Hippocampal interneurons in novel memory formation in health and Alzheimer's disease

记住重要的准确位置是空间记忆的一个重要组成部分。超过了 在过去的几十年里，大量的前期工作表明，海马区的兴奋性锥体细胞 各种空间相关线索的代码。海马区抑制性中间神经元已被认为是 在产生振荡和维持最佳兴奋性活动水平方面发挥重要作用，但 它们在空间记忆形成中的作用尚不清楚。了解中间神经元在脑内的作用 记忆的形成过程是至关重要的，因为一些研究已经揭示了抑制的缺陷 由于阿尔茨海默病(AD)的病理，如淀粉样β蛋白升高。在其他类型的 抑制性中间神经元、小白蛋白阳性中间神经元尤其易患AD 病理和直接抑制兴奋性细胞。空间导航障碍与海马区 功能障碍发生在AD的早期，但海马神经元PV抑制缺陷到底是如何参与 记忆力受损仍不确定。因此，有一种迫切的、尚未得到满足的需要，即理解这一角色 海马区抑制性中间神经元在形成新经验表征中的作用 确定此过程如何因AD病理而失败。阐明PV抑制在血管紧张素转换酶中的作用 记忆的形成需要因果操作来记录和刺激细胞类型中的PV活动 具体的和在时间上精确的方式。因此，这些研究将记录电信号 许多抑制性和兴奋性神经元的活动同时选择性地刺激PV 小鼠获得新的空间记忆的中间神经元。拟议的研究将使用闭环系统 光遗传刺激，以具体取消或产生特定模式的光伏活动 在健康的小鼠和β病理的小鼠模型中。有了这些方法，计划中的研究 将检验一个假设，即完整的抑制活性是正常记忆形成所必需的 抑制活性的改变扰乱了Aβ病理模型小鼠的记忆形成。这 研究将显示PV中间神经元对AD病理的脆弱性如何导致空间受损 学习和记忆的形成。这些发现将带来新的刺激和药理作用 以恢复PV功能为基础治疗AD。

Remembering precise locations of importance is a key component of spatial memory. Over the past few decades, extensive prior work has shown that excitatory pyramidal cells in hippocampus code for various spatially relevant cues. Hippocampal inhibitory interneurons have been ascribed important roles in generating oscillations and maintaining optimal levels of excitatory activity, but their role in spatial memory formation is unclear. Understanding the role of interneurons in memory formation processes is crucial because several studies have revealed deficits in inhibition due to Alzheimer’s disease (AD) pathology such as elevated amyloid beta. Among other types of inhibitory interneurons, parvalbumin-positive (PV) interneurons are especially susceptible to AD pathology and directly inhibit excitatory cells. Spatial navigation deficits and hippocampal dysfunction occur early in AD but exactly how hippocampal PV inhibitory deficits contribute to impaired memory remains uncertain. Thus, there is an urgent unmet need to understand the role of hippocampal inhibitory interneurons in forming representations of new experiences and to determine how this process fails due to AD pathology. Elucidating the role of PV inhibition in memory formation requires causal manipulations to record and stimulate PV activity in a cell-type specific and temporally precise manner. Accordingly, these studies will record the electrical activity of many inhibitory and excitatory neurons simultaneously and selectively stimulate PV interneurons in mice acquiring novel spatial memory. The proposed research will use closed-loop optogenetic stimulation to specifically abolish or generate particular patterns of PV activity in healthy mice and in mouse models of Aβ pathology. With these approaches, the planned studies will test the hypothesis that intact inhibitory activity is necessary for normal memory formation and altered inhibitory activity disrupts memory formation in mouse models of Aβ pathology. This research will show how vulnerability of PV interneurons to AD pathology leads to impaired spatial learning and memory formation. These findings will lead to new stimulation and pharmacological treatments for AD based on restoring PV function.