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: 7594524
• 负责人: Karen FAITH Berman
• 金额: $ 79.69万
• 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/7594524
• 关键词: Accounting; Affect; Alleles; Amygdaloid structure; Animals; Anxiety Disorders; Area; Autopsy; Behavior; Brain; Brain region; Brain scan; Catabolism; Cerebrovascular Circulation; Code; Cognition; Corpus striatum structure; Data; Data Set; Dopa; Dopamine; Emotions; Enzymes; Estrogen Receptors; Estrogens; Event; Fire - disasters; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Genetic; Genetic Polymorphism; Genotype; Gonadal Steroid Hormones; Hippocampus (Brain); Hormones; Human; Individual; Knowledge; Learning; Life; Light; Link; Luteal Phase; Measures; Memory; Menstrual cycle; Menstrual fluid; Menstruation; Mental disorders; Methionine; Methods; Methyltransferase Gene; Midbrain structure; Mood Disorders; Moods; Neurobiology; Neurons; Ovulation; Pattern; Personal Satisfaction; Persons; Pharmaceutical Preparations; Phase; Phenotype; Positron-Emission Tomography; Prefrontal Cortex; Process; Progesterone; Rate; Regulation; Rewards; Risk; Sample Size; Scanning; Schizophrenia; Short-Term Memory; Signal Transduction; Simulate; Single Nucleotide Polymorphism; Specimen; System; Testing; Thinking; Time; Translating; Valine; Variant; Woman; Work; area striata; concept; day; frontal lobe; gene interaction; insight; interest; men; neurogenetics; neuroimaging; neuromechanism; pleasure; presynaptic; proliferative phase Menstrual cycle; radioligand; receptor; relating to nervous system; reward circuitry; tool; uptake

We have used neuroimaging to explore the effects in the brain of allelic variation in the catecholO-methyltransferase gene (COMT), which has been identified as a gene of interest for schizophrenia. It is well-established that, particularly in prefrontal cortex, COMT is prime determinant of dopamine catabolism, thereby influencing intrasynaptic dopamine levels. A common polymorphism in the COMT gene (val108/158met) leads to significantly reduced catabolic activity in the COMT enzyme moiety coded for by the 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, consistent with previous findings in animal that dopamine as being critical to determine the ratio of task-related to task-unrelated neural firing or tuning of PFC neurons. Postmortem studies have shown a direct correlation between valine-encoding alleles and increased dopamine synthesis in the midbrain, which suggested that this functional single nucleotide polymorphism (SNP) can modulate the interaction between the PFC and 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 living 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 F-18 Fluoro-dopa uptake (to measure dopamine synthesis and presynaptic stores) in the same individuals. . We not only demonstrated that valine carriers have increased midbrain FDOPA 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 and 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. These data also explain a neurogenetic mechanism that underlies individual variation in the function of the prefrontal-midbrain network. In another study aimed at identifying effects of gonadal steroid hormones on activity within the dopamine-related reward system, we used functional magnetic resonance imaging (fMRI) and an event-related reward paradigm to reveal that fluctuations in estrogen and progesterone hormone levels during women's menstrual cycles affect the responsiveness of the reward circuitry in the brain. While women were winning rewards, their circuitry was more active if they were in the menstrual phase preceding ovulation, the midfollicular phase which is dominated by estrogen (4-8 days after the onset of menses), compared to the luteal phase, when estrogen and progesterone are present. The reward system circuitry includes: prefrontal cortex - thinking and planning; amygdala - fear and emotions; hippocampus - learning and memory; and striatum - which relays signals from these brain regions to the cortex. Reward circuit neurons have receptors for estrogen and progesterone. However, how these hormones influence reward circuit activity in humans has remained unclear. To evaluate 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 also confirmed that the reward-related brain activity was directly linked to levels of sex hormones. Activity in the amygdala and hippocampus was consistent with estrogen levels regardless of cycle phase; activity in these areas was also triggered by progesterone levels while women were anticipating rewards during the post-ovulatory phase. Activity patterns that emerged when rewards were delivered during the post-ovulatory phase suggested that the effect of estrogen on the reward circuit might be altered by the presence of progesterone during that period. Men showed a different activation profile than women during both anticipation and delivery of rewards. For example, 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. While they were anticipating winning money, brain activity in the orbitofrontal cortex, part of the reward system thought to regulate emotion and reward-related planning behavior, was increased during women's pre-ovulatory (follicular) phase compared to post-ovulatory (luteal) phase. This is the first study of how sex hormones influence reward-evoked brain activity in humans, and may provide 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 may also shed light on the neural mechanism that renders women more vulnerable to addictive drugs during the pre-ovulation phase of the cycle.

我们已经使用神经影像来探索Catecholo-甲基转移酶基因（COMT）中等位基因变异的影响，该基因已被鉴定为精神分裂症感兴趣的基因。众所周知的是，尤其是在前额叶皮层中，COMT是多巴胺分解代谢的主要决定因素，从而影响了鼻内多巴胺水平。 COMT基因（Val108/158met）中常见的多态性导致蛋氨酸等位基因编码的COMT酶部分中的分解代谢活性显着降低，前额叶皮质（PFC）中多巴胺的可用性增加。 Valine等位基因与工作记忆差和效率低下的皮质加工有关，这与动物中多巴胺的先前发现相一致，因为多巴胺对确定与任务无关的神经性神经射击或PFC神经元的调整至关重要。 验尸研究表明，中脑中的丝线编码等位基因和增加的多巴胺合成之间存在直接相关性，这表明这种功能性的单核苷酸多态性（SNP）可以调节PFC与中脑之间的相互作用。在这些发现的基础上，我们的小组进行了一项研究，以证明正常健康活人中PFC与中脑多巴胺合成之间的特定相互作用，这是COMT基因型的函数。我们使用正电子发射断层扫描（PET）在工作记忆过程中测量区域脑血流（RCBF）和同一个体中F-18 Fluoro-Dopa摄取（以测量多巴胺合成和突触前商店）。 。我们不仅证明了Valine载体增加了Midbrain Fdopa的摄取，还证实了活着的人在验尸脑标本中的发现，我们还通过证明COMT基因型确定FDOPA和前脑前胸前RCBF之间的关系方向，从而扩展了对这种基因相关改变的含义的了解。 这项工作证实了PFC与多巴胺之间的强烈相互作用以及PFC-中间调谐机制的遗传控制，并在人类中首次提供了支持当前有关PFC功能多巴胺能调节及其对皮质下多巴胺调节作用的概念的重要佐证证据。 这些数据还解释了一种神经遗传机制，该机制是前额叶中脑网络功能中个体变化的基础。 在另一项旨在鉴定性腺类固醇激素对多巴胺相关奖励系统活动的影响的研究中，我们使用功能磁共振成像（fMRI）和与事件相关的奖励范式来揭示女性在男性月经循环中的雌激素和孕酮激素水平的波动，会影响奖励循环的奖励循环。尽管女性赢得了奖励，但如果她们处于排卵前的月经相，则与雌激素（在月经开始后的4-8天）相比，与雌激素相比，它们的电路阶段更加活跃，这是雌激素（4-8天）的中期相。奖励系统电路包括：前额叶皮层 - 思维和计划；杏仁核 - 恐惧和情感；海马 - 学习和记忆；和纹状体 - 将这些大脑区域的信号传递到皮层。奖励电路神经元具有用于雌激素和孕酮的受体。但是，这些激素如何影响人类的奖励电路活动尚不清楚。为了评估激素对奖励电路的影响，我们在执行涉及模拟老虎机的任务时扫描了男女的大脑活动。妇女在排卵前后被扫描。功能磁共振成像的数据表明，当女性预期获得奖励与奖励的实际交付时，奖励系统的反应不同，具体取决于其月经阶段。当她们赢得大奖并实际上赢得了奖励时，在排卵前的妇女比在卵巢后阶段相比激活了与愉悦和奖励相关的纹状体和巡回赛区域。该研究还证实，与奖励相关的大脑活动与性激素的水平直接相关。杏仁核和海马的活性与雌激素水平一致。这些地区的活性也是由孕激素水平触发的，而妇女期望在卵巢后阶段获得回报。在卵巢后阶段传递奖励时出现的活性模式表明，在此期间，孕酮的存在可能会改变雌激素对奖励电路的影响。在预期和奖励交付期间，男性表现出与女性不同的激活特征。例如，与男性相比，在奖励交付时，男性在预期期间在纹状体区域的活动更多。尽管他们预计赢得金钱，但在妇女的卵巢治疗（卵泡（卵泡））阶段，与后（黄体）阶段相比，在奖励系统中的大脑活动是调节情绪和奖励相关的计划行为的奖励系统的一部分。这是关于性激素如何影响人类奖励引起的大脑活动的第一个研究，并可能提供有关月经相关情绪障碍的见解，女性的情绪和焦虑症的较高率，以及后来的发作，而在精神分裂症中则不太严重。这项研究还可以阐明神经机制，使女性在周期前的流动阶段更容易受到上瘾性药物的影响。