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

海马中间神经元在健康和阿尔茨海默病中新型记忆形成中的作用

• 批准号: 10512199
• 负责人: Annabelle Catherine Singer
• 金额: $ 151.37万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512199
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloidosis; Animals; Behavior; Cells; Cerebrum; Code; Cues; Data; Environment; Exposure to; Functional disorder; Future; Goals; Health; Hippocampus (Brain); Impairment; Interneuron function; Interneurons; Knock-in Mouse; Lead; Learning; Location; Memory; Memory impairment; Methodology; Methods; Mus; Mutation; Output; Parvalbumins; Pathology; Pattern; Performance; Pharmacological Treatment; Positioning Attribute; Process; Pyramidal Cells; Ramp; Research; Rewards; Role; Speed; Testing; Work; apolipoprotein E-4; base; cell type; excitatory neuron; experience; familial Alzheimer disease; genetic risk factor; hippocampal pyramidal neuron; hippocampal subregions; improved; in vivo; inhibitory neuron; innovation; mouse model; novel; optogenetics; relating to nervous system; spatial memory; virtual reality; way finding

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.

记住重要的精确位置是空间记忆的关键组成部分。来 在过去的几十年里，大量的前期工作表明，海马体中的兴奋性锥体细胞 各种空间相关线索的代码。海马抑制性中间神经元被认为是 在产生振荡和维持最佳水平的兴奋性活动中起重要作用，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 记忆形成过程至关重要，因为多项研究表明抑制作用存在缺陷 由于阿尔茨海默病（AD）病理学，如β淀粉样蛋白升高。以及其他类型的 抑制性中间神经元、小清蛋白阳性（PV）中间神经元对AD特别敏感 病理和直接抑制兴奋细胞。空间导航缺陷与海马 功能障碍发生在AD的早期，但海马PV抑制缺陷究竟如何有助于 受损的记忆仍然不确定。因此，迫切需要了解 海马抑制性中间神经元在形成新经验的表征中的作用， 确定这个过程是如何由于AD病理而失败的。阐明PV抑制在 记忆的形成需要因果操纵来记录和刺激细胞类型中的PV活动 具体和时间精确的方式。因此，这些研究将记录 许多抑制性和兴奋性神经元的活动同时和选择性地刺激PV 获得新的空间记忆的小鼠的中间神经元。该研究将使用闭环 光遗传学刺激特异性消除或产生特定模式的PV活性， 在健康小鼠和Aβ病理学小鼠模型中。通过这些方法，计划中的研究 将测试完整的抑制活性是正常记忆形成所必需的假设， 在Aβ病理学小鼠模型中，改变的抑制活性破坏记忆形成。这 研究将显示PV中间神经元对AD病理学的脆弱性如何导致空间神经元受损。 学习和记忆的形成。这些发现将导致新的刺激和药理学 基于恢复PV功能的AD治疗。