Dissecting the role of thalamic inhibition in neurodevelopmental diseases

项目摘要/摘要 感觉异常是一系列神经发育障碍的特征。在自闭症谱系中 精神障碍(ASD)，例如，感觉超负荷是最常见的症状之一。异常 感觉信息流的调节(感觉门控)也在精神分裂症和ADHD中观察到，并且是 被认为在所有这些情况下都会导致整体认知功能障碍。尽管它非常重要， 人们对感觉门控的神经生物学知之甚少，更不知道它在疾病中的失败。 这项提议旨在解决这一关键差距。新皮质是更高级的感觉处理所必需的， 但感觉信息的早期处理和传输是由丘脑执行的。我们和其他人 已经发现丘脑的感觉输入是由丘脑网状核(TRN)控制的， 丘脑中继核周围的GABA能神经元。TRN由各个子网络组成，每个子网络 以特定形态的方式控制丘脑血流。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在感觉加工中的关键作用，我们预计 其回路中的扰动在病理上增加了皮质感觉输入，解释了几个临床 症状。在睡眠中，TRN功能障碍可能导致与感觉相关的觉醒增加，而在注意力集中时 无关紧要的投入可能会变得更加分散注意力。因此，“漏水的丘脑”可能具有深远的影响。 跨障碍对行为和认知的影响。在这个方案中，我们将测试漏水的丘脑 通过在小鼠中操纵丘脑抑制来构建框架，同时监测对感觉功能和 相关行为。此外，我们还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。

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.