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学来探索在大脑中的儿茶酚O-甲基转移酶基因（COMT），已被确定为精神分裂症的感兴趣的基因的等位基因变异的影响。众所周知，特别是在前额叶皮层，COMT是多巴胺catalysts的主要决定因素，从而影响突触内多巴胺水平。COMT基因的一种常见多态性（val 108/158 met）导致由甲硫氨酸等位基因编码的COMT酶部分的分解代谢活性显著降低，前额叶皮质（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层处理相关，这与先前在动物中的发现一致，即多巴胺对于确定任务相关的神经放电或PFC神经元的调谐与任务无关的神经放电或调谐的比率至关重要。 尸检研究表明，缬氨酸编码等位基因和中脑多巴胺合成增加之间存在直接相关性，这表明这种功能性单核苷酸多态性（SNP）可以调节PFC和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PFC和中脑多巴胺合成之间的特定相互作用在正常健康的人作为COMT基因型的函数。我们使用正电子发射断层扫描（PET）来测量同一个体在工作记忆和F-18氟多巴摄取（测量多巴胺合成和突触前储存）期间的局部脑血流量（rCBF）。.我们不仅证明了缬氨酸携带者增加了中脑FDOPA的摄取，证实了在活人死后脑标本中的发现，我们还通过证明COMT基因型决定了工作记忆期间中脑FDOPA和前额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和PFC-中脑调谐机制的遗传控制的想法，并首次提供了重要的确证证据，支持目前关于PFC功能的多巴胺能调制及其对皮质下多巴胺调节的影响的概念。 这些数据还解释了一种神经遗传机制，这种机制是前额叶-中脑网络功能个体差异的基础。 在另一项旨在确定性腺类固醇激素对多巴胺相关奖励系统内活动的影响的研究中，我们使用功能性磁共振成像（fMRI）和事件相关奖励范式来揭示女性月经周期期间雌激素和孕激素水平的波动会影响大脑奖励回路的反应性。虽然女性赢得了奖励，但如果她们处于排卵前的月经期，即以雌激素为主的卵泡中期（月经开始后4-8天），与雌激素和黄体酮为主的黄体期相比，她们的回路更加活跃。存在。奖赏系统的电路包括：前额叶皮层-思考和计划;杏仁核-恐惧和情绪;海马-学习和记忆;纹状体-将这些大脑区域的信号传递到皮层。奖赏回路神经元有雌激素和孕激素受体。然而，这些激素如何影响人类的奖励回路活动仍不清楚。为了评估激素对奖赏回路的影响，我们扫描了女性和男性在执行一项涉及模拟老虎机的任务时的大脑活动。这些妇女在排卵前后接受了扫描。功能磁共振成像数据显示，当女性预期奖励时，奖励系统的反应与实际奖励时不同，这取决于她们的月经期。当她们中了头奖并真的赢得了奖励时，处于排卵前阶段的女性比处于排卵后阶段的女性更能激活与快乐和奖励相关的纹状体和回路区域。该研究还证实，与奖励相关的大脑活动与性激素水平直接相关。杏仁核和海马体的活动与雌激素水平一致，无论周期阶段如何;当女性在排卵后阶段期待奖励时，这些区域的活动也由孕酮水平触发。在排卵后阶段给予奖励时出现的活动模式表明，雌激素对奖励回路的影响可能会因该期间孕酮的存在而改变。在预期和提供奖励的过程中，男性表现出与女性不同的激活模式。例如，在预期期间，男性的纹状体区域比女性更活跃，而在奖励传递时，女性的额叶皮层区域比男性更活跃。当他们期待赢钱时，与排卵后（黄体期）相比，女性排卵前（卵泡期）的眶额皮质（被认为是调节情绪和奖励相关计划行为的奖励系统的一部分）的大脑活动增加了。这是第一项关于性激素如何影响人类奖励诱发的大脑活动的研究，并可能为与婚姻有关的情绪障碍，女性情绪和焦虑障碍的高发病率，以及精神分裂症的晚发病和不太严重的过程提供见解。这项研究也可能揭示神经机制，使妇女更容易在排卵前阶段的周期成瘾药物。