Shared Mechanisms of Absence Epilepsy and Selective Attention

失神癫痫和选择性注意的共同机制

• 批准号: 9808046
• 负责人: Brielle Ferguson
• 金额: $ 6.16万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808046
• 关键词: Absence Epilepsy; Address; Algorithms; Animals; Attention; Attentional deficit; Axon; Behavior; Biological Assay; Calcium; Cell Nucleus; Cells; Cognitive; Cues; Detection; Dorsal; Down-Regulation; Electrophysiology (science); Epilepsy; Etiology; Feedback; Fiber; Flare; Generations; Goals; Image; Impaired cognition; Impairment; Individual; Interruption; Label; Lateral; Lead; Light; Light Exercise; Link; Location; Maintenance; Modality; Modeling; Motor; Mus; Neurons; Opsin; Output; Pathologic; Pathology; Patients; Pattern; Performance; Photometry; Physiologic pulse; Play; Prevalence; Proteins; Quality of life; Regulation; Role; SCN8A gene; Seizures; Sensory; Signal Transduction; Sodium Channel; Synapses; Testing; Thalamic structure; Thinness; Time; Training; Transgenes; Unconscious State; Vision; comorbidity; flexibility; interest; optogenetics; selective attention; sensory gating; single cell analysis; somatosensory; synaptic inhibition; tool; voltage

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.

网状丘脑（RT）是一个薄的GABA能神经元的外壳，可在周围提供侧面边界 背丘脑。它的轴突突触到主要的丘脑继电器核，均提供进料和反馈 皮质和丘脑的抑制作用。 RT在地形上组织起来，主要是 接收特定感觉方式的输入（例如，视觉，节感和试听），可以调节 丘脑神经元在同一继电器中的活性。特别是，体感RT已经 与缺席的产生有关，短暂的无意识时期伴随着失误 运动功能。有趣的是，其他RT区域已与选择性关注有关，这是 癫痫个子经常破坏的认知灵活性。在正常条件下，RT输出 通过选择性抑制代表的丘脑子区域来抑制传入的分心信息 在当前情况下，信息无关，以指导适当的行为。重要的是，自上而下的变化 RT的调节会破坏正常的RT激活模式，并损害所需的感觉门控 选择性注意任务。这表明RT神经元突触调节的变化可能会中断正常 选择性注意的RT活动取决于。我们的实验室最近表明，在有破坏的小鼠中 电压门控钠通道的表达，NAV1.6（SCN8A +/-），体感内部 - RT的减少 突触抑制导致病理丘脑皮质（TC）振荡和频繁癫痫发作。我们 假设这种相同的RT内抑制作用可能会在整个RT中广泛发生，并导致 SCN8A +/-缺勤模型中的注意力缺陷。 RT-RT抑制的损失将减少局部 抑制RT细胞，从而增加总RT活性，并减少抑制的感觉吞吐量 丘脑神经元。使用包括行为，电路和单细胞分析在内的多层次方法，我们将 解决了在缺席癫痫的情况下是否存在广泛的RT失调的基本问题。 此外，我们的结果将使我们能够确定一组共同的RT单元是否负责 缺乏癫痫发作和注意力障碍，突出了两种病理中的共同机制。