Neuromodulation and Cortical Memory Function

描述（由申请人提供）：该竞争性延续申请专注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中的网格细胞放电特性中的作用。目标1中的研究将测试在药物输注影响乙酰胆碱水平和乙酰胆碱受体激活的药物之前和之后内嗅网格细胞的多个单单位记录。实验将测试从网格细胞的细胞机制的计算模型的预测，预测在操纵乙酰胆碱水平的网格场的准确性和间距的变化。目标2的研究将测试在一系列行为任务中海马体和内嗅皮层中网格细胞的生成和上下文相关尖峰活动的模型。实验将测试该模型的替代版本，该模型在由不同刺激重置后获得取决于速度、速度或时间的不同模式的上下文相关放电。目标3中的研究将测试电流的细胞特性，这些电流可能是内嗅皮层中网格细胞放电的基础，并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性M电流的差异是否可能是内侧内嗅皮层背腹轴上网格细胞空间频率沿着差异的基础。研究还将测试胆碱能调节对内嗅神经元的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理学操作相关的网格细胞放电变化联系起来。这些研究将加深我们对情景记忆中内嗅皮层编码空间和时间的动力学机制的理解。这项工作将提高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嗅皮层体积减少有关的抑郁症和精神分裂症等精神障碍，以及与记忆有关的神经系统疾病，如阿尔茨海默病。 公共卫生相关性：这项资助的重点是研究大脑存储生活中的事件并在其他时间检索这些事件的机制，基于神经元的相互作用群体。这项工作包括测试细胞如何编码事件的空间位置以及某些药物如何影响这些细胞编码的实验模型。这些实验和模型与可能在涉及记忆编码和检索扭曲的疾病中崩溃的大脑机制有关，包括与记忆损伤和检索记忆中的负面偏见有关的抑郁症以及涉及记忆功能损伤和扭曲的精神分裂症等疾病。

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.