Neuromodulation and Cortical Memory Function

描述（由申请人提供）：这个竞争性的延续应用侧重于内嗅皮层的神经机制，该机制可能是情景记忆中空间和时间编码的基础。这包括测试胆碱能调节细胞特性在产生和调节内嗅皮层网格细胞放电特性中的作用。Aim #1的研究将测试影响乙酰胆碱水平和乙酰胆碱受体激活的药物输注前后的内嗅网格细胞的多个单单元记录。实验将测试网格细胞机制的计算模型的预测，该模型预测在操纵乙酰胆碱水平期间网格场精度和间距的变化。Aim #2的研究将在一系列行为任务中测试海马体和内嗅皮层中网格细胞的生成和情境依赖的尖峰活动模型。实验将测试模型的不同版本，这些版本在被不同的刺激重置后，根据速度、速度或时间，获得不同的情境依赖的放电模式。Aim #3的研究将测试电流的细胞特性，这些电流可能是内嗅皮层网格细胞放电的基础，由将网格细胞的网络特性与细胞机制联系起来的模型指导。研究将测试乙酰胆碱敏感m电流的差异是否可能是沿内侧内嗅皮层背侧至腹侧轴网格细胞空间频率差异的基础。研究还将测试胆碱能调节对内嗅神经元共振和膜电位振荡频率的影响，以将这些影响与行为动物中与药物操作相关的网格细胞放电变化联系起来。这些研究将增强我们对内嗅皮层在情景记忆中编码空间和时间的动力机制的理解。这项工作将增强我们对涉及记忆功能损伤和扭曲的疾病的细胞和电路机制的理解，包括与记忆损伤和海马体和内吸皮层体积减少相关的精神障碍，如抑郁症和精神分裂症，以及与记忆相关的神经系统疾病，如阿尔茨海默病。

DESCRIPTION (provided by applicant): This competing continuation application focuses on neural mechanisms in entorhinal cortex that could underlie coding of space and time in episodic memory. This includes testing the role of cholinergic modulation of cellular properties in generating and modulating grid cell firing properties in entorhinal cortex. Research in Aim #1 will test multiple single unit recording of entorhinal grid cells before and after pharmacological infusions of drugs influencing acetylcholine levels and acetylcholine receptor activation. Experiments will test predictions from computational models of the cellular mechanisms of grid cells that predict changes in grid field accuracy and spacing during manipulations of acetylcholine levels. Research in Aim #2 will test models of the generation of grid cells and context-dependent spiking activity in the hippocampus and entorhinal cortex in a range of behavioral tasks. Experiments will test alternate versions of the model that obtain different patterns of context-dependent firing dependent on velocity, speed or time after reset by different stimuli. Research in Aim #3 will test cellular properties of currents that could underlie grid cell firing in entorhinal cortex, guided by models linking network properties of grid cells to cellular mechanisms. Studies will test whether differences in the acetylcholine sensitive M-current could underlie differences in grid cell spatial frequency along the dorsal to ventral axis of medial entorhinal cortex. Studies will also test effects of cholinergic modulation on the resonance and membrane potential oscillation frequency of entorhinal neurons to link these effects to changes in grid cell firing associated with pharmacological manipulations in behaving animals. These studies will enhance our understanding of the dynamical mechanisms in the entorhinal cortex for encoding space and time in episodic memory. This work will enhance our understanding of cellular and circuit mechanisms of disorders involving impairments and distortions of memory function, including mental disorders such as depression and schizophrenia, associated with impairments of memory and decreased volume of hippocampus and entorhinal cortex, as well as memory-related neurological disorders such as Alzheimer's disease. PUBLIC HEALTH RELEVANCE: This grant focuses on studying the brain mechanisms for storing episodes from life and retrieving these episodes at other times, based on interacting populations of neurons. This work includes experiments testing models of how cells code the spatial location of episodes and how certain drugs influence the coding by these cells. These experiments and models are relevant to brain mechanisms that may break down in disorders involving distortions of memory encoding and retrieval, including disorders such as depression, which is associated with memory impairments and a negative bias in retrieved memories, as well as schizophrenia, which involves impairments and distortions in memory function.