PROJ 3: NEUROBEHAVIOR: BEHAVIOTAL CONSEQUENCES OF EMBRYONIC DISRUPTION

项目 3：神经行为：胚胎破坏的行为后果

• 批准号: 7764426
• 负责人: ROSLYN HOLLY FITCH
• 金额: $ 30.57万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7764426
• 关键词: Acoustics; Address; Adolescent; Adult; Affect; Age; Anatomy; Animal Model; Auditory; Basic Science; Behavior; Behavior assessment; Behavioral; Behavioral Model; Brain; Candidate Disease Gene; Characteristics; Clinical; Cognition; Cognitive; Complex; Coupled; Data; Detection; Development; Disabled Persons; Discrimination; Down-Regulation; Dyslexia; Electroporation; Embryo; Employee Strikes; Epidemiology; Exhibits; Female; Forebrain Development; Foundations; Gender; Genes; Genetic; Heterogeneity; Homologous Gene; Human; Impairment; Intervention; Knowledge; Language; Language Development Disorders; Language Disorders; Lead; Link; Literature; Maps; Memory; Memory impairment; Microgyria; Modeling; Molecular; Morphology; Motor; Mus; Neuroanatomy; Neuronal Migration Disorder; Neurons; Outcome; Pattern; Performance; Plasmids; Population; Predisposition; Preparation; Process; Proteins; RNA Interference; Rattus; Relative (related person); Research; Rodent; Rodent Model; Sensory; Sensory Process; Series; Short-Term Memory; Stimulus; Susceptibility Gene; Training; Transfection; Translations; Ventricular; analog; auditory discrimination; comparative; experience; gene function; genetic association; in utero; knock-down; male; migration; neural patterning; neurobehavior; neurobehavioral; neuromechanism; neuropathology; overexpression; phonology; postnatal; sex; success; visual learning

Accumulating evidence that core phonological processing problems in language-disabled subjects may relate to more basic deficits in rapid auditory processing has introduced new possibilities for the use of animal models in the study of developmental language disorders (e.g., dyslexia). Studies performed in our lab over the past decade reveal that cortical neuronal migration anomalies (similar to those seen in post mortem brains of dyslexics) are associated with behavioral deficits in rapid auditory processing (RAP), as well as in short-term memory (STM), in rodents. Moreover, RAP deficits are larger in juvenile as compared to adult male rats, are seen following cortical neuronal migration disruption in various species, and are larger in male as compared to female rats and mice. RAP deficits are also consistently seen in the absence of overall auditory processing impairments (e.g., performance on longer-stimulus acoustic discrimination tasks is normal). Thus, convergent findings from rodent models parallels behavioral and anatomic findings from human language disabled populations in a variety of ways. These data led us to perform behavioral assessments in rats following embryonic interference with the functions of gene homologs associated (in humans) with dyslexia. We found that E14/15 transfection with RNAi for the candidate dyslexia susceptibility rat gene homolog, Dyxld, led to subsequent impairments of rapid/complex acoustic discrimination in male rats (though no deficits for discriminating longer gap stimuli were seen). Such findings have enormous translational potential for dyslexia research, by linking data across levels of genetic disruption, neurodevelopmental disruption, and disruption of cognition/ behavior. The proposed studies will continue to address the neuropathological/behavioral consequences of embryonic manipulation of rat homologs for three candidate dyslexia susceptibility genes (Dyxld, Kiaa0319, and Dcdc2). Rats undergoing embryonic transfection with RNAi (or induced gene overexpression) will be evaluated on auditory, visual, and learning/memory tasks, as well as for post mortem neuropathology. Results will be assessed for evidence of genetic and neuropathological factors associated with specific behavioral deficits in RAP and STM that parallel deficits in language-disabled humans (in contrast to more general cognitive, motor, and/or sensory deficits). Such studies may bridge the gap between disrupted brain function/behavior in dyslexics, epidemiological evidence of genetic associations with dyslexia, and the critical intervening neurodevelopmental processes that are so difficult to study in humans, but so amenable to study in rodent models.

累积证据表明语言可持续学科中的核心语音处理问题可能 与快速听觉处理中更基本的缺陷有关，引入了新的可能性 动物模型在发展语言障碍研究（例如阅读障碍）中。在我们的研究中进行的研究 在过去的十年中，实验室表明皮质神经元迁移异常（类似于邮政 阅读障碍的尸体大脑）与快速听觉处理（RAP）中的行为缺陷有关 以及在啮齿动物中的短期记忆（STM）。此外，与少年相比，说唱缺陷较大 对于成年雄性大鼠，在各种物种中的皮质神经元迁移破坏后看到 与雌性大鼠和小鼠相比，男性的较大。说唱缺陷也始终在 缺乏整体听觉处理障碍（例如，在长期声学歧视上的表现 任务是正常的）。因此，来自啮齿动物模型的收敛发现与行为和解剖学相似 人类语言的发现以多种方式残障人群。 这些数据导致我们在胚胎干扰后对大鼠进行行为评估 与阅读障碍相关的基因同源物的功能。我们发现E14/15转染 候选阅读障碍性大鼠基因同源物DyxLD的RNAi导致随后的损害 雄性大鼠的快速/复杂声学歧视（尽管没有歧视较长间隙的缺陷 看到刺激）。通过联系 跨遗传破坏，神经发育破坏以及认知中的破坏/ 行为。 拟议的研究将继续解决胚胎的神经病理/行为后果 操纵三个候选阅读障碍基因的大鼠同源物（Dyxld，Kiaa0319， 和DCDC2）。通过RNAi（或诱导基因过表达）进行胚胎转染的大鼠将是 对听觉，视觉和学习/记忆任务以及验尸神经病理学进行了评估。 将评估结果的结果，以证明与特定有关的遗传和神经病理学因素 RAP和STM中的行为缺陷，与语言可持续人类的人类平行缺陷（与更多相反 一般认知，运动和/或感觉缺陷）。这样的研究可能会弥合干扰之间的差距 阅读障碍中的大脑功能/行为，遗传与阅读障碍的流行病学证据和 在人类中很难研究的关键干预神经发育过程，但 可以在啮齿动物模型中学习。