Thalamic Reticular Dysfunction as a Circuit Endophenotype in Neurodevelopmental Disorders.
Thalamic Reticular Dysfunction as a Circuit Endophenotype in Neurodevelopmental Disorders.
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DOI：
10.1016/j.neuron.2018.03.021
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发表时间：
2018-04-18
期刊：
影响因子：
16.2
通讯作者：
Feng G
中科院分区：
文献类型：
--
作者：
Krol A;Wimmer RD;Halassa MM;Feng G
行为障碍的诊断，如自闭症谱系障碍和精神分裂症，是基于症状的描述，一直难以连接到机制。尽管精神遗传学提供了对这些疾病的遗传基础的深入了解，大多数病例可以由多基因因素解释，但仍然很难设计合理的治疗方法。在这篇综述中，我们强调了理解神经回路功能的价值，既可以作为将基因与行为联系起来的中间层次的解释性描述，也可以作为开发行为障碍的合理诊断和治疗方法的途径。由于神经回路执行分层组织的计算功能并产生网络级过程（例如宏观节律，目标导向或稳态行为），相关的网络级缺陷可能表明特定回路的扰动。因此，识别这种相关缺陷或“回路内表型”将提供一个机制切入点，增强给定行为障碍的诊断和治疗。我们专注于回路内表型的丘脑网状核（TRN），以及如何在神经发育障碍的损害引起一组相关的读数在睡眠和注意。由于TRN神经元表达通过全基因组关联研究鉴定的几种疾病相关基因，因此探索不同TRN中断的后果可能具有广泛的翻译意义。
Diagnoses of behavioral disorders such as autism spectrum disorder and schizophrenia are based on symptomatic descriptions that have been difficult to connect to mechanism. Although psychiatric genetics provide insight into the genetic underpinning of such disorders, with a majority of cases explained by polygenic factors, it remains difficult to design rational treatments. In this review, we highlight the value of understanding neural circuit function both as an intermediate-level of explanatory description that links gene to behavior as well as a pathway for developing rational diagnostics and therapeutics for behavioral disorders. As neural circuits perform hierarchically organized computational functions and give rise to network-level processes (e.g. macroscopic rhythms, goal-directed or homeostatic behaviors), correlated network-level deficits may indicate perturbation of a specific circuit. Therefore, identifying such correlated deficits or a ‘circuit endophenotype’ would provide a mechanistic point of entry, enhancing both diagnosis and treatment of a given behavioral disorder. We focus on a circuit endophenotype of the thalamic reticular nucleus (TRN) and how its impairment in neurodevelopmental disorders gives rise to a correlated set of readouts across sleep and attention. Because TRN neurons express several disorder-relevant genes identified through genome wide association studies, exploring the consequences of different TRN disruptions may be of broad translational significance.
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