Cellular mechanisms of hippocampal theta oscillations

海马θ振荡的细胞机制

• 批准号: 10371384
• 负责人: Andres Barria
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371384
• 关键词: Acetylcholine; Acute; Alzheimer' s Disease; Anatomy; Animals; Attention; Attenuated; Bathing; Behavior; Brain; Carbachol; Cell Communication; Cell model; Cell physiology; Cells; Cholinergic Receptors; Clinical Trials; Cognition; Communication; Complex; Epilepsy; Foundations; Frequencies; Fresh Tissue; Functional disorder; Goals; Hippocampus (Brain); Human; In Vitro; Learning; Mediating; Membrane; Membrane Potentials; Memory; Memory impairment; Modeling; Monkeys; Mus; Muscarinics; Neocortex; Neuromodulator; Neurons; Outcome; Periodicity; Pharmacology; Physiological; Physiology; Primates; Process; Property; Pyramidal Cells; Research; Rodent; Shapes; Slice; Stimulus; Structure; Study models; System; Testing; Translating; Washington; Work; basal forebrain; cholinergic; electric impedance; electrical property; experimental study; hippocampal pyramidal neuron; in vitro Model; information processing; memory encoding; nervous system disorder; neuronal circuitry; nonhuman primate; novel; patch clamp; response; theories; translation to humans; voltage

PROJECT SUMMARY/ABSTRACT The mammalian brain has an incredible capacity to learn and store information that can be subsequently retrieved. A key brain structure that supports cognition and the formation of new memories is the hippocampus. Damage to the hippocampus impairs memory and results in debilitating maladies like Alzheimer's disease or epilepsy. Studies in primates and rodents have provided a rich systems-level understanding of hippocampal function and its interaction with other structures like neocortex. However, models that explain hippocampus physiology at the cellular and microcircuit level exclusively come from studies in rodents. Due in part to our limited understanding of the mechanisms that govern primate cellular physiology, treatments for complex neurological diseases have fared poorly when introduced in human clinical trials. Our long-range goal is to better understand how the primate hippocampus processes information in support of memory at the cellular and microcircuit level, thus connecting cellular physiology to network function in primates. Here we propose to develop a non-human primate model that allows the study of the cellular and microcircuit physiology of the primate hippocampus. We will combine whole-cell patch clamping and pharmacology in a novel in vitro approach to delineate the mechanisms that support theta oscillations in monkeys. Theta oscillations reflect temporally coordinated network activity in the hippocampus that occurs while attending to incoming stimuli and during successful memory encoding. They are present in both rodents and primates, but this activity only sparsely occurs in primates, suggesting that there are substantial differences in the neuronal circuits of the hippocampus and the properties of its neurons across species. To understand how cellular physiology shapes the theta oscillation in primates, we will both characterize the physiological properties of principal cells in the monkey hippocampus and the effect that the critical theta neuromodulator acetylcholine has in regulating the intrinsic properties of hippocampal neurons in vitro. The proposed experiments have the following potential outcomes: 1) establish whether the cellular physiology of pyramidal neurons in the hippocampus of monkeys differ from that of rodents, 2) identify mechanisms in monkeys at the cellular level that contribute to coordinated network activity. These experiments will provide species-specific evidence for a model that may translate better to human physiology.

项目摘要/摘要 哺乳动物的大脑具有不可思议的学习和存储信息的能力 检索。支持认知和形成新记忆的关键大脑结构是 海马。海马的损害会损害记忆力并导致疾病衰弱 阿尔茨海默氏病或​​癫痫病。灵长类动物和啮齿动物的研究提供了丰富的系统级别 了解海马功能及其与新皮层等其他结构的相互作用。然而， 在细胞和微电路水平上解释海马生理学的模型仅来自 研究啮齿动物。部分原因是我们对管理灵长类动物细胞的机制有限 人类引入时，生理学，复杂神经系统疾病的治疗效果很差 临床试验。我们的远程目标是更好地了解灵长类动物海马程序如何 支持在细胞和微电路水平上的记忆的信息，从而连接细胞生理 到灵长类动物中的网络功能。在这里，我们建议开发一个非人类灵长类动物模型，以允许 灵长类动物海马的细胞和微电路生理学的研究。我们将结合全细胞 斑块夹具和药理学在一种新型的体外方法中，以描绘支持机制 猴子中的theta振荡。 theta振荡反映了暂时协调的网络活动 照顾传入刺激和成功记忆编码时发生的海马。 它们都存在于啮齿动物和灵长类动物中，但是这种活动仅在灵长类动物中出现， 表明海马和 其跨物种神经元的特性。了解细胞生理如何塑造theta 灵长类动物的振荡，我们既表征了主要细胞在 猴子海马以及关键theta神经调节剂乙酰胆碱对调节的影响 海马神经元体外的内在特性。提出的实验具有以下 潜在结果：1）确定海马锥体神经元的细胞生理学是否是 猴子与啮齿动物的不同，2）在细胞水平上确定猴子的机制 有助于协调的网络活动。这些实验将为物种特定的证据提供 一个可能更好地转化为人类生理的模型。