Endophenotypes of Dopaminergic Dysregulation in 22q11.2 Deletion Syndrome

描述（由申请人提供）：奖赏回路异常是多种神经精神疾病的特征；然而，阐明这种功能障碍背后的确切生物学机制已被证明具有挑战性。22q11.2缺失综合征（veloccardiofacial /DiGeorge Syndrome; 22qDS）为研究这些机制提供了一个引人注目的模型，因为这种神经遗传疾病与多种精神疾病，特别是与多巴胺能功能障碍相关的疾病，如精神分裂症和注意力缺陷障碍，的风险极高。缺失区域内的几个基因与大脑发育和前额皮质（PFC）多巴胺代谢有关。因此，这种疾病提供了一个理想的模型来研究大脑区域的结构和功能，这些区域对依赖于最佳多巴胺水平的额叶介导的认知功能至关重要。我们的假设是，由于对多巴胺调节至关重要的特定基因的单倍不足，导致22qDS患者的行为和与奖励系统相关的神经解剖学改变，从而导致终生的生物脆弱性。检查这些内表型可以为这些基因的功能如何在全系统水平上影响大脑提供经验支持，[以及这些影响如何在发育过程中变化（特别是在脆弱的青春期）]。该项目的目的是量化22qDS患者的行为和结构神经解剖学改变（包括横断面和纵向），并研究完整染色体中等位基因变异对这些神经解剖学和行为改变的贡献。目的1将首先研究22qDS患者的风险承担和最佳决策的实验测量，[以及现实世界执行控制的测量]，我们假设这两个指标在该人群中受损。Aim 2将检查对决策和奖励预期至关重要的大脑区域（例如，眶额和背外侧前额叶皮层）的体积、厚度和表面积的变化，假设22qDS患者将表现出相对于典型发育对照的这些结构的基线异常，以及前额叶皮层成熟的异常轨迹。目的3将采用遗传技术检测22qDS患者中半合子缺失的与多巴胺能和谷氨酸能功能相关的特定基因（分别为COMT和PRODH）的变异，以确定22qDS完整染色体中的等位基因变异如何转化为基因表达的差异，进而确定PFC结构变异和对行为的下游影响。总之，为追求这些目标而计划的实验结果将扩大目前关于多巴胺和奖赏回路背景下遗传学与大脑结构和功能之间关系的知识领域。对这一独特的临床人群的调查使我们能够直接研究遗传变异和脑功能障碍之间的联系，从而有助于阐明复杂的神经生物学机制，通过这些机制，奖励相关的功能障碍和精神疾病可能会出现。

DESCRIPTION (provided by applicant): Abnormalities in reward circuitry are characteristic of multiple neuropsychiatric disorders; however, elucidating the precise biological mechanisms underlying this dysfunction has proved challenging. 22q11.2 Deletion Syndrome (Velocardiofacial/DiGeorge Syndrome; 22qDS) presents a compelling model for investigating these mechanisms, as this neurogenetic disorder is associated with extremely high risk for multiple psychiatric disorders, particularly those associated with dopaminergic dysfunction, such as schizophrenia and attention deficit disorder. Several genes within the deletion region are implicated in brain development and prefrontal cortical (PFC) dopamine metabolism. As such, this disorder provides an ideal model in which to study the structure and function of brain regions known to be essential for frontally-mediated cognitive functions that rely on optimal dopamine levels. Our hypothesis is that a life-long biological vulnerability, resulting from haploinsufficiency for specific genes critical for dopamine regulation, leads to alterations in behavior and neuroanatomy related to the reward system in patients with 22qDS. Examining these endophenotypes can offer empirical support for how the function of these genes impacts the brain at a system-wide level, [and how these effects may change over the course of development (particularly during the vulnerable adolescent period)]. The purpose of the proposed project is to quantify behavioral and structural neuroanatomic alterations in patients with 22qDS, [both cross-sectionally and longitudinally], and to investigate the contribution of allelic variation in the intact chromosome to these neuroanatomic and behavioral alterations. Aim 1 will first investigate an experimental measure of risk- taking and optimal decision-making in patients with 22qDS, [as well as a measure of real-world executive control], both of which we hypothesize to be impaired in this population. Aim 2 will examine alterations in volume, thickness and surface area in brain regions critical for decision-making and reward expectation (e.g., orbitofrontal and dorsolateral prefrontal cortex), with the hypothesis that 22qDS patients will show baseline abnormalities in these structures relative to typically developing controls, as well as abnormal trajectories of prefrontal cortical maturation. Aim 3 will employ genetic techniques to examine variation in specific genes relevant to dopaminergic and glutamatergic function (COMT and PRODH, respectively) that are hemizygously deleted in patients with 22qDS, in order to determine how allelic variation in the intact chromosome in 22qDS translates into differences in gene expression and, in turn, PFC structural variation and downstream effects on behavior. Together, the results of the experiments planned in pursuit of these aims will expand the current sphere of knowledge about the relationship between genetics and brain structure and function in the context of dopamine and reward circuitry. Investigation of this unique clinical population allows us to directly investigate links between genetic variation and brain dysfunction, thereby helping to elucidate the complex neurobiological mechanisms by which reward-related dysfunction and psychiatric illness may arise.