Dissecting the role of thalamic inhibition in neurodevelopmental diseases

剖析丘脑抑制在神经发育疾病中的作用

• 批准号: 9187544
• 负责人: Guoping Feng
• 金额: $ 64.14万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187544
• 关键词: Address; Adult; Animals; Arousal; Attention; Attention deficit hyperactivity disorder; Attentional deficit; Behavior; Behavioral; CDH13 gene; Cell Nucleus; Cells; Chloride Ion; Chlorides; Clinical; Clinical Data; Cognition; Data; Defect; Development; Disease; Disease model; Drops; Electrodes; Electrophysiology (science); ErbB4 gene; Failure; Functional disorder; Genes; Human; Impaired cognition; Individual; Intervention; Knockout Mice; Link; Modality; Modeling; Molecular; Monitor; Mus; Nature; Neocortex; Neurobiology; Neurodevelopmental Disorder; Neurons; Pharmacogenetics; Phenotype; Photometry; Physiology; Play; Process; Psychophysics; Regulation; Reporting; Resolution; Role; Schizophrenia; Sensory; Sensory Process; Sleep; Staging; Symptoms; Synapses; Testing; Thalamic structure; Therapeutic; Therapeutic Effect; autism spectrum disorder; human tissue; in vivo; optogenetics; research study; selective expression; sensory gating; sensory input; transmission process

PROJECT SUMMARY/ABSTRACT Sensory abnormalities characterize a wide range of neurodevelopmental disorders. In autism spectrum disorder (ASD), for example, sensory overload is one of the most frequently reported symptoms. Abnormal regulation of sensory information flow (sensory gating) is also observed in schizophrenia and ADHD, and is thought to contribute to overall cognitive dysfunction across all these conditions. Despite its central importance, little is known about the neurobiology of sensory gating, and even less is known about its failure in disease. This proposal aims to address this critical gap. The neocortex is requires for higher level sensory processing, but early processing and transmission of sensory information is performed by the thalamus. We and others have found that thalamic sensory input is controlled by the thalamic reticular nucleus (TRN), a shell of GABAergic neurons surrounding thalamic relay nuclei. The TRN is composed of individual subnetworks, each controlling thalamic flow in a modality-specific manner. Recent clinical data have shown thalamic and TRN dysfunction in neurodevelopmental disorders. Given the critical role for TRN in sensory processing, we expect perturbations in its circuits to pathologically augment cortical sensory input, explaining several clinical symptoms. In sleep, TRN dysfunction may result in increased sensory-related arousals, while in attention irrelevant inputs may become much more distracting. As such, a `leaky thalamus' may have profound consequences on behavior and cognition across disorders. In this proposal, we will test the leaky thalamus framework by manipulating thalamic inhibition in mice while monitoring the impact on sensory function and related behaviors. In addition, we will investigate the therapeutic potential of reversing thalamic inhibition deficits in models of human neurodevelopmental disorders.

项目概要/摘要 感觉异常是多种神经发育障碍的特征。在自闭症谱系中 例如，自闭症谱系障碍（ASD），感觉超负荷是最常报告的症状之一。异常 在精神分裂症和多动症中也观察到感觉信息流的调节（感觉门控），并且 据认为会导致所有这些情况下的整体认知功能障碍。尽管它具有核心重要性， 人们对感觉门控的神经生物学知之甚少，对其在疾病方面的失败知之甚少。 该提案旨在解决这一关键差距。新皮质需要更高水平的感觉处理， 但感觉信息的早期处理和传输是由丘脑进行的。我们和其他人 发现丘脑感觉输入是由丘脑网状核（TRN）控制的，TRN 是 丘脑中继核周围的 GABA 能神经元。 TRN 由单独的子网组成，每个子网 以特定方式控制丘脑血流。最近的临床数据显示丘脑和 TRN 神经发育障碍中的功能障碍。鉴于 TRN 在感觉处理中的关键作用，我们预计 扰动其电路以病理性地增强皮质感觉输入，解释了一些临床症状 症状。在睡眠中，TRN 功能障碍可能会导致感觉相关的唤醒增加，而在注意力集中时 不相关的输入可能会变得更加分散注意力。因此，“丘脑渗漏”可能具有深远的影响。 对跨疾病行为和认知的影响。在这个提案中，我们将测试漏泄的丘脑 通过操纵小鼠的丘脑抑制，同时监测对感觉功能的影响来构建框架 相关行为。此外，我们将研究逆转丘脑抑制的治疗潜力 人类神经发育障碍模型的缺陷。