CRCNS: Role of mAChRs on CA 1 pyramidal neurons in memory formation and stability

CRCNS：mAChR 对 CA 1 锥体神经元在记忆形成和稳定性中的作用

• 批准号: 10831251
• 负责人: Yingxue Wang
• 金额: $ 34.72万
• 依托单位: MAX PLANCK FLORIDA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10831251
• 关键词: Acetylcholine; Address; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Animals; Arousal; Attention; Behavior; Behavioral; Brain region; Cells; Choline; Cholinergic Receptors; Code; Compensation; Computer Models; Cues; Data; Dementia; Dendrites; Deterioration; Development; Disease; Disease Progression; Elements; Environment; Episodic memory; Event; Head; Health; Hippocampus; Image; In Vitro; Individual; Learning; Locomotion; Mediating; Memory; Memory Disorders; Memory impairment; Molecular; Motivation; Mus; Muscarinic Acetylcholine Receptor; Muscarinics; Nature; Neurodegenerative Disorders; Neurons; Neuropharmacology; Outcome; Output; Pattern; Physiological; Play; Population; Rodent; Role; Sensory; Shapes; Signal Transduction; Specificity; Synapses; Synaptic plasticity; Task Performances; Theoretical model; Training; Visit; attentional modulation; awake; basal forebrain; cell type; cholinergic; design; experience; experimental study; hippocampal pyramidal neuron; in vivo; in vivo two-photon imaging; insight; member; memory process; memory retention; nerve supply; neuronal excitability; neuroregulation; novel; receptor; response; spatial memory; tool

The formation and retention of memories of our daily experiences depend on a brain region called the hippocampus. Among the extensive neuromodulatory inputs the hippocampus receives, cholinergic inputs from the basal forebrain are crucial for learning and memory. These same inputs elicit reduced neuronal response with aging, and degenerate in patients suffering from Alzheimer's disease. Despite its critical role in memory formation and stability, how cholinergic modulation mediates memory functions through individual circuit elements in the hippocampus remains largely unknown. In CA 1, the major output of the hippocampus, acetylcholine receptors are expressed in multiple cell types and cellular compartments. Until now, it has been difficult to determine the contribution of individual elements to the overall network effects of acetylcholine. In this project, we will study the role of muscarinic cholinergic receptors located on the pyramidal neurons of the CA1 region in the formation and long-term stability of Internally Generated Sequences (IGS), the sequences generated during locomotion while sensory cues are held constant and as animals perform memory tasks. We will use IGS as a representative of memory-related activity patterns to reveal how cholinergic activity modulates the formation of and the long timescale drift in the hippocampal code and in turn refines the behavior by activating cell-type-specific acetylcholine receptors. Our experimental approach is to manipulate the strength and locus of cholinergic modulation in CA1 while imaging large numbers of neurons in awake head-fixed mice engaged in a hippocampus-dependent memory task. Specifically, we will selectively modulate the CA1 pyramidal neurons with cell-type specific neuropharmacological tools. Integrating computational modeling with findings from experiments, we will elucidate possible plasticity and network mechanisms responsible for the observed neuronal dynamics. By combining experimental and computational approaches to elucidate the cholinergic control of plasticity over memory formation and stability across the cellular, circuit, and behavioral levels, we will contribute novel insights into the effects of a disruption in cholinergic signaling. Our results may indicate which physiological parameters could be altered to compensate for the loss of cholinergic signals, and lead to the development of new treatment options for memory disorders.

我们日常经验的记忆的形成和保持依赖于大脑中一个叫做 海马体。在海马体接受的广泛的神经调节输入中，胆碱能输入 对于学习和记忆来说是至关重要的。这些相同的输入导致神经元减少 随着年龄的增长，阿尔茨海默病患者会出现退化。尽管它很关键 在记忆形成和稳定性中的作用，胆碱能调节如何通过 海马体中的个别电路元件在很大程度上仍不清楚。在CA1中，主要输出是 在海马区，乙酰胆碱受体表达于多种细胞类型和细胞室。 到目前为止，很难确定单个元素对整个网络的贡献 乙酰胆碱的作用。在这个项目中，我们将研究定位于M胆碱能受体的作用。 大鼠脑内CA1区锥体神经元的形成及其长期稳定性 生成序列(IGS)，即在保持感觉线索的情况下在移动过程中生成的序列 恒定的，当动物执行记忆任务时。我们将使用IGS作为内存相关的代表 揭示胆碱能活动如何调节长时间尺度漂移的形成的活动模式 并通过激活特定细胞类型的乙酰胆碱来改善行为 感受器。我们的实验方法是操纵胆碱能调节的强度和轨迹。 CA1在对清醒的头部固定小鼠的大量神经元进行成像时进行 依赖海马体的记忆任务。具体地说，我们将选择性地调制CA1锥体 具有细胞类型特定神经药理工具的神经元。将计算建模与 实验结果，我们将阐明可能的可塑性和网络机制负责 观察到的神经元动力学。通过结合实验和计算方法来阐明 胆碱能对记忆形成和稳定性的可塑性控制跨越细胞、回路和 在行为水平上，我们将为胆碱能信号中断的影响提供新的见解。 我们的结果可能表明哪些生理参数可以被改变来补偿 胆碱能信号，并导致开发新的记忆障碍治疗方案。