The Retrosplenial Gate Hypothesis for Anterior Thalamic Stimulation in Temporal Lobe Epilepsy (Diversity Supplement)

颞叶癫痫前丘脑刺激的压后门假说（多样性补充）

• 批准号: 10405679
• 负责人: Omar Jamil Ahmed
• 金额: $ 8.52万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405679
• 关键词: Anterior; Anterior Nuclear Group; Axon; Brain region; Cells; Chronic; Deep Brain Stimulation; Disease remission; Epilepsy; Hippocampal Formation; Hippocampus (Brain); Motor Cortex; Motor Seizures; Neocortex; Neurons; Output; Pathway interactions; Patients; Rest; Rodent Model; Secondary to; Seizures; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Thalamic structure; Therapeutic; cell type; effective therapy; excitatory neuron; firewall; inhibitory neuron; neocortical; novel; optogenetics; prevent; recruit

PROJECT SUMMARY / ABSTRACT Deep brain stimulation of the anterior thalamic nuclei can reduce the number of seizures in patients with intractable temporal lobe epilepsy, but rarely leads to complete remission. The mechanisms of action underlying these therapeutic benefits remain unknown. We have identified a specific pathway by which anterior thalamic stimulation may induce an inhibitory firewall in a brain region called the retrosplenial cortex, potentially preventing the spread of seizures. The hippocampal formation sends dense outputs to the superficial layers of the retrosplenial granular cortex (RSG) via the subiculum. Anterior thalamic axons converge onto exactly the same RSG circuit. The retrosplenial cortex then projects to dozens of neocortical regions, including the secondary motor cortex, and is thus a critical gateway via which seizures can spread from the hippocampus to the neocortex, leading to secondarily generalized motor seizures. Despite this important connectivity, the cells and circuits of the retrosplenial cortex are massively understudied in epilepsy. We have discovered a new cell type in the RSG and found that this brain region is dominated by local inhibition. Our recordings show that anterior thalamic inputs to the retrosplenial cortex strongly recruit this inhibitory circuitry and identify a unique pathway for the thalamic recruitment of fast-spiking inhibitory neurons in RSG, via both layer 1 and layer 3. This pronounced inhibition can silence the excitatory neurons of the RSG, potentially preventing the propagation of seizure activity to the rest of the neocortex. Our retrosplenial gate hypothesis posits that the inhibition-dominated retrosplenial circuitry recruited by anterior thalamic stimulation can prevent the spread of temporal lobe seizures to the neocortex and partially explain the therapeutic mechanisms underlying anterior thalamic DBS. In Aim 1 we will characterize simultaneous neuronal dynamics in the hippocampus, retrosplenial cortex, secondary motor cortex and anterior thalamus in a rodent model of chronic temporal lobe epilepsy. In Aim 2, we will causally test the retrosplenial gate hypothesis by attempting to prevent the spread of temporal lobe seizures to the neocortex using the closed- loop optogenetic stimulation of anterior thalamic projections specifically to the retosplenial cortex. Therapeutic benefits will be compared to optogenetic stimulation of anterior thalamic projections to alternative cortical regions. The successful completion of these aims has the potential to identify a novel, precise and rational therapeutic pathway for the treatment of temporal lobe epilepsy.

项目摘要 /摘要 深脑刺激前丘脑核可以减少患者的癫痫发作次数 顽固的颞叶癫痫病，但很少导致完全缓解。作用机理 这些治疗益处的基础仍然未知。我们已经确定了一个特定的途径 丘脑刺激可能会在称为脾后皮质的大脑区域诱导抑制性防火墙，可能 防止癫痫发作的传播。海马地层将密集输出发送到 通过亚致的脾后颗粒皮层（RSG）。前丘脑轴突完全收敛到 相同的RSG电路。然后，脾后皮层将数十个新皮质区域投射 次级运动皮层，因此是一个关键的门户，癫痫发作可以从海马传播到 新皮层，导致次要的通用运动癫痫发作。尽管这种重要的连通性，细胞 癫痫后，脾后皮层的电路和电路大量研究。 我们已经在RSG中发现了一种新的细胞类型，发现该大脑区域由局部主导 抑制。我们的录音表明，丘脑前丘脑的输入是腹膜后皮质的强烈招募 抑制性电路，并确定丘脑快速抑制神经元的丘脑募集的独特途径 在RSG中，通过第1层和第3层。这种明显的抑制可以使RSG的兴奋性神经元保持沉默， 有可能阻止癫痫发作活性传播到新皮层的其余部分。 我们的脾后门假设认为，前部募集的抑制作用后回路 丘脑刺激可以防止颞叶癫痫发作传播到新皮层，并部分解释 丘脑前DBS的治疗机制。在AIM 1中，我们将同时表征 海马，脾后皮层，次级运动皮层和前丘脑的神经元动力学 慢性颞叶癫痫的啮齿动物模型。在AIM 2中，我们将因因果测试后肾上腺闸门测试 通过试图防止使用闭合的颞叶癫痫发作到新皮层的假设 循环光遗传学刺激前丘脑前凸位专门针对雷神皮层。治疗性 将益处与替代皮质的前丘脑投影的光遗传学刺激进行比较 地区。这些目标的成功完成有可能确定一种新颖，精确和理性的 治疗颞叶癫痫的治疗途径。