过程中中脑多巴胺功能与奖励系统之间相互作用的特征；并确定这一调节回路在成人一生中的变化。这些结果可能会促进对已确定的回路进行更多研究，并可能导致涉及多巴胺系统的机械靶向治疗干预措施的研究。 我们还评估了激素对奖励回路的影响。我们扫描了女性和男性执行涉及模拟老虎机的任务时的大脑活动。这些女性在排卵前和排卵后接受了扫描。功能磁共振成像数据显示，当女性预期奖励与实际获得奖励时，奖励系统的反应不同，具体取决于她们的月经阶段。当她们中了大奖并真正赢得了奖励时，排卵前阶段的女性比排卵后阶段更能激活与快乐和奖励相关的纹状体和回路区域。研究证实，与奖励相关的大脑活动与性激素水平直接相关。在期待和提供奖励时，男性表现出与女性不同的激活特征。与女性相比，男性在预期期间纹状体区域的活动更多，而女性在奖励交付时的额叶皮层区域的活动比男性更多。这是第一项关于性激素如何影响奖赏诱发的大脑活动的研究，并提供了对月经相关情绪障碍、女性情绪和焦虑障碍的较高发生率以及精神分裂症发病较晚且较轻的病程的见解。这项研究还揭示了使女性在周期前排卵阶段更容易受到成瘾药物影响的神经机制。