Shared Mechanisms of Absence Epilepsy and Selective Attention

项目总结 网状丘脑(RT)是GABA能神经元的一层薄壳，它提供了围绕 背侧丘脑。其轴突突触入丘脑初级中继核，既提供前馈又提供反馈 分别来自皮层和丘脑的抑制作用。RT是按地形组织的，因此它主要 接收特定感觉模式(例如，视觉、躯体感觉和听力)的输入，并可以调节 在相同的继电器内丘脑神经元的活动。特别是，体感RT一直是 与失神癫痫的产生有关，短暂的意识丧失伴随着 运动功能。有趣的是，其他RT区域与选择性注意有关，这是大脑的一个重要特征 癫痫患者的认知灵活性经常被打乱。正常情况下，RT输出 通过选择性抑制丘脑子区域来抑制传入的分散注意力的信息 在当前环境中不相关的信息，用于指导适当的行为。重要的是，自上而下的变化 调节RT可以扰乱正常的RT激活模式，并损害必要的感觉门控 选择性注意任务。这表明，RT神经元突触调节的变化可以中断正常 选择性注意所依赖的RT活动。我们的实验室最近表明，在患有精神障碍的小鼠中 电压门控钠通道Nav1.6(Scn8a+/-)的表达，体感RT内的减少 突触抑制导致病理性丘脑皮质(TC)振荡和频繁的失神发作。我们 假设同样的RT内抑制的丧失可能在整个RT过程中广泛发生，并导致 失神癫痫Scn8a+/-模型中的注意缺陷。失去RT-RT抑制会减少局部 抑制RT细胞，从而提高RT的整体活性，并降低被抑制的感官吞吐量 丘脑神经元。使用包括行为、电路和单电池分析在内的多层次方法，我们将 解决失神癫痫患者是否普遍存在RT调节失调的根本问题。 此外，我们的结果将使我们能够确定是否一组共同的RT细胞负责这两个 失神发作的产生和注意力障碍，突出了两种病理中的共同机制。

PROJECT SUMMARY The reticular thalamus (RT) is a thin shell of GABAergic neurons that provides a lateral border around the dorsal thalamus. Its axons synapse into primary thalamic relay nuclei supplying both feedforward and feedback inhibition from the cortex and thalamus respectively. The RT is topographically organized such that it primarily receives inputs of specific sensory modalities (e.g., vision, somatosensation, and audition) and can regulate the activity of the thalamic neurons within that same relay. In particular, the somatosensory RT has been implicated in the generation of absence seizures, brief periods of unconsciousness accompanied by a lapse in motor function. Interestingly, other RT regions have been linked to selective attention, an important feature of cognitive flexibility that is often disrupted in epileptic individuals. Under normal conditions, RT output suppresses incoming distracting information by selectively inhibiting thalamic subregions that represent information irrelevant in the current context for guiding appropriate behavior. Importantly, changes in top-down regulation of the RT can disrupt normal RT activation patterns and impair the sensory gating necessary for selective attention tasks. This suggests that changes in synaptic regulation of RT neurons can interrupt normal RT activity on which selective attention depends. Our lab has recently shown that in mice with disrupted expression of the voltage gated sodium channel, Nav1.6 (Scn8a+/-), reductions in somatosensory intra-RT synaptic inhibition lead to pathological thalamocortical (TC) oscillations and frequent absence seizures. We hypothesize that this same loss of intra-RT inhibition may occur broadly throughout the RT and lead to attentional deficits in the Scn8a+/- model of absence epilepsy. A loss of RT-RT inhibition would reduce local inhibition of RT cells, thus increasing overall RT activity, and decreasing the sensory throughput of inhibited thalamic neurons. Using a multi-level approach including behavior, circuit, and single-cell analysis we will address the fundamental question of whether there is widespread dysregulation of the RT in absence epilepsy. Further, our results will enable us to determine whether a common set of RT cells is responsible for both absence seizure generation and attentional impairments, highlighting shared mechanisms in both pathologies.