Endophenotypes of Dopaminergic Dysregulation in 22q11.2 Deletion Syndrome

描述(申请人提供)：奖赏回路的异常是多种神经精神障碍的特征；然而，阐明这种功能障碍的确切生物学机制被证明是具有挑战性的。22q11.2缺失综合征(VelHearofacial/DiGeorge综合征；22qDS)为研究这些机制提供了一个令人信服的模型，因为这种神经遗传性疾病与多种精神疾病的极高风险有关，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。缺失区域内的几个基因与大脑发育和前额叶皮质(PFC)多巴胺代谢有关。因此，这种障碍提供了一个理想的模型，用来研究大脑区域的结构和功能，这些区域是依赖于最佳多巴胺水平的额叶调节认知功能所必需的。我们的假设是，由于对多巴胺调节至关重要的特定基因单倍体不足而导致的终身生物脆弱性，会导致22qDS患者与奖励系统相关的行为和神经解剖学改变。检查这些内部表型可以为这些基因的功能如何在系统范围内影响大脑提供经验支持，[以及这些影响如何在发育过程中(特别是在脆弱的青春期)发生变化]。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]，并调查完整染色体中的等位基因变异对这些神经解剖学和行为改变的贡献。目标1将首先调查22qDS患者的风险承担和最佳决策的实验指标，[以及现实世界执行控制的指标]，我们假设这两项指标在这一人群中都受到了损害。目标2将检测大脑中对决策和奖励预期至关重要的区域(例如，眼眶前额叶和背外侧前额叶皮质)的体积、厚度和表面积的变化，假设22qDS患者将显示这些结构相对于典型发育中的对照组的基线异常，以及额叶前皮质成熟的异常轨迹。目的3将利用基因技术检测22qDS患者中与多巴胺和谷氨酸功能相关的特定基因(分别为COMT和PROSH)的变异，以确定22QDS患者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PFC结构变异和下游对行为的影响。总而言之，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范围。对这一独特的临床人群的研究使我们能够直接调查基因变异和脑功能障碍之间的联系，从而有助于阐明可能导致奖赏相关功能障碍和精神疾病的复杂神经生物学机制。

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.