Cellular mechanisms of hippocampal theta oscillations

项目总结/摘要 哺乳动物的大脑具有惊人的学习和存储信息的能力， 找回了支持认知和新记忆形成的一个关键大脑结构是 海马体。海马体的损伤会损害记忆力，导致衰弱性疾病， 老年痴呆症或癫痫。对灵长类和啮齿类动物的研究提供了丰富的系统水平 了解海马的功能及其与新皮层等其他结构的相互作用。然而，在这方面， 在细胞和微回路水平上解释海马体生理学的模型仅来自 啮齿动物的研究。部分原因是我们对灵长类动物细胞的控制机制了解有限， 在生理学上，复杂神经系统疾病的治疗在引入人类时表现不佳 临床试验我们的长期目标是更好地了解灵长类动物的海马体是如何处理 在细胞和微电路水平上支持记忆的信息，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灵长类动物模型， 研究灵长类动物海马的细胞和微电路生理学。我们将联合收割机 膜片钳和药理学在一种新的体外方法，以描绘机制，支持 猴子的θ振荡Theta振荡反映了时间上协调的网络活动， 海马体在注意输入刺激和成功的记忆编码过程中出现。 它们存在于啮齿动物和灵长类动物中，但这种活动只在灵长类动物中很少发生， 这表明海马体和大脑皮层的神经元回路存在实质性差异。 不同物种的神经元特性。为了了解细胞生理学如何塑造θ 振荡在灵长类动物中，我们将同时表征主细胞的生理特性， 以及关键的θ神经调质乙酰胆碱在调节 海马神经元的内在特性。所提出的实验具有以下内容 潜在的结果：1）确定海马锥体神经元的细胞生理学是否 2）确定猴子在细胞水平上的机制， 有助于协调网络活动。这些实验将提供物种特异性证据， 一个可以更好地转化为人类生理学的模型。

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.