COMT and Developmental Memory Capacity

COMT 和发育记忆容量

• 批准号: 9134376
• 负责人: Noboru Hiroi
• 金额: $ 0.2万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-18 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134376
• 关键词: COMT; Developmental; Memory; Capacity

DESCRIPTION (provided by applicant): Memory deficits are one of the disabling impairments associated with autism, mental retardation, and schizophrenia. Because the underlying genetic and neuronal mechanisms of memory impairments are still poorly understood, mechanism-based therapeutic options do not exist to ameliorate such impairment, hindering the effective integration of patients into society. Interestingly, a high activity allele of catechol-O-methyl-transferase (COMT) is associated with lower levels of working memory performance after, but not before, puberty in children and adolescents. Our published mouse work shows that elevated activity of human COMT impairs working memory of mice at 2 months but not 1 month of age, where 1 month of age corresponds to puberty in the mouse. While this correlation in humans and mice suggests that there is a developmental timetable along which COMT levels begin to exert an influence on working memory, these studies did not elevate COMT levels at specific brain loci and developmental time points. The precise anatomical and cellular substrates and their developmental programming through which high COMT activity affects working memory capacity are still poorly understood. The objective of the proposed project is to test the overarching hypothesis that working memory and associated synaptic plasticity become increasingly dependent on an endogenous dopamine tone in the medial prefrontal cortex or hippocampus during postnatal development. To test this hypothesis, the PI has developed a lentiviral vector that temporally and spatially up-regulates COMT in the mouse brain. A team of investigators will achieve the following Specific Aims: Specific Aim 1: To ascertain the impact of elevated COMT expression in the medial prefrontal cortex or hippocampus on working memory capacity at specific developmental time points. Specific Aim 2: To determine the impact of spatially and temporally targeted reductions in an endogenous dopamine tone on synaptic plasticity in the prefrontal cortex and hippocampus. Upon completion of the proposed studies, these technically innovative experiments will, for the first time, identify the anatomical and cellular mechanisms through which an endogenous dopamine tone determines the developmental maturation of working memory capacity and synaptic plasticity. Identifying the developmental time window, anatomical region(s), and cellular substrate(s) necessary for an endogenous dopamine tone to induce behavioral and cellular working memory phenotypes will have a major impact on our understanding of working memory. Because working memory deficits have been observed in individuals with mental retardation, autism, and schizophrenia, this proposal could lead to a better understanding of the neurobiological substrates for one aspect of developmental neuropsychiatric disorders.

描述（由申请人提供）：记忆缺陷是与自闭症，智力低下和精神分裂症相关的残疾障碍之一。由于记忆障碍的潜在遗传和神经元机制仍然很少了解，因此不存在基于机制的治疗选择来改善这种障碍，从而阻碍了患者的有效整合到社会中。有趣的是，在儿童和青少年的青春期之后但不在之前，Catechol-O-甲基转移酶（COMT）的高活动等位基因与较低的工作记忆表现水平相关。我们已发表的鼠标工作表明，人类COMT的活动升高会损害2个月但1个月大的小鼠的工作记忆，其中1个月的年龄与小鼠的青春期相对应。尽管人类和小鼠的这种相关性表明，沿着COMT级别开始对工作记忆产生影响的发育时间表，但这些研究并未提高特定的大脑基因座和发育时间点的COMT水平。高COMT活性影响工作记忆能力的精确解剖和细胞底物及其发育编程仍然很少了解。拟议项目的目的是检验总体假设，即工作记忆和相关的突触可塑性越来越依赖于内侧前额叶皮层中的内源性多巴胺张张力，或者是在产后发育过程中的海马。为了检验这一假设，PI开发了慢病毒载体，该载体载体在时间和空间上上调小鼠大脑中的COMT。一个研究人员将达到以下特定目标：具体目的1：确定COMT表达在内侧前额叶皮层中的影响对特定发育时间点的工作记忆能力的影响。具体目标2：确定内源性多巴胺张力中的空间和时间靶向减少对前额叶皮层和海马的突触可塑性的影响。 拟议的研究完成后，这些技术创新的实验将首次确定内源性多巴胺张的解剖学和细胞机制决定了工作记忆能力和突触可塑性的发展成熟。确定内源性多巴胺音调诱导行为和细胞工作记忆表型所需的发育时间窗口，解剖区域和细胞底物，将对我们对工作记忆的理解产生重大影响。由于在患有智力低下，自闭症和精神分裂症的个体中已经观察到工作记忆缺陷，因此这一建议可能会使对发育神经精神疾病的一个方面的神经生物学底物有更好的了解。