ADENOSINE AND SLEEP REGULATION IN AGING RATS

随着年龄的增长，睡眠会明显减少。这种随着年龄增长而导致的睡眠不足是老年人的一个主要问题，会导致白天困倦和警觉性下降。然而，这种睡眠周期随年龄增长而改变的机制尚不清楚。在本项目资助的前一个周期中，对老年人睡眠不足的假设是由于昼夜节律起搏器，即视交叉上核(SCN)的恶化所致。然而，切斯勒的研究小组的结果表明，年龄较大的受试者的体温节律周期没有变化。这些发现提出了这样一种可能性，即SCN的起搏能力没有变化，但其他耦合通路可能会随着年龄的增长而下降。一种可能性是，调节睡眠-觉醒的动态平衡因素可能会随着年龄的增长而受损。我们的研究将直接解决这一假设，即衰老导致的睡眠缺陷是腹外侧视前核(VLPO)神经元对腺苷积累缺乏反应。具体目标1将测试幼年和老年大鼠VLPO神经元的完整性。我们预测，在老年动物中，对于给定数量的预先觉醒，VLPO中c-fos的表达较少。这将表明VLPO神经元的水平。我们预测，与年轻大鼠相比，对于预先清醒的特定数量的老年大鼠，VLPO中的甘丙素mRNA水平较低。特定目的2将验证VLPO神经元对腺苷积累的反应性降低的假设，这是由于VLPO神经元或其传入细胞在衰老过程中腺苷受体表达减少所致。《特定目标3》将检验这样一种假设，即老年动物的视前神经元本身对腺苷反应迟钝。

A pronounced decline in sleep occurs with aging. This deficit in sleep with aging presents a major problem for elderly individuals, causing daytime sleepiness and impairing alertness. However, the mechanism for this change in the sleep cycle with aging is not understood. In the previous cycle of this Program Project Grant, the hypothesis was explored that the deficit in sleep in aged individuals was due to a deterioration in the circadian pacemaker, i.e, suprachiasmatic nucleus (SCN). However, results from Czeisler's group indicate that older subjects show no change in period of the temperature rhythm. These findings raise the possibility that there is no change in the SCN's pacemaking ability, but that other coupling pathways might decline with age. One possibility is that homeostatic elements regulating sleep- wakefulness might be impaired with aging. Our studies will directly address the hypothesis that the defect in sleep caused by aging is a lack of responsiveness in the ventrolateral preoptic nucleus (VLPO) neurons to the accumulation of adenosine. Specific aim 1 will test the integrity of the VLPO neurons in young and old rats. We predict that in older animals for a given amount of prior wakefulness there is less c-fos expression in VLPO. This would indicate levels in VLPO neuron. We predict that for a given amount for prior wakefulness older rats will have less galanin mRNA levels in VLPO compared to young rats. Specific aim 2 will test the hypothesis that there may be reduced responsiveness of VLPO neurons to accumulation of adenosine because of a reduction in expression of adenosine receptors by VLPO neurons or their afferents during aging. Specific aim 3 will test the hypothesis that preoptic neurons themselves are hyporesponsive to adenosine in aged animals.