The Retrosplenial Gate Hypothesis for Anterior Thalamic Stimulation in Temporal Lobe Epilepsy

项目摘要/摘要 丘脑深部刺激丘脑前核团可减少癫痫发作次数 难治性颞叶癫痫，但极少导致完全缓解。作用机制 这些治疗效果的潜在原因仍不清楚。我们已经确定了一种特定的途径，通过这种途径，前 丘脑刺激可能在被称为脾后皮质的大脑区域诱发抑制性防火墙，潜在地 防止癫痫的蔓延。海马结构将密集的输出信号发送到大脑皮质的浅层。 经下丘脑的脾后颗粒皮质(RSG)。丘脑前轴突恰好汇聚到 相同的RSG电路。然后，脾后皮质投射到数十个新皮质区域，包括 次级运动皮质，因此是癫痫发作从海马体扩散到 新皮质，导致继发性全身性运动性癫痫发作。尽管有这种重要的连通性，细胞 而在癫痫中，对脾后皮质的环路研究还很少。 我们在RSG中发现了一种新的细胞类型，并发现这一大脑区域由局部 抑制力。我们的记录显示，丘脑前部传入脾后皮质强烈地招募这一信息。 抑制回路和确定丘脑快速峰抑制神经元募集的独特途径 在RSG，通过第1层和第3层。这种明显的抑制可以使RSG的兴奋性神经元沉默， 潜在地阻止癫痫发作活动传播到大脑皮层的其余部分。 我们的脾后门假说认为，抑制主导的脾后环路是由前 丘脑刺激可以防止颞叶癫痫扩散到新皮质，并部分解释了 丘脑前部DBS的治疗机制。在目标1中，我们将同时描述 大鼠海马、脾后皮质、次级运动皮质和丘脑前部的神经元动力学 慢性颞叶癫痫的啮齿动物模型。在目标2中，我们将对脾后门进行因果测试 这一假说是通过使用闭合的大脑皮质来防止颞叶癫痫发作扩散到新皮质的。 丘脑前部投射到视网膜脾皮质的环状光遗传刺激。治疗性的 我们将比较光遗传刺激丘脑前部投射到替代皮质的益处。 地区。这些目标的成功实现有可能确定一个新颖、准确和合理的 治疗颞叶癫痫的治疗路径。

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.