Age-associated changes in hippocampal circuits and cognitive function

海马回路和认知功能与年龄相关的变化

• 批准号: 9888294
• 负责人: ANDREW Porter MAURER
• 金额: $ 38.07万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888294
• 关键词: Accounting; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Animals; Behavior; Behavioral; Biological; Brain region; Cognition; Communication; Coupling; Data; Deafferentation procedure; Disease; Elderly; Electrodes; Exhibits; Fiber; Foundations; Functional disorder; Goals; Hippocampus (Brain); Impaired cognition; Impairment; Individual; Interneurons; Intervention; Knowledge; Lesion; Link; Longevity; Maps; Measures; Medial; Memory; Memory Loss; Memory impairment; Mission; Modeling; Monitor; Neurobiology; Neurodegenerative Disorders; Neurons; Output; Pattern; Perforant Pathway; Performance; Positioning Attribute; Process; Property; Public Health; Pyramidal Cells; Quality of life; Rattus; Recurrence; Research; Role; Series; Synapses; System; Techniques; Temporal Lobe; Testing; Translating; Work; age related; aged; aging hippocampus; cognitive function; cognitive performance; density; dentate gyrus; design; entorhinal cortex; experience; experimental study; healthspan; hippocampal pyramidal neuron; hippocampal subregions; improved; innovation; juvenile animal; neuronal excitability; neurophysiology; normal aging; senescence; synaptic function; therapeutic development; therapy development; treatment strategy

Over the past century, we have witnessed remarkable increases in the average life span. Unfortunately, increased longevity is not matched by the typical health span, and most elderly individuals will experience memory decline that interferes with their quality of life and ability to maintain independence. The hippocampus is critical for memory and is one of the brain regions vulnerable in advanced age and Alzheimer’s disease. Because onset of Alzheimer’s disease is generally after the age of 65, the biological foundations of this neurodegenerative disorder are compounded by normal age-associated declines that we do not fully understand. In fact, alterations in the hippocampal circuit with old age could either reflect synaptic senescence or adaptive plasticity compensating to normalize output. Unfortunately, we have insufficient information to distinguish between these two competing hypotheses that would lend to distinct treatment strategies. The long-term goal of the proposed research is to determine the alterations in hippocampal subregion interactions that underlie cognitive dysfunction. The primary objective of the current proposal is to determine how altered communication within the hippocampal circuit in old age produces memory deficits. Linking neurobiology directly to behavior, will allow us to determine if synaptic alterations are adaptive or the underlying cause of dysfunction. We will attain this by testing the central hypothesis that altered communication between CA3 and CA1 results from a deafferentation of the hippocampus from the entorhinal cortical (ERC), which leads to CA3 hyperexcitability. Old animals that maintain high performance, adapt to the loss of ERC input by weakening the CA3 to CA1 Schaffer collateral synapse to impede the propagation of aberrant activity. In contrast, aged animals will impairments show enhanced CA3-CA1 coupling. This hypothesis will be tested with the following specific aims: 1) Determine how CA3-CA1 neuron spike timing contributes to memory decline in old animals, 2) Determine the role of perforant path loss in intrinsic hippocampal dysfunction, and 3) Determine how changes in medial temporal lobe synchrony in old age map onto memory dysfunction. The rationale is that by elucidating how aging and disease influence systems-level dynamics, we will be better positioned to develop interventions that broadly improve cognition. The proposed research is innovative, in our opinion, as neurophysiological techniques will be integrated with measures of behavior in young and aged rats in order to probe how local dysfunction manifests as network impairments or incites compensatory processes. The significance of the successful completion of this work will be to determine how distinct types of cellular dysfunction alter global circuit properties in order to identify and exploit network mechanisms to ultimately improve cognition.

在过去的世纪里，我们目睹了平均寿命的显著增长。不幸的是， 增加的寿命与典型的健康寿命不匹配，大多数老年人将经历 记忆力下降，影响他们的生活质量和保持独立的能力。海马 对记忆力至关重要，是老年人和阿尔茨海默病患者大脑中易受伤害的区域之一。 由于阿尔茨海默病的发病年龄一般在65岁以后，因此其生物学基础 神经退行性疾病是由正常的年龄相关的下降，我们不完全 明白事实上，海马回路随着年龄的增长而发生的变化， 衰老或适应性可塑性补偿正常输出。不幸的是，我们没有足够的 信息来区分这两个相互竞争的假设，这将有助于不同的治疗 战略布局这项研究的长期目标是确定海马神经元的改变， 认知功能障碍的亚区域相互作用。本提案的主要目标是 确定老年时海马回路内改变的通信如何导致记忆缺陷。 将神经生物学与行为直接联系起来，将使我们能够确定突触的改变是适应性的还是非适应性的。 功能障碍的根本原因我们将通过测试改变了的中心假设来实现这一点。 CA 3和CA 1之间的通讯是由海马体从内嗅神经传入神经阻滞引起的。 皮质（ERC），导致CA 3过度兴奋。保持高性能的老年动物，适应 通过削弱CA 3到CA 1的Schaffer侧支突触来阻止ERC输入的传播， 异常活动相比之下，老年动物将显示增强的CA 3-CA 1偶联损伤。这 将以以下具体目标来检验假设：1）确定CA 3-CA 1神经元发放时间 导致老年动物记忆力下降，2）确定穿透性路径损失在固有的 海马功能障碍，以及3）确定中颞叶同步性在老年地图中的变化 记忆功能障碍基本原理是，通过阐明衰老和疾病如何影响系统水平， 动态，我们将更好地开发广泛改善认知的干预措施。拟议 在我们看来，研究是创新的，因为神经生理学技术将与 行为，以探讨局部功能障碍如何表现为网络损伤或 刺激补偿过程。这项工作顺利完成的意义将是确定 不同类型的细胞功能障碍如何改变全局电路特性，以识别和利用网络 最终改善认知的机制。