Endophenotypes of Dopaminergic Dysregulation in 22q11.2 Deletion Syndrome

22q11.2 缺失综合征多巴胺能失调的内表型

• 批准号: 8988311
• 负责人: Rachel Karen Jonas
• 金额: $ 3.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-16 至 2017-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8988311
• 关键词: 22q11.2; Adolescence; Adolescent Development; Alleles; Area; Attention; Attention Deficit Disorder; Attention deficit hyperactivity disorder; Behavior; Behavioral; Biological; Brain; Brain region; Catechols; Cerebrum; Characteristics; Chromosomes; Clinical; Codon Nucleotides; Cognition; Complex; Corpus striatum structure; DNA Sequence Alteration; Decision Making; Development; DiGeorge Syndrome; Disease; Dopamine; Enzymes; Equipment and supply inventories; Etiology; Executive Dysfunction; Functional disorder; Gene Dosage; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Techniques; Genetic Variation; Glutamates; Human; Individual; Investigation; Knowledge; Life; Link; Measures; Mediating; Mental disorders; Metabolism; Methionine; Modeling; Neuroanatomy; Patients; Performance; Play; Population; Prefrontal Cortex; Proline; Proline Dehydrogenase; Proteins; Psychopathology; Psychotic Disorders; Regulation; Rewards; Risk; Risk-Taking; Role; Schizophrenia; Single Nucleotide Polymorphism; Source; Structural defect; Structure; Surface; System; Thick; Time; Transferase; Translating; Valine; Variant; Vulnerable Populations; analog; behavioral impairment; brain dysfunction; cognitive control; cognitive function; conotruncal anomaly face syndrome; course development; endophenotype; executive function; expectation; gene function; high risk; improved; interest; nerve supply; neural circuit; neurobiological mechanism; neurogenesis; neurogenetics; neuropsychiatric disorder; neuropsychiatry; nonhuman primate; patient population; psychotic symptoms; public health relevance; receptor density; relating to nervous system; research study; reward circuitry; reward processing; transmission process; vulnerable adolescent

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.

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精确生物学机制已被证明具有挑战性。 22q11.2 缺失综合征（Velocardiofacial/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相关，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，用于研究已知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的大脑区域的结构和功能。 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体不足而导致终生的生物学脆弱性，导致 22qDS 患者与奖励系统相关的行为和神经解剖学的改变。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影响大脑提供经验支持，[以及这些影响如何在发育过程中发生变化（特别是在脆弱的青少年时期）]。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（横向和纵向），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。目标 1 将首先研究 22qDS 患者的冒险和最佳决策的实验测量，[以及现实世界执行控制的测量]，我们假设这两者在该人群中都受到损害。目标 2 将检查对决策和奖励期望至关重要的大脑区域（例如，眶额和背外侧前额皮质）的体积、厚度和表面积的变化，假设 22qDS 患者相对于典型发育对照，将在这些结构中表现出基线异常，以及前额皮质成熟的异常轨迹。目标 3 将采用遗传技术来检查 22qDS 患者中半合子缺失的与多巴胺能和谷氨酸能功能（分别为 COMT 和 PRODH）相关的特定基因的变异，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，进而转化为 PFC 结构变异和下游对行为的影响。总之，为实现这些目标而计划的实验结果将扩大当前关于多巴胺和奖励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研究使我们能够直接研究遗传变异与脑功能障碍之间的联系，从而有助于阐明可能引起奖赏相关功能障碍和精神疾病的复杂神经生物学机制。