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缺陷，同时抑制对先前相关信息的使用。越来越多的证据表明，当情况需要改变策略时，神经递质血清素（5-HT）可能会促进学习。最近的研究结果表明，特别是5-HT4受体的激活可能会改善认知，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，使用选择性5-HT4激动剂治疗是否能改善学习。先前试图减轻衰老和阿尔茨海默病的认知缺陷的尝试集中在直接改变大脑胆碱能系统上。这种方法取得了有限的成功。最近有证据表明5-HT4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-HT4受体的激活是否会增强学习。一项研究将检验在年轻成年和老年大鼠中使用选择性5-HT4激动剂RS 67333是否会影响双选择地点辨别的逆转学习。老年人和阿尔茨海默病患者有时只在困难程度增加的情况下表现出认知缺陷。第二个实验将确定给药RS 67333是否会影响青年和老年大鼠在四选择地点识别中的逆转学习。因为这项任务中的两个选择作为干扰选择，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。已知大脑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输出和反转学习。这些初步实验对于发展更广泛的研究计划至关重要，以了解特定脑回路中的神经化学机制是如何改变的，从而导致衰老过程中认知灵活性的缺陷。总的来说，这些研究结果将为认知灵活性可能与年龄相关的缺陷提供新的重要信息，以及激活5-HT4受体是否能有效缓解认知灵活性障碍。正常衰老和阿尔茨海默病的特点是学习能力和转换策略的能力不足。该项目的主要目标是确定激活血清素4受体是否可以减轻衰老过程中的学习缺陷。这些研究有可能开发出一种新的治疗衰老和阿尔茨海默病中观察到的学习和记忆缺陷的方法。

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.