Aging, Serotonin and Reversal Learning

描述（由申请人提供）：正常衰老和阿尔茨海默病的特征是学习新信息的能力严重不足，同时抑制使用先前相关的信息。有越来越多的证据表明，神经递质，5-羟色胺（5-HT）可能使学习时，条件需要改变策略。最近的研究结果表明，5-HT 4受体的激活，特别是，可以改善认知，以及产生神经保护。这项建议的长期目标是确定是否与选择性，5-HT 4激动剂治疗改善学习条件时，需要在年轻的成年和老年大鼠的反应模式的转变。以前试图减轻衰老和阿尔茨海默病中的认知缺陷，主要集中在直接改变大脑胆碱能系统。这种方法取得的成功有限。最近有证据表明，5-HT 4激动剂治疗可以改善记忆，然而，未知的是，当条件需要改变策略时，5-HT 4受体的激活是否会增强学习。一项研究将检查在年轻成年大鼠和老年大鼠中给予选择性5-HT 4激动剂RS 67333是否会影响两个选择位置辨别中的逆转学习。老年人和阿尔茨海默病患者有时只在难度增加的条件下表现出认知缺陷。第二项实验将确定在年轻成年大鼠和老年大鼠中给予RS 67333是否会影响四选择位置辨别中的逆转学习。由于该任务中的两个选择充当干扰物选择，因此该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-HT 4受体的激活是否可以减少这种缺陷。已知脑5-HT 4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输出和逆转学习。这些初步实验对于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，导致衰老中的认知灵活性缺陷。总体而言，拟议研究的结果将提供有关认知灵活性中可能与年龄相关的缺陷的潜在过程的新的重要信息，以及5-HT 4受体的激活是否可以有效缓解认知灵活性障碍。正常衰老和阿尔茨海默病的特征是学习和转换策略的能力不足。该项目的主要目标是确定激活5-羟色胺4受体是否可以减轻衰老中的学习缺陷。这些研究有可能开发一种新的治疗方法，用于治疗在衰老和阿尔茨海默病中观察到的学习和记忆缺陷。

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.