2023 NINDS Landis Mentorship Award - Administrative Supplement to NS121106 Control of Axon Initial Segment in Epilepsy

2023 年 NINDS 兰迪斯指导奖 - NS121106 癫痫轴突初始段控制的行政补充

• 批准号: 10896844
• 负责人: Attila Losonczy
• 金额: $ 15.66万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10896844
• 关键词: Acceleration; Action Potentials; Administrative Supplement; Anatomy; Animals; Area; Award; Axon; Biological Assay; Brain; Career Mobility; Cell physiology; Cells; Chronic; Cognitive; Control Animal; Development; Electroencephalography; Electrophoresis; Electroporation; Epilepsy; Exhibits; Funding; Future; Goals; Grant; Hippocampus; Image; In Vitro; Interneurons; Investigation; Knowledge; Mediating; Membrane Potentials; Mentors; Mentorship; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Output; Parvalbumins; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Production; Regulation; Research; Resolution; Seizures; Signal Transduction; Synapses; Techniques; Temporal Lobe Epilepsy; Testing; Therapeutic; Universities; axonal sprouting; cell type; comorbidity; excitatory neuron; experience; improved; in vivo; inhibitory neuron; novel; optogenetics; parent grant; rabies viral tracing; response; training opportunity; transmission process; treatment strategy; two-photon; voltage

Over half of all people with temporal lobe epilepsy (TLE) are currently believed to suffer from inadequately controlled seizures despite existing pharmacotherapies. One of the main obstacles to developing improved epilepsy therapies is our insufficient understanding of the precise cellular and circuit mechanisms underlying TLE. An important, but unresolved, question in TLE concerns the mechanisms underlying the excessive and dysregulated production of action potentials at the axon initial segment (AIS) of excitatory principal cells (PCs). Highly targeted synaptic control of the AIS is provided by a unique, evolutionarily conserved GABAergic cell type, the axo-axonic cell (AAC). AACs are the only GABAergic neuron that forms synaptic contacts with the PC AIS, placing AACs in a strategic position to regulate action potential transmission. However, due to technical limitations, our knowledge of the exact connectivity of AACs and their in vivo function, along with their regulation within the normal and epileptic hippocampus has remained extremely limited. Our R01 grant (NS121106) focuses on leveraging a combination of recent technical breakthroughs to test the hypothesis that AAC-mediated inhibition of PC discharges in hippocampal area CA1 is altered in chronic TLE in vivo, and that AAC optogenetic modulation may exert effective seizure control and decrease cognitive comorbidities. While the prevailing dogma has been that AACs exclusively innervate the PC AIS, our recent preliminary results surprisingly suggest that AACs may also directly synapse on parvalbumin (PV) interneurons and thus regulate their activity. Additional investigation into our finding would bring further nuance to our understanding of how AACs act as a central controller of both excitatory and inhibitory network in CA1, and thus as key players responsible for TLE network hyperexcitability. In this administrative supplement project, we propose to combine state-of-the-art in vivo techniques to specifically probe the anatomical and functional connectivity of AACs with CA1 PV INs. In parallel, we will perform similar approaches to study whether TLE mice show increased aberrant connectivity of AACs onto PV INs or altered PV INs output activity in CA1. Together, the aims in our Landis award-related administrative supplement will both benefit from and contribute to our R01 grant’s goal to define the function, regulation and therapeutic potential of AACs in TLE, while also expanding opportunities to mentor trainees in advanced approaches. Overall, this project will have a significant impact in advancing our understanding of key circuit control mechanisms in chronic epilepsy and will aid in the future development of novel antiseizure treatment strategies.

目前据信临时叶癫痫（TLE）的所有患者中有一半以上的人遭受不足的困扰 受控癫痫发作目的地现有药物治疗。发展改进的主要障碍之一 癫痫疗法是我们对确切的细胞和电路机制的理解不足 TLE。一个重要但尚未解决的问题涉及过度和 兴奋性主细胞（PC）的轴突初始段（AIS）的作用电位的产生失调。 AIS的高度靶向合成控制由独特的，进化的GABA能细胞类型提供， Axo轴突细胞（AAC）。 AAC是唯一与PC AI形成突触接触的GABA能神经元， 将AAC置于战略位置，以调节动作潜在传播。但是，由于技术 局限性，我们对AAC及其体内功能的确切连通性的了解，以及它们的调节 在正常和癫痫发作的海马中，海马仍然非常有限。我们的R01赠款（NS121106） 着重于利用最近的技术突破的结合来检验AAC介导的假设 在体内慢性TLE中，海马区域CA1中PC放电的抑制作用改变了，并且AAC光学遗传学 调节可能行使有效的癫痫发作控制并降低认知合并症。而普遍的教条 一直是AACS专门支配PC AIS，我们最近的初步结果令人惊讶地表明 AAC也可以直接在白蛋白（PV）中间神经元上突触，从而调节其活性。额外的 对我们发现的调查将使我们对AAC如何作为中心的理解更加细微 CA1中兴奋性和抑制网络的控制器，因此作为负责TLE网络的关键参与者 过度兴奋。在这个行政补充项目中，我们建议将最先进的体内结合起来 专门探测AAC与CA1 PV INS的解剖和功能连接的技术。并联， 我们将采用类似的方法来研究TLE小鼠是否显示AAC的异常连通性增加 在CA1中的PV INS或更改PV INS输出活动。共同的目标是我们与Landis奖有关 行政补充剂将从我们的R01赠款定义功能的目标中受益并为此做出贡献， AAC在TLE中的监管和治疗潜力，同时也扩大了对心理学生的机会 高级方法。总体而言，该项目将对我们对关键的理解产生重大影响 慢性癫痫中的电路控制机制，将有助于未来的新抗原发展 治疗策略。

项目成果

behaviorMate: An Intranet of Things Approach for Adaptable Control of Behavioral and Navigation-Based Experiments.

behaviorMate：一种用于行为和基于导航的实验的适应性控制的物联网方法。

• DOI: 10.1101/2023.12.04.569989
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Bowler,JohnC;Zakka,George;Yong,HyunChoong;Li,Wenke;Rao,Bovey;Liao,Zhenrui;Priestley,JamesB;Losonczy,Attila
• 通讯作者: Losonczy,Attila

A tool for monitoring cell type-specific focused ultrasound neuromodulation and control of chronic epilepsy.

• DOI: 10.1073/pnas.2206828119
• 发表时间: 2022-11-16
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

tension: A Python package for FORCE learning.

• DOI: 10.1371/journal.pcbi.1010722
• 发表时间: 2022-12
• 期刊: PLoS computational biology
• 影响因子: 4.3

Signatures of rapid plasticity in hippocampal CA1 representations during novel experiences.

• DOI: 10.1016/j.neuron.2022.03.026
• 发表时间: 2022-06-15
• 期刊: NEURON
• 影响因子: 16.2
• 作者: Priestley, James B.;Bowler, John C.;Rolotti, Sebi, V;Fusi, Stefano;Losonczy, Attila
• 通讯作者: Losonczy, Attila

2P-NucTag: on-demand phototagging for molecular analysis of functionally identified cortical neurons.

2P-NucTag：按需照片标记，用于功能识别的皮质神经元的分子分析。

• DOI: 10.1101/2024.03.21.586118
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Shi,Jingcheng;Nutkovich,Boaz;Kushinsky,Dahlia;Rao,BoveyY;Herrlinger,StephanieA;Mihaila,TiberiuS;Malina,KatayunCohen-Kashi;O'Toole,CliodhnaK;CondeParedes,MargaretE;Yong,HyunChoong;Varol,Erdem;Losonczy,Attila;Spiegel,Ivo
• 通讯作者: Spiegel,Ivo