Control of the Hippocampal Formation by the Supramammillary Hypothalamus - Anatomy Physiology and in a Model of Medial Temporal Lobe Epilepsy

项目摘要/摘要 美国有340万人患有癫痫，内侧颞叶癫痫(MTLE)是最常见的类型。 齿状回(DG)是MTLE的病理生理学中心。在MTLE中，DG变得超兴奋 由于DG抑制中间神经元的丢失和DG颗粒再发突触数量的增加 细胞(GC)产生正的兴奋性反馈。而激活DG抑制的中间神经元可以有一个 抗癫痫作用，这些在MTLE中消失，并由GC驱动，促使我们研究替代机制 来控制DG。令人惊讶的是，DG几乎没有投入。内嗅区传递来自大脑的信息 大脑皮层，是兴奋的。隔面积和总和是同样大的输入，但隔面积起间接作用 通过MTLE中丢失的抑制性中间神经元作用于GCs。相比之下，总和直接影响GC， 包括释放GABA(一种抑制性神经递质)和谷氨酸(AN)的极不寻常的神经元 兴奋性神经递质)。这些神经元的作用尚不清楚，而且与其他SUM神经元类型不同，这些神经元 GABA/谷氨酸神经元不会促进觉醒或theta脑电活动。初步数据显示， 干扰这些神经元的GABA释放会导致没有进行监测的小鼠的高死亡率 视频/脑电，以及间歇性监测小鼠的低电压异常脑电，两者都与已建立的 癫痫持续状态。拟议研究的中心假设是，这些神经元和GABA/谷氨酸神经元 稳定DG，为MTLE的治疗提供了一个有前景的选择性靶点。Aim I将描述输入内容 和神经元群的输出关系，有助于理解和效应和和的电路基础。 海马区的相互作用。AIM II将研究从SUM中干扰GABA释放的影响 GABA/谷氨酸神经元(使用CRE/LOX技术)，慢性记录视频/脑电和海马区 电位，假设小鼠将在海马区发生自发性癫痫发作，以及 进展到癫痫持续状态。Aim III将研究SUM的化学激活作用 杏仁核海绵体内GABA/谷氨酸神经元对自发性癫痫发作频率和严重程度的影响 MTLE模型。总体而言，这些研究将提供对正常情况下SUM-DG相互作用的更好理解 生理学和MTLE，为MTLE的治疗提供了潜在的特异性调节靶点。 这些研究将提供关键的培训和职业发展经验，使申请者能够 职业发展目标成为一名严谨和成功的独立内科医生-科学家研究 癫痫的系统神经科学。指导团队在指导青少年方面拥有成熟的专业知识。 将提供癫痫基础科学、神经解剖学、电生理学、病媒和 化学遗传学，以及赠款和手稿的准备工作。职业发展计划包括 负责任地进行研究、统计、设计和再现性以及信号处理方面的培训 如出席会议，促进职业发展、培训和科学工作的交流。

PROJECT SUMMARY/ABSTRACT Epilepsy affects 3.4 million people in the US, with medial temporal lobe epilepsy (MTLE) the most common type. The dentate gyrus (DG) is central to the pathophysiology of MTLE. The DG becomes hyperexcitable in MTLE due to the loss of DG inhibitory interneurons and an increase in the number of recurrent synapses of DG granule cells (GCs) resulting positive excitatory feedback. While activation of DG inhibitory interneurons can have an anti-seizure effect, these are lost in MTLE and driven by GCs, urging us to examine an alternative mechanism to control the DG. Surprisingly, the DG has few inputs. The entorhinal area conveys information from the cerebral cortex and is excitatory. The septal area and SuM are similarly large inputs, but the septal area acts indirectly on GCs by way of inhibitory interneurons that are lost in MTLE. The SuM, by contrast, directly innervates GCs, including with highly unusual neurons that release both GABA (an inhibitory neurotransmitter) and glutamate (an excitatory neurotransmitter). The role of these neurons is unclear, and, unlike other SuM neuronal types, these GABA/glutamate neurons do not promote wakefulness or theta EEG activity. Preliminary data reveals that disruption of GABA release from these neurons results in high mortality in mice that were not monitored with video/EEG, and a low-voltage abnormal EEG in intermittently monitored mice, both consistent with established status epilepticus. The central hypothesis of the proposed studies is that these SuM GABA/glutamate neurons stabilize the DG and provide a promising selective target for the treatment of MTLE. Aim I will delineate the input and output relations of SuM neuronal groups, helping to understand the circuit basis for SuM effects and SuM- hippocampal interactions. Aim II will examine the effects of disruption of GABA release from SuM GABA/glutamate neurons (using the Cre/lox technique), chronically recording video/EEG and hippocampal field potentials, with the hypothesis that the mice will develop spontaneous seizures arising in the hippocampus, and progress to status epilepticus. Aim III will examine the effects of chemogenetic activation of SuM GABA/glutamate neurons on the frequency and severity of spontaneous seizures in the intra-amygdala kainate model of MTLE. Overall, these studies will provide an improved understanding of SuM-DG interaction in normal physiology and MTLE, providing a potentially specific modulatory target for the treatment of MTLE. These studies will provide key training and career development experiences enabling the applicant to reach the career development goal of becoming a rigorous and successful independent physician-scientist studying the systems neuroscience of epilepsy. The mentorship team has well-established expertise in mentoring junior faculty, and will provide training in epilepsy basic science, neuroanatomy, electrophysiology, vectors and chemogenetics, as well as in the preparation of grants and manuscripts. The Career Development plan includes training in the responsible conduct of research, statistics, design and reproducibility, signal processing, as well as conference attendance enabling career development training and the communication of scientific work.