Mossy cells in temporal lobe epilepsy

颞叶癫痫中的苔藓细胞

基本信息

批准号：
10586664
负责人：
Helen E Scharfman
金额：
$ 46.1万
依托单位：
NATHAN S. KLINE INSTITUTE FOR PSYCH RES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586664
关键词：
Address Anticonvulsants Anxiety Area Attention Behavior Behavioral Brain Cell Survival Cells Characteristics Chronic Cognition Designer Drugs Development Disease Dorsal Epilepsy Epileptogenesis Frequencies Future Glutamates Hippocampus Injections Injury Kainic Acid Knowledge Lead Methods Modeling Mus Neurons Outcome Output Patients Pharmaceutical Preparations Pilocarpine Play Positioning Attribute Pyramidal Cells Quality of life Rattus Recurrence Research Research Personnel Role Seizures Site Status Epilepticus Syndrome Temporal Lobe Epilepsy Testing Work behavior test behavioral impairment cell type clinically relevant cognitive task comorbidity dentate gyrus entorhinal cortex excitotoxicity experimental study granule cell hippocampal cell loss improved improved outcome novel novel therapeutic intervention optogenetics receptor

项目摘要

ABSTRACT Temporal lobe epilepsy (TLE) is a disorder with recurrent, debilitating seizures as well as comorbidities that greatly decrease quality of life. Many patients respond poorly to medications, making research important to develop new treatments. A focus of research has been a part of the hippocampus called the dentate gyrus (DG), and a glutamatergic cell type in the DG called the mossy cell (MC). MCs have a direct excitatory projection to the main neuronal cell type, granule cells (GCs), so MCs are theoretically in an important position to regulate the role of the DG in TLE. Although MCs can excite GCs, many investigators consider MC-GC excitation is weak. Instead, MCs are thought to primarily activate DG GABAergic neurons that inhibit GCs. In this proposal we hypothesize that both the excitatory and inhibitory actions of MCs on GCs have important roles, particularly when an initial insult leads to TLE. Our central hypothesis is that during the initial insult, MC excitation of GCs plays a critical role because it strengthens greatly, leading to strong excitation of GC targets and excitotoxicity. In contrast, in chronic epilepsy, we hypothesize a very different MC role. We suggest that MCs resume their normal role to activate DG GABAergic neurons and inhibit GCs, which reduces chronic seizures. Therefore, during the initial insult, MCs should be inhibited for the best outcomes and during chronic epilepsy the MCs should be activated. If supported, this hypothesis would be a paradigm shift by changing the view of MCs in TLE. In addition, the proposed experiments will fill major gaps in knowledge because little is known about MCs during the initial insult, latent period, and chronic epilepsy. Notably, MCs regulate behavior and cognitive tasks in normal mice. We recently showed MCs regulate tasks related to anxiety and cognition, which are comorbidities in TLE. Therefore, we hypothesize a role of MCs in the behavioral comorbidities in TLE. Together these experiments will challenge prevailing views and fill several knowledge gaps about MCs, the DG, and TLE. Furthermore, the experiments will potentially give rise to new approaches for therapeutics.

抽象的颞叶癫痫 (TLE) 是一种具有反复发作、使人衰弱的癫痫发作以及合并症的疾病从而大大降低生活质量。许多患者对药物反应不佳，因此研究很重要开发新的治疗方法。研究的一个焦点是海马体中称为齿状回的部分 (DG)，DG 中的谷氨酸能细胞类型称为苔藓细胞 (MC)。 MC具有直接兴奋性投射到主要神经元细胞类型颗粒细胞（GC），因此理论上 MC 处于重要地位调节 DG 在 TLE 中的作用。尽管 MC 可以激发 GC，但许多研究者认为 MC-GC 激励较弱。相反，MC 被认为主要激活 DG GABA 能神经元，从而抑制 GC。在根据这个建议，我们假设 MC 对 GC 的兴奋和抑制作用都具有重要意义角色，特别是当最初的侮辱导致 TLE 时。我们的中心假设是，在最初的侮辱期间， GC 的 MC 激发起着至关重要的作用，因为它大大增强，从而导致 GC 的强烈激发 GC 目标和兴奋性毒性。相反，在慢性癫痫中，我们假设 MC 的作用非常不同。我们建议 MC 恢复其正常作用，激活 DG GABA 能神经元并抑制 GC，从而减少慢性癫痫发作。因此，在最初的损伤过程中，MCs应该被抑制最好的结果是，在慢性癫痫期间，MCs 应该被激活。如果得到支持，这个假设通过改变 MC 对 TLE 的看法，将是一种范式转变。此外，拟议的实验将填补知识上存在重大差距，因为人们对 MC 在最初的损伤、潜伏期和慢性损伤期间知之甚少。癫痫。值得注意的是，MCs 调节正常小鼠的行为和认知任务。我们最近展示了 MC 的监管与焦虑和认知相关的任务，这是 TLE 的合并症。因此，我们假设一个角色 TLE 行为合并症中的 MC。这些实验将共同挑战主流观点并填补有关 MC 的若干知识空白， DG 和 TLE。此外，这些实验可能会产生新的治疗方法。