AGE-RELATED CHANGES IN MONKEY CORTICAL PYRAMIDAL CELLS

猴皮质锥体细胞与年龄相关的变化

• 批准号: 7265253
• 负责人: JENNIFER I LUEBKE
• 金额: $ 29.13万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7265253
• 关键词: 3-Dimensional; Action Potentials; Address; Agaricales; Age; Architecture; Cell Aging; Cells; Characteristics; Cognitive; Computer software; Data; Dendritic Spines; Dependence; Development; Exhibits; Experimental Models; Fire - disasters; Frequencies; Future; Glutamates; Goals; Human; Impaired cognition; In Vitro; Individual; Kinetics; Laser Scanning Microscopy; Lead; Macaca mulatta; Manuals; Mediating; Membrane; Memory; Monkeys; Morphology; Neurobiology; Neurons; Numbers; Pattern; Performance; Physiology; Play; Pliability; Prefrontal Cortex; Problem Solving; Property; Pyramidal Cells; Rate; Research Personnel; Role; Score; Short-Term Memory; Signal Transduction; Slice; Structure; Synapses; Synaptic Transmission; System; Techniques; Testing; Therapeutic Intervention; Thinking; abstracting; age effect; age group; age related; aged; aging population; base; cell age; density; design; innovation; lucifer yellow; morphometry; nonhuman primate; normal aging; patch clamp; postsynaptic; relating to nervous system; research study; response; voltage; voltage clamp

DESCRIPTION (provided by applicant): Working memory, which is essential for abilities such as abstract thinking, problem solving, and cognitive flexibility, is significantly impaired with normal aging in a large proportion of humans and non-human primates. While it is known that these abilities are mediated in large part by pyramidal cells of the prefrontal cortex (PFC), the specific neural substrates of age-related decline in PFC function are not known. Given our aging population, this is a highly relevant question that will be directly addressed in an innovative manner by the proposed studies, which employ a unique experimental model- the behaviorally characterized rhesus monkey. Information during working memory tasks is encoded in a temporally dynamic and specific manner by the action potential (AP) firing rates of layer 3 pyramidal cells in the PFC. Preliminary studies demonstrate that there is a significant age-related increase in the firing rates of these cells in vitro, and their firing rates are significantly associated with cognitive performance. The overall goal of this proposal is to comprehensively and simultaneously examine, within individual layer 3 pyramidal cells, age-related alterations in interrelated cellular properties (ionic currents, synaptic responses, morphology), which likely contribute to functionally significant alterations in firing rate. Aged and young rhesus monkeys will be assessed on a battery of cognitive tasks, enabling determination of degree of cognitive impairment. Whole-cell patch-clamp recordings and Lucifer Yellow (LY) filling of layer 3 pyramidal cells in PFC slices prepared from these monkeys will then be employed in three highly integrated Specific Aims. In Aim 1, intrinsic membrane and AP firing properties will be assessed with current-clamp recordings; subsequently, voltage-clamp analyses of currents that influence the temporal pattern of AP firing, (lc, IAHP, sIAHP and lh), will be used to test the specific hypothesis that age-related changes in the properties of these currents lead to increased firing rates. In Aim 2, voltage-clamp recordings will assess age-related changes in glutamatergic and GABAergic postsynaptic currents in these cells, testing the specific hypothesis that changes in synaptic transmission are related to altered signaling. Aim 3 experiments will explore age-related changes in the detailed dendritic architecture and dendritic spines of LY-filled layer 3 pyramidal cells, testing the specific hypothesis that alterations in morphological structure underlie changes in the signaling properties of these cells. Data from each of these aims will be cross correlated and also correlated with cognitive performance scores within the aged group of monkeys. This multi-faceted approach will provide unique information on the effects of normal aging on diverse but interrelated cellular properties within individual neurons that play a critical role in the execution of working memory tasks. Such information is vital to the development of a detailed understanding of the cellular mechanisms of cognitive decline, and a prerequisite for the future development of therapeutic interventions.

描述（由申请人提供）：工作记忆对于抽象思维、解决问题和认知灵活性等能力至关重要，随着正常年龄的增长，大部分人类和非人类灵长类动物的工作记忆明显受损。虽然已知这些能力在很大程度上是由前额皮质（PFC）的锥体细胞介导的，但PFC功能与年龄相关的衰退的特定神经基质尚不清楚。考虑到我们的人口老龄化，这是一个高度相关的问题，将通过拟议的研究以一种创新的方式直接解决，该研究采用了一种独特的实验模型-具有行为特征的恒河猴。工作记忆任务中的信息是由pfc第3层锥体细胞的动作电位（AP）放电率以一种时间动态和特定的方式编码的。初步研究表明，这些细胞的放电率在体外有明显的年龄相关性，并且它们的放电率与认知表现显著相关。本提案的总体目标是全面和同时检查单个第3层锥体细胞中相关细胞特性（离子电流，突触反应，形态学）中与年龄相关的变化，这些变化可能导致放电率的功能显著改变。老年和年轻的恒河猴将在一系列认知任务中进行评估，从而确定认知障碍的程度。全细胞膜片钳记录和Lucifer Yellow （LY）填充从这些猴子制备的PFC切片中的第3层锥体细胞，然后将用于三个高度整合的特定目的。在Aim 1中，将使用电流钳记录评估固有膜和AP发射特性；随后，对影响AP放电时间模式的电流（lc， IAHP， sIAHP和lh）进行电压钳分析，将用于验证这些电流特性的年龄相关变化导致放电率增加的特定假设。在Aim 2中，电压钳记录将评估这些细胞中谷氨酸能和氨基丁酸能突触后电流的年龄相关变化，验证突触传递变化与信号改变有关的特定假设。目的3实验将探索ly填充的第3层锥体细胞的详细树突结构和树突棘的年龄相关变化，验证形态结构改变是这些细胞信号特性变化的基础这一特定假设。来自这些目标的数据将相互关联，也与老年猴子组的认知表现得分相关。这种多方面的方法将为正常衰老对个体神经元中多种但相互关联的细胞特性的影响提供独特的信息，这些神经元在工作记忆任务的执行中起着关键作用。这些信息对于详细了解认知衰退的细胞机制至关重要，也是未来治疗干预发展的先决条件。