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.

我们日常经历的记忆的形成和保持取决于大脑中一个叫做 海马体。在海马接受的广泛的神经调节输入中，胆碱能输入 对学习和记忆至关重要这些相同的输入引起减少的神经元 随着年龄的增长，和退化的患者患有阿尔茨海默氏病。尽管其关键 在记忆形成和稳定中的作用，胆碱能调节如何通过 海马体中的单个电路元件在很大程度上仍然未知。在CA 1中， 在海马中，乙酰胆碱受体在多种细胞类型和细胞区室中表达。 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，我们将研究毒蕈碱胆碱能受体的作用， 对CA1区锥体神经元的形成和长期稳定性的影响 生成序列（IGS），在运动过程中产生的序列，同时保持感官线索 恒定和动物执行记忆任务。我们将使用IGS作为内存相关的代表 活动模式，以揭示胆碱能活动如何调节的形成和长时间尺度漂移 并通过激活细胞类型特异性乙酰胆碱来改善行为 受体。我们的实验方法是操纵胆碱能调节的强度和位点， CA1在对清醒的头部固定小鼠的大量神经元进行成像时， 校园记忆任务。具体来说，我们将选择性地调节CA1锥体 神经元与细胞类型特异性神经药理学工具。将计算建模与 从实验结果，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的控制贯穿细胞、回路和神经系统。 行为水平，我们将贡献新的见解胆碱能信号中断的影响。 我们的研究结果可能表明哪些生理参数可以改变，以弥补损失的 胆碱能信号，并导致记忆障碍的新的治疗选择的发展。