ADENOSINE AND SLEEP REGULATION IN AGING RATS

随着年龄的增长，睡眠时间明显减少。随着年龄的增长，睡眠不足对老年人来说是一个大问题，它会导致白天嗜睡，降低警觉性。然而，睡眠周期随年龄变化的机制尚不清楚。在本项目资助的前一个周期中，研究人员探索了老年人睡眠不足是由于昼夜节律起搏器（即视交叉上核（SCN））的恶化所致的假设。然而，Czeisler小组的结果表明，年龄较大的受试者在温度节律周期上没有变化。这些发现提出了一种可能性，即SCN的起搏能力没有变化，但其他的偶联途径可能会随着年龄的增长而下降。一种可能是调节睡眠-觉醒的体内平衡因素可能随着年龄的增长而受损。我们的研究将直接解决由衰老引起的睡眠缺陷是腹外视前核（VLPO）神经元对腺苷积累缺乏反应性的假设。特异性目标1将测试年轻和年老大鼠VLPO神经元的完整性。我们预测，在年龄较大的动物中，对于给定的先前清醒量，VLPO中的c-fos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，在给定的清醒量下，年龄较大的大鼠VLPO中的甘丙氨酸mRNA水平较低。特异性目的2将验证一个假设，即在衰老过程中，由于VLPO神经元或其传入神经中腺苷受体的表达减少，VLPO神经元对腺苷积累的反应性可能降低。具体目标3将验证老年动物视前神经元本身对腺苷反应迟钝的假设。

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.