Perisomatic inhibition in epilepsy

癫痫的围期抑制

基本信息

批准号：
10210458
负责人：
Barna Dudok
金额：
$ 8.85万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2022-11-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10210458
关键词：
Adverse effects Affect Animal Model Animals Antiepileptic Agents Area Automobile Driving Brain Calcium Cells Cessation of life Cholecystokinin Chronic Code Cognitive Data Educational process of instructing Electrophysiology (science)Embryo Environment Epilepsy Failure Foundations Frequencies Functional disorder Gamma synuclein Glutamates Goals Grant High Frequency Oscillation Hippocampus (Brain)Image Immunohistochemistry Impaired cognition Impairment In Vitro Injury Interneurons Intervention Label Lead Medial Mentors Modeling Molecular Morphology Mus Myoepithelial cell Neurons Neurotransmitters Outcome Parvalbumins Pathologic Patients Pharmaceutical Preparations Pharmacogenetics Phase Population Property Pyramidal Cells Recurrence Research Research Methodology Research Training Risk Role Seizures System Temporal Lobe Epilepsy Testing Time Training Transgenic Mice Transgenic Organisms Universities Writing awake career career development cell type cognitive function entorhinal cortex excitatory neuron experimental study genetic strain in vivo inhibitory neuron kainate nervous system disorder neuronal circuitry neurotransmission novel optogenetics preservation prevent programs recruit segregation side effect therapy development tool training opportunity treatment strategy two-photon

项目摘要

Epilepsy affects 50 million people worldwide. In 40% of patients with temporal lobe epilepsy (TLE), antiepileptic drugs fail to prevent seizures, increasing the risk of injury, cognitive decline, and death. The impairment of inhibition by GABAergic interneurons (IN) is a key pathomechanism of epilepsy, however, our incomplete understanding of the network function of the diverse types of IN limits the development of treatment strategies. Perisomatic inhibition by basket cells controls the rate and synchrony of the firing of excitatory neurons. The two types of basket cells, expressing either cholecystokinin (CCK) or parvalbumin (PV), are equally abundant and are both preserved in chronic epilepsy. However, why there are two distinct classes of perisomatic IN, and how their function is altered in epilepsy, is not known. The candidate’s long-term goal is to develop a career as an independent neuroscientist to understand the role of interneuron diversity in neuronal microcircuit function, and how dysfunction in various interneuron subtypes is involved in and leads to epilepsy. Using recently developed tools to record the activity of CCK and PV IN selectively in awake, behaving animals, preliminary results show that in the hippocampus, the brain area most affected by TLE, CCK and PV IN are recruited in distinct brain states. Moreover, the activity of PV IN is correlated positively, while the activity of CCK IN is correlated negatively to the activity of excitatory neurons on the time scale of seconds, suggesting that CCK IN are suited to control average firing rates and associativity across the network. Therefore, the hypothesis of the current proposal is that the two classes of perisomatic IN are recruited in separate brain states in epilepsy, and this may lead to distinct outcome of antiepileptic interventions that selectively target CCK or PV IN. This proposal presents a plan to test this hypothesis in a chronic animal model of TLE (intrahippocampal kainate), using in vitro electrophysiology and in vivo 2-photon calcium imaging with correlated hippocampal field potential recording, to: 1) Test the hypothesis that CCK and PV IN are recruited in different brain states in epilepsy; 2) Test the hypothesis that excitatory inputs and reciprocal inhibition contribute to the differential recruitment of PV and CCK IN; and 3) Test the hypothesis that CCK IN are effective in dampening network activity in TLE without disrupting the representation of spatial information. Completion of the proposed study may advance the field by: 1) establishing a previously unknown temporal segregation of the activity of interneurons; 2) determining the underlying circuit mechanism; and 3) determining the efficacy of CCK IN for antiepileptic intervention. In addition, the candidate proposes a personalized plan to obtain training in scientific background (particularly in the epilepsy field), research methods (chronic epilepsy models and in vitro electrophysiology), and career development (grant writing, teaching and scientific management). The mentoring of Prof Ivan Soltesz at Stanford University will provide an ideal environment for the candidate to carry out the research and training plan successfully and thus will enable the candidate to establish an independent research program.

全球有 5000 万人患有癫痫症，在 40% 的颞叶癫痫 (TLE) 患者中，抗癫痫药物无法预防癫痫发作，从而增加了受伤、认知能力下降和死亡的风险。然而，我们对不同类型 IN 的网络功能的不完全了解限制了篮细胞周围抑制的治疗策略的发展。表达胆囊收缩素 (CCK) 或小白蛋白 (PV) 的两种类型的篮子细胞数量相同，并且都保留在慢性癫痫中。以及它们的功能在癫痫中如何改变尚不清楚，该候选人的长期目标是发展成为一名独立的神经科学家，以了解中间神经元多样性在神经元中的作用。微电路功能，以及各种中间神经元亚型的功能障碍如何参与并导致癫痫。使用最近开发的工具选择性记录清醒、行为动物的 CCK 和 PV IN 活性，初步结果表明，在海马体中，大脑区域最活跃。受 TLE 影响，CCK 和 PV IN 在不同的大脑状态下被招募，而且，PV IN 的活动在时间尺度上与兴奋性神经元的活动呈正相关，而 CCK IN 的活动与兴奋性神经元的活动呈负相关。秒，表明 CCK IN 适合控制整个网络的平均放电率和关联性，因此，当前提议的假设是，两类周期 IN 在癫痫的不同大脑状态下被招募，这可能会导致选择性针对 CCK 或 PV IN 的抗癫痫干预措施的不同结果该提案提出了一项计划，利用体外电生理学和体内试验，在 TLE（海马内红藻氨酸）慢性动物模型中检验这一假设。具有相关海马场电位记录的 2 光子钙成像，目的是：1) 检验 CCK 和 PV IN 在癫痫的不同大脑状态下被募集的假设；2) 检验兴奋性输入和相互抑制有助于差异募集的假设。 PV 和 CCK IN；以及 3) 检验 CCK IN 能够有效抑制 TLE 中的网络活动而不破坏空间信息表示的假设，完成所提出的研究可能会通过以下方式推进该领域的发展： 1) 建立先前未知的中间神经元活动的时间隔离；2) 确定潜在的回路机制；以及 3) 确定 CCK IN 抗癫痫干预的功效此外，候选人还提出了获得科学背景培训的个性化计划。（特别是在癫痫领域）、研究方法（慢性癫痫模型和体外电生理学）以及职业发展（资助写作、教学和科学管理）将得到斯坦福大学 Ivan Soltesz 教授的指导。为候选人成功开展研究和培训计划提供理想的环境，从而使候选人能够建立独立的研究计划。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neural and behavioural state switching during hippocampal dentate spikes.

海马齿状尖峰期间的神经和行为状态切换。

DOI：
发表时间：
2024-04
期刊：
影响因子：
64.8
作者：
Farrell, Jordan S;Hwaun, Ernie;Dudok, Barna;Soltesz, Ivan
通讯作者：
Soltesz, Ivan

In vivo endocannabinoid dynamics at the timescale of physiological and pathological neural activity.

生理和病理神经活动时间尺度上的体内内源性大麻素动力学。

DOI：
发表时间：
2021-08-04
期刊：
影响因子：
16.2
作者：
Farrell, Jordan S;Colangeli, Roberto;Dong, Ao;George, Antis G;Addo;Kingsley, Philip J;Morena, Maria;Wolff, Marshal D;Dudok, Barna;He, Kaikai;Patrick, Toni A;Sharkey, Keith A;Patel, Sachin;Marnett, Lawrence J;Hill, Matthew N;Li
通讯作者：
Li

Ripple-selective GABAergic projection cells in the hippocampus.

海马体中的波纹选择性 GABA 能投射细胞。

DOI：
发表时间：
2022-06-15
期刊：
影响因子：
16.2
作者：
Szabo, Gergely G;Farrell, Jordan S;Dudok, Barna;Hou, Wen;Ortiz, Anna L;Varga, Csaba;Moolchand, Prannath;Gulsever, Cafer Ikbal;Gschwind, Tilo;Dimidschstein, Jordane;Capogna, Marco;Soltesz, Ivan
通讯作者：
Soltesz, Ivan

A fluorescent sensor for spatiotemporally resolved imaging of endocannabinoid dynamics in vivo.

用于体内内源性大麻素动力学时空分辨成像的荧光传感器。

DOI：
发表时间：
2022-05
期刊：
影响因子：
46.9
作者：
Dong, Ao;He, Kaikai;Dudok, Barna;Farrell, Jordan S;Guan, Wuqiang;Liput, Daniel J;Puhl, Henry L;Cai, Ruyi;Wang, Huan;Duan, Jiali;Albarran, Eddy;Ding, Jun;Lovinger, David M;Li, Bo;Soltesz, Ivan;Li, Yulong
通讯作者：
Li, Yulong

Imaging the endocannabinoid signaling system.

内源性大麻素信号系统成像。