Neuromodulation and Cortical Memory Function

描述(由申请人提供)：这项竞争性的延续申请侧重于了解在每个周期的theta节奏的不同阶段的生理特性的变化如何在记忆引导行为所必需的功能动力学中发挥作用。生理学实验将测试来自海马结构神经元的详细网络模拟的假设，这些网络模拟指导虚拟大鼠在虚拟环境中执行记忆引导的行为任务的运动。这些模型复制了清醒行为动物的电生理记录，包括来自电流源密度分析的数据，以及显示theta相位进动和“分裂细胞”等现象的单位记录数据。我们将测试两个关于记忆引导行为如何通过theta节奏的特定特征来增强的具体假设： 假设1：在theta节律过程中，LTP和突触输入的变化在海马环路中提供了编码和检索的不同阶段。 假设2：突触输入的阶段性计时为记忆引导行为提供了最有效的情景提取。 这些假设的测试包括：测量暴露在新环境中的单位相对于theta节律的时序；在延迟匹配样本任务的执行过程中测量前额皮质和海马区相对于theta节律的单位时序；在不同路径长度的延迟空间交替中测量单位相对于theta节律的活动；在线性轨迹中测试随机探索和单侧奖赏的单位活动；测试定向投射到腔隙单层的层中神经元激活介导的突触传递调制的时程(S i-m)，以及测试S i-m的mGluR传递的时程。了解这些机制可能有助于开发阿尔茨海默病的药物治疗方法。

DESCRIPTION (provided by applicant): This competing continuation application focuses on understanding how changes in physiological properties at different phases of each cycle of the theta rhythm play a role in the functional dynamics necessary for memory guided behavior. Physiological experiments will test hypotheses from detailed network simulations of neurons in the hippocampal formation, which guide the movements of a virtual rat in a virtual environment performing memory-guided behavioral tasks. These models replicate electrophysiological recordings from awake behaving animals, including data from current source density analysis, and unit recording data showing phenomena such as theta phase precession and "splitter cells". We will test two specific hypotheses about how memory-guided behavior is enhanced by specific features of theta rhythm: Hypothesis #1. Changes in LTP and synaptic input during theta rhythm provide separate phases of encoding and retrieval in hippocampal circuits. Hypothesis #2. Phasic timing of synaptic input provides the most effective episodic retrieval for memory-guided behavior. Tests of these hypotheses include measuring timing of units relative to theta rhythm during exposure to a novel environment, measuring theta phase reset and spike timing relative to theta rhythm in prefrontal cortex and hippocampus during performance of a delayed match to sample task, testing unit activity relative to theta rhythm during delayed spatial alternation with different path lengths, testing unit activity during random exploration and single sided reward in a linear track, testing time course of modulation of synaptic transmission mediated by activation of interneurons in stratum oriens projecting to stratum lacunosummolecutare (s. I-m), and testing time course of mGluR modulation of transmission in s. I-m. Understanding these mechanisms may assist in development of pharmacological treatments for Alzheimer's disease.