Cellular and circuit mechanisms of hippocampal dentate engram formation and seizure-induced alterations

海马齿状印迹形成和癫痫引起的改变的细胞和回路机制

• 批准号: 10316111
• 负责人: Laura Dovek
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316111
• 关键词: Adopted; Automobile Driving; Axon; Behavioral Assay; Biological Assay; Brain; Cell model; Cell physiology; Cells; Code; Cognitive; Collection; Computer Models; Coupled; Development; Disease; Electrophysiology (science); Epilepsy; Equilibrium; Event; Experimental Models; Feedback; Future; Hilar; Hippocampus (Brain); Histologic; Immediate-Early Genes; Injections; Knowledge; Label; Lateral; Learning; Medial; Mediating; Memory; Memory impairment; Methods; Modeling; Morphology; Mus; Neurons; Opsin; Output; Pathway interactions; Pattern; Pilocarpine; Play; Population; Preventive; Process; Property; Recurrence; Regulation; Reporter; Role; Saline; Seizures; Sensory; Shapes; Slice; Stains; Status Epilepticus; Structure; Structure of molecular layer of cerebellar cortex; Supporting Cell; Synapses; System; Temporal Lobe Epilepsy; Testing; Transgenic Organisms; Update; Viral; Whole-Cell Recordings; acquired epilepsy; base; comorbidity; dentate gyrus; entorhinal cortex; experience; granule cell; improved; in vivo; information processing; inhibitory neuron; insight; memory process; multimodality; neuron loss; neuronal circuitry; novel; patch clamp; preventable epilepsy; receptive field; reconstruction; recruit; response; simulation environment; spatial memory

Proposal Summary Neuronal circuits maintain a delicate balance of excitatory drive and inhibitory regulation to execute high order functions, such as learning and memory, and maintain network stability which is severely compromised in temporal lobe epilepsy (TLE). With a better understanding of mechanisms of memory formation and how TLE disrupts the processes, we gain insights that can be used to improve memory deficits in disease. The hippocampal dentate gyrus (DG) acts as a functional gate into the hippocampal trisynaptic circuit and plays a key role in learning and memory. Formation of memories is believed to be coded by activity of a distinct collection of neurons which represent a memory or experience known as an engram. Sparse activity in dentate granule cells (GCs) has been shown to be involved in engram formation; however, the circuit mechanism that underlie formation of these neuronal activity patterns are not fully understood. The DG is a circuit with low spontaneous activity and robust inhibition of the projection neurons, the GCs, by local inhibitory neurons (IN). Recent studies have found that a sparse subtype of dentate projection neurons, semilunar granule cell (SGC) are preferentially recruited in engrams. SGCs differ from GCs in their wide dendritic arbors, molecular layer axon collaterals and persistent firing and have been proposed to support feedback inhibition of GCs. However, circuit connectivity and functional effects of SGCs are not known. My objective is to better understand SGC’s role in information processing as well as their involvement in microcircuit changes related to epilepsy. I hypothesize SGCs differ from GCs in their input integration and SGCs that outputs directly activate a subset of GCs involved memory engrams and further refine GC engrams by engaging feedback inhibition of surrounding “non-engram” GCs. In acquired epilepsy, I propose that SGC’s support of the DG inhibitory gate is compromised and SGC dependent excitation increased resulting learning deficits. Aim 1 will identify differences in afferent inputs to GCs and SGCs using virally mediated pathway specific expression of channelrhodopsin to activate distinct DG inputs and adopt morphometric computational modeling to test the effect of dendritic structure on input integration in SGCs and GCs. Aim 2 will use the inducible cFOS TRAP2 system coupled to fluorescent reporters to label neurons active during a specific memory task followed by electrophysiology to determine how SGC output influences activity of GCs within and outside the shared engram. Finally, in Aim 3, will examine how engram stability, SGC activity and its influence on GC activity are altered in the pilocarpine model of experimental epilepsy. Together these studies will provide novel fundamental insights into dentate circuit function and memory processing and how these are altered in epilepsy and enable future development of circuit-based therapies to improve memory function.

建议书摘要 神经元回路维持兴奋性驱动和抑制性调节的微妙平衡，以执行高阶 功能，如学习和记忆，并维持网络稳定性，这是严重损害 颞叶癫痫(TLE)。更好地了解记忆形成的机制以及TLE是如何形成的 扰乱了这一过程，我们获得了可以用来改善疾病记忆缺陷的见解。这个 海马齿状回(DG)作为进入海马三突触回路的功能门，在中枢神经系统中起着重要的作用。 在学习和记忆中起关键作用。记忆的形成被认为是由不同集合的活动编码的 代表记忆或经验的神经元，称为印记。齿状颗粒中的稀疏活性 细胞(GC)已被证明参与印迹的形成；然而，其基础的电路机制 这些神经元活动模式的形成尚不完全清楚。DG是一种低自发辐射的电路 局部抑制神经元(IN)对投射神经元(GC)的活动和强烈抑制。最新研究 已发现齿状投射神经元的一种稀疏亚型半月颗粒细胞(SGC)优先 以铭文的形式招募。SGCs与GC的不同之处在于其树枝较宽，分子层轴突侧支和 持续放电，并已被提出支持反馈抑制的GC。但是，电路连接 而SGCs的功能效应尚不清楚。我的目标是更好地理解SGC在信息方面的角色 以及它们参与与癫痫相关的微电路变化。我假设SGC不同 从其输入整合中的GC和输出直接激活涉及记忆的GC的子集的SGC 通过对周围“非印记”GC的反馈抑制，进一步提炼GC印记。在……里面 获得性癫痫，我认为SGC对DG抑制门的支持是妥协的，SGC依赖于SGC 兴奋增加了由此导致的学习缺陷。目标1将确定GCs和SGCs的传入输入的差异 利用病毒介导的通道视紫红质通路特异性表达激活不同的DG传入并采用 用形态计量学计算模型检验树枝状结构对SGCS和 GCS。AIM 2将使用可诱导的CFOS TRAP2系统偶联到荧光记者来标记神经元活性 在特定的记忆任务中，随后进行电生理，以确定SGC的输出如何影响脑电活动 共享图章内外的GCS。最后，在目标3中，将检查如何印记稳定性、SGC活性 在匹罗卡品实验性癫痫模型中，其对GC活性的影响发生了改变。把这些放在一起 研究将提供对齿状回功能和记忆处理的新的基本见解以及如何 这些在癫痫中被改变，并使基于电路的治疗的未来发展能够改善记忆 功能。