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 - 解剖生理学和内侧颞叶癫痫模型

• 批准号: 10462576
• 负责人: Nigel Paul Pedersen
• 金额: $ 19.26万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462576
• 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; Genetic; Glutamates; Glycoproteins; Goals; Grant; Head; Hippocampal Formation; Hippocampus; Histopathology; Hypothalamic structure; Immersion; Infusion procedures; Interneurons; Ipsilateral; Kainic Acid; LoxP-flanked allele; 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; Nitric Oxide Synthase Type I; Output; Patients; Persons; 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; career development; cell type; dentate gyrus; design; entorhinal cortex; experience; experimental study; gamma-Aminobutyric Acid; genetic manipulation; granule cell; improved; kainate; mortality; nerve supply; neurophysiology; novel; novel strategies; public health relevance; reinnervation; 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.

项目摘要/摘要 癫痫在美国影响340万人，颞叶癫痫（MTLE）最常见的类型。 齿状回（DG）是Mtle的病理生理学的核心。 DG在MTLE中变得过度兴奋 由于DG抑制性中间神经元的丧失以及DG颗粒的复发突触数量增加 细胞（GC）产生阳性兴奋性反馈。虽然激活DG抑制性中间神经元可以具有 抗塞氏症效应，这些效果在mtle中丢失，并由GC驱动，敦促我们检查替代机制 控制DG。令人惊讶的是，DG几乎没有输入。内河地区从大脑传达信息 皮质，是兴奋性的。中间区域和总和类似于大的输入，但间隔区域间接起作用 在GC上，通过抑制性中间神经元在mtle中丢失。相比之下，总和直接支配GC， 包括释放GABA（抑制性神经递质）和谷氨酸的高度不寻常的神经元（一个） 兴奋性神经递质）。这些神经元的作用尚不清楚，与其他总和类型不同，这些 GABA/谷氨酸神经元不会促进清醒或theta EEG活性。初步数据表明 从这些神经元中释放GABA的破坏导致小鼠死亡率高，但未与未经监测的小鼠死亡 视频/脑电图和间歇性监测小鼠的低压异常脑电图都与已建立的 癫痫持续状态。拟议研究的中心假设是这些总和GABA/谷氨酸神经元 稳定DG并为治疗MTLE提供有希望的选择目标。目的我将描述输入 和总和神经元组的输出关系，有助于理解总和效应和总和的电路基础 海马相互作用。 AIM II将检查加巴释放中断的影响 GABA/GABA/谷氨酸神经元（使用CRE/LOX技术），长期记录视频/EEG和海马场 潜力，假设小鼠会出现海马中产生的自发癫痫发作，并且 进展到癫痫持续状态。 AIM III将检查总和化学发生激活的影响 GABA/GABA/谷氨酸神经元在杏仁核内海藻中自发性癫痫发作的频率和严重程度上 Mtle的模型。总体而言，这些研究将为正常中的sum-dg相互作用提供改进的理解 生理学和MTLE，为治疗MTLE提供了潜在的特定调节靶标。 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格而成功的独立医师科学家，正在研究 癫痫的系统神经科学。指导团队在指导初级方面拥有完善的专业知识 教师，将提供癫痫基础科学，神经解剖学，电生理学，向量和 化学遗传学以及赠款和手稿的制备。职业发展计划包括 在负责任的研究，统计，设计和可重复性，信号处理的培训中培训 作为会议出勤，可以实现职业发展培训和科学工作的交流。