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: 10410036
• 负责人: Brielle Ferguson
• 金额: $ 3.52万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410036
• 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

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.

项目摘要 网状丘脑（RT）是GABA能神经元的薄壳，其提供围绕丘脑的外侧边界。 背侧丘脑它的轴突与初级丘脑中继核团形成突触，提供前馈和反馈 抑制作用分别来自皮层和丘脑。RT的拓扑结构主要是 接收特定感觉模态的输入（例如，视觉、躯体感觉和听觉），并且可以调节 丘脑神经元的活动在同一个继电器。特别是，体感RT已经被 与失神发作的产生有关，短暂的无意识伴随着短暂的 运动功能有趣的是，其他RT区域与选择性注意有关，选择性注意是一个重要的特征。 癫痫患者的认知灵活性经常被破坏。正常情况下，RT输出 通过选择性地抑制丘脑亚区域来抑制传入的分散注意力的信息， 与当前上下文无关的信息，以指导适当的行为。重要的是，自上而下的变化 RT的调节可以破坏正常的RT激活模式，并损害感觉门控， 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的 选择性注意所依赖的RT活动。我们的实验室最近表明，在小鼠中， 电压门控钠通道Nav1.6（Scn 8a +/-）的表达，体感内RT中的减少 突触抑制导致病理性丘脑皮质（TC）振荡和频繁失神发作。我们 假设RT内抑制的这种相同丧失可能广泛地发生在整个RT中，并导致 Scn 8a +/-失神癫痫模型中的注意力缺陷。RT-RT抑制的丧失将降低局部 抑制RT细胞，从而增加整体RT活性，并降低受抑制的感觉通量。 丘脑神经元使用多层次的方法，包括行为，电路和单细胞分析，我们将 解决了一个根本问题，即在失神癫痫中是否存在广泛的RT失调。 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，突出了两种病理学的共同机制。