Neuroimaging of Brain Circuits and Neurogenetic Mechanisms in Normal Cognition

我们使用神经成像技术来探索儿茶酚- o -甲基转移酶（COMT）基因等位基因变异在大脑中的作用，该基因已被确定为精神分裂症的一个感兴趣的基因。已经证实，特别是在前额皮质，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）的常见多态性导致蛋氨酸等位基因显著降低COMT酶的分解代谢活性，增加前额皮质（PFC）中多巴胺的可用性。缬氨酸等位基因与较差的工作记忆和低效的皮层处理有关。死后研究表明，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关联。在这些发现的基础上，我们的研究小组进行了一项研究，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基因型的功能。我们使用正电子发射断层扫描（PET）来测量工作记忆期间的区域脑血流量（rCBF）和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，证实了在活体脑标本中的发现，我们还通过证明COMT基因型决定了工作记忆中中脑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含义的认识。这项工作证实了PFC和多巴胺之间的强相互作用以及PFC-中脑调节机制的遗传控制的观点。这也首次为人类提供了重要的确凿证据，支持了目前关于多巴胺能调节PFC功能及其对皮层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序列的功能突变。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成分的影响。

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.