Cellular mechanisms of hippocampal theta oscillations

海马θ振荡的细胞机制

• 批准号: 10668962
• 负责人: Andres Barria
• 金额: $ 23.33万
• 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/10668962
• 关键词: Acetylcholine; Acute; Alzheimer' s Disease; Anatomy; Animals; Attenuated; Bathing; Behavior; Brain; Carbachol; Cell Communication; Cell model; Cell physiology; Cells; Cholinergic Receptors; Clinical Trials; Cognition; Communication; Complex; Disparity; Epilepsy; Frequencies; Fresh Tissue; Functional disorder; Goals; Hippocampus; Human; In Vitro; Learning; Mediating; Membrane; Membrane Potentials; Memory; Memory impairment; Modeling; Monkeys; Mus; Muscarinic Antagonists; 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; neocortical; nervous system disorder; neuronal circuitry; nonhuman primate; novel; patch clamp; pharmacologic; 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.

项目概要/摘要 哺乳动物的大脑具有令人难以置信的学习和存储信息的能力，这些信息可以随后被利用 检索到。支持认知和新记忆形成的关键大脑结构是 海马体。海马体受损会损害记忆力并导致衰弱的疾病，例如 阿尔茨海默病或癫痫症。对灵长类动物和啮齿类动物的研究提供了丰富的系统水平 了解海马功能及其与新皮质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体生理学的模型完全来自 对啮齿动物的研究。部分原因是我们对灵长类动物细胞控制机制的了解有限 从生理学角度来看，复杂神经系统疾病的治疗方法在引入人类时效果不佳 临床试验。我们的长期目标是更好地了解灵长类海马体的处理方式 在细胞和微电路层面支持记忆的信息，从而连接细胞生理学 灵长类动物的网络功能。在这里，我们建议开发一种非人类灵长类动物模型，允许 研究灵长类海马的细胞和微电路生理学。我们将结合全细胞 膜片钳和药理学在一种新颖的体外方法中描述支持机制 猴子的θ振荡。 Theta 振荡反映了时间协调的网络活动 海马体在注意传入刺激和成功记忆编码期间发生。 它们存在于啮齿类动物和灵长类动物中，但这种活性仅很少发生在灵长类动物中， 表明海马体和大脑的神经元回路存在显着差异 其神经元在不同物种中的特性。了解细胞生理学如何塑造 theta 灵长类动物的振荡，我们都将表征主细胞的生理特性 猴海马及关键θ神经调节剂乙酰胆碱的调节作用 体外海马神经元的内在特性。建议的实验有以下内容 潜在结果：1）确定海马锥体神经元的细胞生理学是否 猴子与啮齿动物的不同，2）在细胞水平上确定猴子的机制 有助于协调网络活动。这些实验将提供物种特异性的证据 一个可以更好地转化为人类生理学的模型。