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留取决于一个名为的大脑区域 海马。海马收到的广泛神经调节输入中，胆碱能输入 从基础上，前脑对于学习和记忆至关重要。这些相同的输入引起的神经元减少 患有阿尔茨海默氏病的患者的衰老反应和退化。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 海马中的单个电路元素在很大程度上仍然未知。在CA 1中，主要产出 海马，乙酰胆碱受体在多种细胞类型和细胞室中表达。 到目前为止，很难确定各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 在CA1区域的锥体神经元上，内部形成和长期稳定性 生成的序列（IG），在保持感觉提示的同时生成的序列 恒定并随着动物执行记忆任务。我们将使用IG作为内存相关的代表 活动模式以揭示胆碱能活性如何调节形成和长时间漂移的形成和 在海马代码中，进而通过激活细胞型特异性乙酰胆碱来完善行为 受体。我们的实验方法是操纵胆碱能调节的强度和轨迹 CA1在成像大量的神经元中，在醒着的头部固定小鼠中进行 海马依赖的内存任务。具体而言，我们将选择性调制CA1锥体 具有细胞型特异性神经药物工具的神经元。将计算建模与 实验的发现，我们将阐明负责的可塑性和网络机制 观察到的神经元动力学。通过结合实验和计算方法来阐明 在整个细胞，电路和电路上对可塑性的胆碱能控制和稳定性的胆碱能控制 行为水平，我们将对胆碱能信号破坏的影响有新颖的见解。 我们的结果可能表明可以更改哪些生理参数以补偿 胆碱能信号，并导致为记忆障碍的新治疗选择开发。