Dissecting the role of thalamic inhibition in neurodevelopmental diseases

项目总结/摘要 感觉异常表征了广泛的神经发育障碍。在自闭症谱系中 例如，在自闭症（ASD）中，感觉超负荷是最常报告的症状之一。异常 在精神分裂症和ADHD中也观察到感觉信息流的调节（感觉门控）， 被认为是导致所有这些疾病的整体认知功能障碍的原因。尽管其至关重要， 人们对感觉门控的神经生物学知之甚少，对它在疾病中的失效更是知之甚少。 本提案旨在弥补这一关键差距。新皮层需要更高层次的感觉处理， 但感觉信息的早期处理和传递是由丘脑完成的。我们和其他人 已经发现丘脑感觉输入是由丘脑网状核（TRN）控制的，TRN是一个外壳， 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在感觉加工中的关键作用，我们预计 在其电路的扰动，以病理性地增加皮层感觉输入，解释了几个临床 症状在睡眠中，TRN功能障碍可能导致感觉相关觉醒增加，而在注意力方面， 不相关的输入可能变得更加分散注意力。因此，一个“丘脑渗漏”可能有深刻的 行为和认知的影响。在这个提议中，我们将测试泄漏的丘脑 通过操纵小鼠的丘脑抑制，同时监测对感觉功能的影响， 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.