Aging, Serotonin and Reversal Learning

描述(申请人提供)：正常衰老和阿尔茨海默病的特点是学习新信息的能力严重不足，同时抑制使用以前相关的信息。越来越多的证据表明，当条件需要改变策略时，神经递质5-羟色胺(5-HT)可能会使学习成为可能。最近的发现表明，激活5-HT4受体可能会改善认知，并产生神经保护作用。这项建议的长期目标是确定当条件要求改变年轻成年和老年大鼠的反应模式时，选择性5-HT4激动剂的治疗是否能改善学习。以前缓解衰老和阿尔茨海默病认知缺陷的尝试都集中在直接改变大脑胆碱能系统上。这种方法收效甚微。最近有证据表明，5-HT4激动剂治疗可以改善记忆，然而，当条件需要改变策略时，激活5-HT4受体是否会增强学习能力尚不清楚。一项研究将考察在年轻成年和老年大鼠中使用选择性5-羟色胺4激动剂RS 67333是否会影响在两个选择的地点辨别中的反转学习。老年人和阿尔茨海默病患者有时只在难度增加的情况下才表现出认知缺陷。第二个实验将确定年轻成年大鼠和老年大鼠服用RS 67333是否会影响在四个选择的地点辨别中的反向学习。因为这项任务中的两个选项是分心选项，所以这项研究将能够确定干扰的增加是否可能导致可能的年龄相关损伤，以及5-HT4受体的激活是否可以减少这种缺陷。众所周知，大脑5-HT4受体的激活会影响乙酰胆碱的释放。第三个实验将确定RS 67333是否同时增强纹状体乙酰胆碱的输出和逆转学习。这些初步实验将对开发更广泛的研究计划至关重要，以了解特定大脑回路中的神经化学机制发生了什么变化，从而导致衰老过程中的认知灵活性缺陷。总体而言，拟议研究的结果将为认知灵活性可能与年龄相关的缺陷的潜在过程提供新的重要信息，以及激活5-HT4受体是否可能在缓解认知灵活性损伤方面有效。正常衰老和阿尔茨海默病的特点是学习障碍和转换策略的能力。该项目的主要目标是确定激活5-羟色胺4受体是否可以缓解衰老过程中的学习障碍。这些研究有可能为衰老和阿尔茨海默病中观察到的学习和记忆缺陷开发一种新的治疗方法。

DESCRIPTION (provided by applicant): Normal aging and Alzheimer's disease are characterized by severe deficits in the ability to learn new information while inhibiting the use of previously relevant information. There is accumulating evidence that the neurotransmitter, serotonin (5-HT) may enable learning when conditions require a shift in strategies. More recent findings suggest that activation of 5-HT4 receptors, in particular, may improve cognition, as well as produce neuroprotection. The long-term objective of this proposal is to determine whether treatment with a selective, 5-HT4 agonist improves learning when conditions demand a shift in response patterns in young adult and aged rats. Previous attempts to alleviate cognitive deficits in aging and Alzheimer's disease have focused on directly altering the brain cholinergic system. This approach has had limited success. There is recent evidence that 5-HT4 agonist treatment may improve memory, however, unknown is whether activation of 5-HT4 receptors enhances learning when conditions require a shift in strategies. One study will examine whether administration of the selective 5-HT4 agonist, RS 67333, in young adult and aged rats affects reversal learning in a two-choice place discrimination. Aged individuals and those with Alzheimer's disease sometimes only manifest cognitive deficits under conditions that have an increased level of difficulty. A second experiment will determine whether administration of RS 67333 in young adult and aged rats affects reversal learning in a four-choice place discrimination. Because two of the choices in this task act as distracter choices this study will be able to determine whether increases in interference may contribute to possible age-related impairments and whether activation of 5-HT4 receptors may reduce this deficit. Activation of brain 5-HT4 receptors is known to affect acetylcholine release. A third experiment will determine whether RS 67333 concomitantly enhances striatal acetylcholine output and reversal learning. These initial experiments will be essential in developing a broader research program to understand what neurochemical mechanisms in specific brain circuitry is altered that leads to cognitive flexiblity deficits in aging. Overall, the findings from the proposed studies will provide new and significant information on the processes underlying possible age-related deficits in cognitive flexibility and whether activation of 5-HT4 receptors may be effective in alleviating cognitive flexibility impairments. Normal aging and Alzheimer's disease is characterized by deficits in learning and the ability to switch strategies. The major goal of this project is to determine whether activating serotonin 4 receptors may alleviate learning deficits in aging. These studies have the potential of developing a novel treatment for the learning and memory deficits observed in aging and Alzheimer's disease.