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）：工作记忆对于诸如抽象思维，解决问题和认知灵活性等能力至关重要，正常老化在很大一部分的人类和非人类灵长类动物中都会显着损害。尽管众所周知，这些能力在很大程度上是由前额叶皮层（PFC）的锥体细胞介导的，但尚不清楚与年龄相关的特定神经底物的特定神经底物。鉴于我们的老龄化人群，这是一个高度相关的问题，该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 - 行为表征的恒河猴。在工作记忆任务期间的信息是通过PFC中第3层锥体细胞的动作电位（AP）发射速率以时间动态和特定方式编码的。初步研究表明，这些细胞在体外的发射率显着增加，其发射速率与认知性能显着相关。该提案的总体目标是在单个第3层锥体细胞中进行全面和同时研究相互关联的细胞性质（离子电流，突触反应，形态学）的年龄相关变化，这可能在功能上有助于发射速率的功能重大变化。老年和年轻的恒河猴将在一系列认知任务上进行评估，从而确定认知障碍的程度。然后将使用这些猴子制备的PFC切片中的3层锥体细胞的全细胞斑块钳记录和Lucifer黄色（LY）填充，然后将用于三个高度集成的特定目的。在AIM 1中，将通过电流夹记录来评估固有的膜和AP射击特性；随后，将使用影响AP放电时间模式的电流的电压分析（LC，IAHP，SIAHP和LH），以测试特定的假设，即这些电流的年龄变化这些电流的变化会导致发射率提高。在AIM 2中，电压钳记录将评估这些细胞中与年龄相关的谷氨酸能和GABA能的突触后电流的变化，从而检验了特定假设，即突触传播的变化与信号传导有关。 AIM 3实验将探索与年龄相关的详细树突结构的变化和液体3层锥体细胞的树突状刺，检验了以下特定假设：这些细胞信号传导特性的变化是这些细胞的形态结构变化的变化。这些目标中每个目标的数据将互为相关，并且与老年猴子群体内的认知性能得分相关。这种多方面的方法将提供有关正常衰老对各个神经元内不同但相互关联的细胞特性影响的独特信息，这些信息在执行工作记忆任务中起着至关重要的作用。此类信息对于对认知能力下降的细胞机制的详细理解以及治疗干预措施未来发展的先决条件至关重要。