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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

基本信息

批准号：
10673905
负责人：
Laura Dovek
金额：
$ 3.41万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-03-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10673905
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 Episodic memory Equilibrium Event Experimental Models Feedback Future Hilar Hippocampus Histologic Immediate-Early Genes Injections Knowledge Label Lateral Learning Medial Mediating Memory Memory impairment Methods Modeling Molecular Morphology Mus Neurons Opsin Output Pathway interactions Pattern Pilocarpine Play Population Preventive Process Property Recurrence Regulation Reporter Reporter Genes Role Saline Seizures Sensory Shapes Slice Stains Status Epilepticus Structure Supporting Cell Synapses System Temporal Lobe Epilepsy Testing Transgenic Organisms Update Viral Whole-Cell Recordings acquired epilepsy comorbidity dentate gyrus entorhinal cortex excitatory neuron experience granule cell improved in vivo information processing inhibitory neuron insight memory process multimodality neural circuit neuron loss neuronal circuitry novel patch clamp preventable epilepsy receptive field reconstruction recruit response simulation environment spatial memory

项目摘要

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.

提案摘要神经元回路维持兴奋驱动和抑制调节的微妙平衡以执行高阶指令功能，如学习和记忆，并保持网络的稳定性，这是严重损害，颞叶癫痫（TLE）。随着对记忆形成机制以及TLE如何扰乱了这个过程，我们获得了可以用来改善疾病记忆缺陷的见解。的海马齿状回（DG）是进入海马三突触回路的功能门，在学习和记忆中的关键作用。记忆的形成被认为是由一个独特的集合的活动编码的代表记忆或经验的记忆印迹。齿状颗粒活动稀疏细胞（GC）已被证明参与了记忆印迹的形成;然而，这些神经元活动模式的形成尚未完全了解。DG是一种低自发放电的电路活动和强大的抑制投射神经元，GC，由本地抑制神经元（IN）。最近的研究发现齿状突起投射神经元的一种稀疏亚型，半月颗粒细胞（SGC）优先被在记忆印记中被招募SGCs与GC的不同之处在于其广泛的树突状乔木，分子层轴突侧支，持续放电，并已提出支持GC的反馈抑制。然而，电路连接并且SGCs的功能作用是未知的。我的目标是更好地理解SGC在信息方面的作用处理以及参与与癫痫相关的微电路变化。我假设SGCs 从GC在其输入整合和SGCs的输出直接激活一个子集的GC涉及的记忆并且通过对周围的“非痕迹”GC进行反馈抑制来进一步细化GC痕迹。在对于获得性癫痫，我认为SGC对DG抑制门的支持受到损害，并且依赖于SGC 兴奋增加导致学习缺陷。目标1将确定GC和SGCs的传入输入的差异使用病毒介导的通道视紫红质的途径特异性表达来激活不同的DG输入，形态计量学计算建模，以测试树突状结构对SGCs中输入整合的影响， GC。目的2将使用可诱导的cFOS TRAP 2系统与荧光报告分子偶联来标记神经元活性在特定的记忆任务中，然后进行电生理学，以确定SGC输出如何影响在共享印迹内和共享印迹外的GC。最后，在目标3中，将研究记忆印迹的稳定性、SGC活动和对GC活性的影响。综合这些研究将提供新的基本见解齿状电路功能和记忆处理以及如何这些在癫痫中发生改变，并使未来开发基于回路的治疗以改善记忆功能