Basal Ganglia - Brainstem Networks in the Control of Seizures

项目摘要。癫痫是第二种最普遍的神经系统疾病，影响约20%的人。 在美国的百万人。虽然许多患者通过以下方法实现了令人满意的癫痫控制， 在药物治疗中，很大一部分（20-40%）具有医学上难治的癫痫发作。对于这些患者， 确定控制癫痫发作的新方法是一个高度优先事项。其中一种方法可能是利用 大脑中的内源性癫痫抑制回路因为癫痫发作可能有多个或未知的 起始位点，局灶刺激方法（例如，脑深部电刺激[DBS]），可以控制癫痫发作 起源于不同的大脑网络是非常理想的。基底神经节的电路已经接收到 在这方面要特别注意。虽然四十年的研究已经详细阐述了特定的细胞核， 尽管这些因素对这种效应有贡献，但精确的通路、投射和电路结构仍然模糊不清。基础上 我们在项目前期的发现，以及临床前癫痫研究的大量文献，我们的目标是定义 上游调节器（基底神经节直接和间接通路; Aim 1）、中脑局部回路（深层 上级丘[DLSC]-脚桥核[PPN]相互作用;目的2）和PPN投射靶点 (Aim 3）介导基底神经节的抗癫痫作用。我们的目标是发展一个全面的 宏网络图，并确定如何，在电路层面，在这个电路中的操作导致广泛的， 抗癫痫谱我们希望，对这种电路的更深入了解将导致新的 控制癫痫发作的干预措施。在特定目标1中，我们将监测和调节基底神经节的活动 通过光遗传学、体内单单位记录和光纤的组合的直接和间接途径 在颞叶癫痫（TLE）和失神癫痫模型中的光度测定。在具体目标2中，我们将定义 中脑（DLSC-PPN）回路参与边缘系统和失神发作活动，并测试功能性 DLSC与PPN控制癫痫发作的关系我们将通过结合体内单- 单位记录、切片电生理学和光遗传学。在具体目标3中，我们将定义PPN输出目标 介导对边缘系统和失神发作的保护，集中在内侧背和网状 丘脑核，使用颞叶和失神癫痫模型。拟议的研究将 为来自单个回路的不同网络中癫痫发作的光遗传学调节提供原理证明。 此外，这种方法使我们能够检查以前无法验证的关于连接的假设， 介导基底神经节癫痫发作控制。最后，所提出的实验旨在揭示电路， 神经递质机制通过其在运动控制区域中的病灶操纵（即，SNpr/DLSC）翻译 转化为大脑兴奋性的变化

Project Summary. Epilepsy is the second most prevalent neurological disorder, affecting approximately 2 million people in the United States. While many patients achieve satisfactory seizure control with pharmacotherapy, a significant proportion (20-40%) have medically intractable seizures. For these patients, identification of novel methods for seizure control is a high priority. One such method may be to harness endogenous seizure suppressive circuits in the brain. Because seizures may have multiple or unknown initiation sites, focal stimulation approaches (e.g., deep brain stimulation [DBS]) that can control seizures originating in diverse brain networks are highly desirable. The circuitry of the basal ganglia has received particular attention in this regard. While four decades of research have elaborated the specific nuclei that can contribute to this effect, the precise pathways, projections, and circuit architecture remain obscure. Building on our findings in the prior project period, and a robust literature in preclinical epilepsy research, we aim to define the upstream regulators (basal ganglia direct and indirect pathways; Aim 1), midbrain local circuits (deep layers of superior colliculus [DLSC]-pedunculopontine nucleus [PPN] interactions; Aim 2), and PPN projection targets (Aim 3) that mediate the antiseizure effects of the basal ganglia. Our goal is to develop a comprehensive macro-network map and to determine how, at the circuit level, manipulations in this circuit lead to broad- spectrum resistance to seizures. We expect that a deeper understanding of this circuitry will lead to novel interventions to control seizures. In Specific Aim 1, we will monitor and modulate activity in the basal ganglia direct and indirect pathways through a combination of optogenetics, in vivo single-unit recording, and fiber photometry in models of temporal lobe epilepsy (TLE) and absence epilepsy. In Specific Aim 2, we will define the midbrain (DLSC-PPN) circuits engaged by limbic and absence seizure activity and test the functional relationship between DLSC and PPN in controlling seizures. We will address this by combining in vivo single- unit recording, slice electrophysiology, and optogenetics. In Specific Aim 3, we will define PPN output targets that mediate protection against limbic and absence seizures, focusing on the mediodorsal and reticular thalamic nucleus, using temporal lobe and absence epilepsy models. Together the proposed studies will provide proof of principle for optogenetic modulation of seizures in diverse networks from a single circuit. Moreover, this approach allows us to examine previously untestable hypotheses about the connections that mediate basal ganglia seizure control. Finally, the proposed experiments aim to uncover the circuit and neurotransmitter mechanism by which focal manipulations in motor control regions (i.e., SNpr/DLSC) translate into brain-wide changes in excitability.