Basal Ganglia - Brainstem Networks in the Control of Seizures

项目摘要。癫痫是第二大最常见的神经系统疾病，影响约2 美国有一百万人。虽然许多患者通过治疗达到满意的癫痫控制 在药物治疗方面，有很大比例(20%-40%)的人患有药物难治性癫痫。对于这些患者来说， 确定控制癫痫发作的新方法是一个高度优先事项。一种这样的方法可能是利用 大脑中的内源性癫痫抑制回路。因为癫痫发作可能有多发性或不明原因 可控制癫痫发作的起始点、局灶性刺激方法(例如脑深部刺激[DBS]) 起源于不同的大脑网络是非常可取的。基底神经节的回路已经接收到 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原子核可以 对于这种效果，精确的路径、投影和电路架构仍然模糊不清。在基础上建设 我们在之前项目期间的发现，以及临床前癫痫研究的有力文献，我们的目标是定义 上游调节(基底节直接和间接通路；目标1)，中脑局部回路(深层 上丘[DLSC]-桥脚核[PPN]的相互作用；目标2)，和PPN投射靶点 (目的3)介导基底神经节的抗癫痫作用。我们的目标是开发一个全面的 宏观网络图，并确定在电路级，此电路中的操作如何导致广泛的- 对癫痫的光谱抵抗力。我们期待着对这种电路的更深入的理解将导致新的 控制癫痫发作的干预措施。在具体目标1中，我们将监测和调节基底节的活动。 通过光遗传学、在体单单位记录和光纤相结合的直接和间接途径 颞叶癫痫(TLE)和失神癫痫模型的光度测定在具体目标2中，我们将定义 中脑(DLSC-PPN)环路参与边缘和失神惊厥活动并测试其功能 DLSC与PPN在控制癫痫发作中的关系我们将通过在活体内结合单个- 单位记录学、切片电生理学和光遗传学。在具体目标3中，我们将确定购买力平价产出目标 对边缘癫痫和失神癫痫的保护作用主要集中在背侧和网状核 丘脑核团，采用颞叶和失神癫痫模型。综合起来，拟议的研究将 为从单个电路对不同网络中的癫痫发作进行光遗传调制提供原理证据。 此外，这种方法允许我们检查以前无法检验的关于以下联系的假设 调节基底节癫痫发作控制。最后，提出的实验旨在揭示电路和 运动控制区(如SNPR/DLSC)焦点操作的神经递质机制 整个大脑兴奋性的变化。

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.