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

乳头上下丘脑对海马结构的控制 - 解剖学、生理学和内侧颞叶癫痫模型

• 批准号: 9789964
• 负责人: Nigel Paul Pedersen
• 金额: $ 19.26万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789964
• 关键词: Accounting; Address; Affect; Amygdaloid structure; Anatomy; Basic Science; Behavioral; Bilateral; Brain Stem; Cannulas; Cells; Cerebral cortex; Chronic; Communication; Contralateral; Data; Dendrites; Development; Development Plans; Disease; Dose; Electroencephalography; Electrophysiology (science); Epilepsy; Faculty; Feedback; Frequencies; Functional disorder; Future; Glutamates; Glycoproteins; Goals; Grant; Head; Hippocampal Formation; Hippocampus (Brain); Histopathology; Hypothalamic structure; Immersion Investigative Technique; Infusion procedures; Interneurons; Ipsilateral; Kainic Acid; Manuscripts; Medial; Medical; Mentors; Mentorship; Microinjections; Mission; Modeling; Monitor; Mus; NOS1 gene; National Institute of Neurological Disorders and Stroke; Neuroanatomy; Neurobiology; Neurons; Neurosciences; Neurotransmitters; Nitric Oxide Synthase; Output; Patients; Physicians; Physiological; Physiology; Pilocarpine; Population; Preparation; Prosencephalon; Rabies; Rattus; Recurrence; Reproducibility; Research Personnel; Role; Saline; Scientist; Seizures; Septal Area; Severities; Sleep; Status Epilepticus; Synapses; System; Techniques; Temporal Lobe Epilepsy; Time; Training; Venus; Video Recording; Wakefulness; Work; basal forebrain; base; career development; cell type; dentate gyrus; design; entorhinal cortex; experience; experimental study; gamma-Aminobutyric Acid; granule cell; improved; kainate; mortality; nerve supply; neurophysiology; novel; novel strategies; public health relevance; responsible research conduct; signal processing; skills; statistics; symposium; therapeutic target; vector; voltage

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.

项目总结/摘要 癫痫影响美国340万人，其中内侧颞叶癫痫（MTLE）是最常见的类型。 齿状回（DG）是MTLE病理生理学的中心。在MTLE中DG变得超兴奋 由于DG抑制性中间神经元的丢失和DG颗粒的复发性突触数量的增加， 细胞（GC）产生正兴奋性反馈。虽然DG抑制性中间神经元的激活可以具有 抗癫痫作用，这些在MTLE中丢失并由GC驱动，促使我们研究替代机制 来控制DG令人惊讶的是，总干事的投入很少。内嗅区传递来自大脑的信息 皮质和兴奋性。隔区和SuM是类似的大输入，但隔区间接起作用 通过抑制性中间神经元对GC的影响，这些中间神经元在MTLE中丢失。相比之下，SuM直接支配GCs， 包括释放GABA（一种抑制性神经递质）和谷氨酸（一种抑制性神经递质）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 GABA/谷氨酸神经元不促进觉醒或θ EEG活动。初步数据显示， 从这些神经元释放GABA的中断导致小鼠的高死亡率 视频/脑电图，和低电压异常脑电图在间歇监测小鼠，都符合既定的 癫痫持续状态所提出的研究的中心假设是，这些SuM GABA/谷氨酸神经元 稳定DG并为MTLE的治疗提供有希望的选择性靶点。目标我将描述输入 和输出关系的SuM神经元组，有助于了解电路基础的SuM效应和SuM- 海马的相互作用目的II将研究干扰GABA从SuM释放的影响 GABA/谷氨酸神经元（使用Cre/lox技术），长期记录视频/EEG和海马场 电位，假设小鼠将在海马体中发生自发性癫痫发作，以及 进展为癫痫持续状态目的III将检查SuM的化学发生活化的影响， 杏仁核内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模型总的来说，这些研究将提供一个更好的理解SuM-DG相互作用在正常 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，使申请人能够达到 职业发展目标是成为一个严谨和成功的独立的医生，科学家研究 癫痫的神经系统科学导师团队在指导初级学员方面拥有成熟的专业知识， 教师，并将提供培训癫痫基础科学，神经解剖学，电生理学，载体和 化学遗传学，以及在赠款和手稿的准备。职业发展计划包括 在负责任的研究，统计，设计和再现性，信号处理，以及 参加会议，使职业发展培训和科学工作的交流成为可能。