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: 7473909
• 负责人: JENNIFER I LUEBKE
• 金额: $ 28.55万
• 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/7473909
• 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，但在大部分人类和非人类灵长类动物中，工作记忆会随着正常衰老而受到显着损害。虽然众所周知，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，但与年龄相关的 PFC 功能下降的具体神经基质尚不清楚。鉴于我们的人口老龄化，这是一个高度相关的问题，将通过拟议的研究以创新的方式直接解决，该研究采用了独特的实验模型 - 行为特征恒河猴。工作记忆任务期间的信息通过 PFC 中第 3 层锥体细胞的动作电位 (AP) 放电率以时间动态和特定的方式进行编码。初步研究表明，在体外，这些细胞的放电率与年龄相关，放电率显着增加，并且它们的放电率与认知表现显着相关。该提案的总体目标是在单个第 3 层锥体细胞内全面、同时检查相关细胞特性（离子电流、突触反应、形态）中与年龄相关的变化，这可能有助于功能上显着的放电率变化。老年和年轻的恒河猴将接受一系列认知任务的评估，从而确定认知障碍的程度。由这些猴子制备的 PFC 切片中的全细胞膜片钳记录和第 3 层锥体细胞的荧光黄 (LY) 填充将用于三个高度集成的特定目标。在目标 1 中，将通过电流钳记录评估内在膜和 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，将用于测试特定假设，即这些电流特性的与年龄相关的变化会导致放电增加费率。在目标 2 中，电压钳记录将评估这些细胞中谷氨酸能和 GABA 能突触后电流与年龄相关的变化，测试突触传递变化与信号改变相关的具体假设。 Aim 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与年龄相关的变化，检验形态结构的变化是这些细胞信号传导特性变化的基础的具体假设。每个目标的数据都将相互关联，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提供关于正常衰老对单个神经元内不同但相互关联的细胞特性的影响的独特信息，这些神经元在工作记忆任务的执行中发挥着关键作用。这些信息对于详细了解认知衰退的细胞机制至关重要，也是未来开发治疗干预措施的先决条件。