CRCNS: Role of Mossy Cells in Gating Plasticity Hippocampal Granule Cells

CRCNS：苔藓细胞在门控可塑性海马颗粒细胞中的作用

• 批准号: 10222247
• 负责人: AARON D MILSTEIN
• 金额: $ 18.61万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222247
• 关键词: Affect; Biophysics; Brain; Brain region; Calcium Signaling; Calcium Spikes; Cells; Cognition; Communication; Computer Models; Dendrites; Detection; Development; Distal; Elements; Epilepsy; Exhibits; Feedback; Frequencies; Functional Imaging; Functional disorder; Germany; Goals; Hippocampus (Brain); Human; Image; In Vitro; Instruction; Interdisciplinary Study; International; Interneurons; Learning Disorders; Maps; Memory; Memory Disorders; Neurons; Pathway interactions; Patients; Pattern; Pattern Recognition; Pharmacological Treatment; Population; Process; Research; Research Project Grants; Rodent; Role; Seizures; Severities; Supporting Cell; Synapses; Synaptic plasticity; Techniques; Temporal Lobe Epilepsy; Testing; Traumatic Brain Injury; Work; artificial neural network; cell type; classical conditioning; dentate gyrus; design; entorhinal cortex; experience; granule cell; in vivo; information processing; insight; interdisciplinary approach; long term memory; neural circuit; place fields; response; spatial memory; treatment strategy; two-photon; way finding

We propose an international collaborative multidisciplinary research project to investigate neural circuit mechanisms of spatial memory formation in the mammalian brain. In both humans and rodents, the hippocampus is a brain region required to store long-term memories. This process depends on activity- dependent changes in the strengths of connections between neurons, known as synaptic plasticity. In the input layer of the hippocampus, the dentate gyrus, a principal cell type called the granule cell receives synaptic inputs from cortex carrying information about spatial navigation, and it is thought that synaptic plasticity at these inputs stores a map of space in dentate granule cells. Like most hippocampal and cortical circuits, the dentate gyrus is comprised of multiple neuronal cell types, many of which are inhibitory interneurons. However, the dentate gyrus also contains a unique class of local excitatory interneurons,, called mossy cells, which form local synapses onto granule cells and inhibitory interneurons, but do not project outside the dentate gyrus. It is a major goal of this project to reconcile the direct excitatory and indirect inhibitory influences of mossy cells on granule cells, which could have opposing effects on spatial information processing and memory storage. Recent work has shown that mossy cells are required for the formation of new spatial memories, though the underlying mechanism is completely unknown. Interestingly, the mossy cell inputs and cortical inputs to granule cells segregate onto proximal and distal regions of granule cell dendrites, respectively. In other cell types, synchronous activation of proximal and distal input pathways evokes local dendritic spikes that potently induce synaptic plasticity. However, whether this occurs in granule cells in response to coincidence of feedforward input from cortex and feedback input from mossy cells has not been investigated. Therefore, in order to test the role of mossy cell input in gating dendritic spiking and plasticity in dentate granule cells, we propose to 1) directly record from granule cell dendrites in vitro in response to precisely controlled input patterns, 2) directly image the activity of granule cell dendrites in vivo during spatial navigation while chemogenetically silencing mossy cells, and 3) develop experimentally-constrained computational models of dentate gyrus cells and circuits to investigate how a dedicated feedback neuron type like mossy cells affects the storage and recall of information in a neural circuit. RELEVANCE (See instructions): Humans with temporal lobe epilepsy and traumatic brain injury exhibit specific degeneration of hippocampal mossy cells, and suffer from deficits in memory and cognition. While existing pharmacological treatments reduce seizure frequency and severity in some epileptic patients, no treatments exist for the associated learning and memory disorders. We expect our research to generate new insight and inform the development of new treatment strategies for neural circuit dysfunction.

我们提出了一个国际合作的多学科研究项目来研究神经回路机制。 哺乳动物大脑中空间记忆的形成。在人类和啮齿动物中，海马体都是一个大脑区域 需要用来储存长期记忆。这一过程依赖于活动依赖的力量的变化 神经元之间的连接，称为突触可塑性。在海马体的输入层，即齿状回， 一种称为颗粒细胞的主要细胞类型从大脑皮层接收携带空间信息的突触输入 导航，并被认为在这些输入的突触可塑性存储了齿状颗粒细胞的空间地图。喜欢 大多数海马区和皮层环路，齿状回由多种神经细胞类型组成，其中许多 是抑制性中间神经元。然而，齿状回也含有一类独特的局部兴奋性中间神经元， 被称为苔藓细胞，形成局部突触到颗粒细胞和抑制性中间神经元，但不向外投射。 齿状回。本项目的一个主要目标是协调直接兴奋和间接抑制的影响 颗粒细胞上的苔藓细胞，这可能对空间信息处理和记忆产生相反的影响 储藏室。最近的研究表明，苔藓细胞是形成新的空间记忆所必需的，尽管 潜在的机制是完全未知的。有趣的是，苔藓细胞和皮质对颗粒细胞的输入 分别分离到颗粒细胞树突的近端和远端。在其他单元类型中，同步 近端和远端输入通路的激活可激发局部树突棘，从而有效地诱导突触可塑性。 然而，这种情况是否发生在颗粒细胞中，以响应来自皮质的前馈输入和 苔藓细胞的反馈输入还没有被研究过。因此，为了测试苔藓细胞在体内的作用 门控齿状颗粒细胞的树突状突起和可塑性，我们建议1)直接从颗粒细胞记录 体外树突状细胞对精确控制的输入模式的响应，2)直接成像颗粒细胞的活动 在化学上沉默苔藓细胞的空间导航过程中体内的树突，以及3)发展 齿状回细胞和电路的实验受限计算模型，以研究专用的 反馈神经元类型，如苔藓细胞，影响神经回路中信息的存储和回忆。 相关性(请参阅说明)： 患有颞叶癫痫和创伤性脑损伤的人表现出特异性的海马苔藓变性 细胞，并遭受记忆和认知缺陷的困扰。虽然现有的药物治疗可以减少癫痫发作 一些癫痫患者的频率和严重程度，相关的学习和记忆没有治疗方法 精神错乱。我们期待我们的研究产生新的见解，并为新治疗策略的开发提供信息 治疗神经回路功能障碍。