NEURAL MECHANISMS RESETTING THE AGED CIRCADIAN PACEMAKER

重置老化昼夜节律起搏器的神经机制

• 批准号: 6016799
• 负责人: Marilyn J. Duncan
• 金额: $ 18.85万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-17 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6016799
• 关键词: G protein; aging; circadian rhythms; cyclic AMP; enzyme activity; fenfluramine; fluoxetine; forskolin; gene induction /repression; hamsters; neuropharmacology; neurotransmitter transport; phosphodiesterases; potassium; radioimmunoassay; receptor coupling; receptor expression; serotonin; serotonin receptor; sodium channel; suprachiasmatic nucleus; synapses; tissue /cell culture; vasoactive intestinal peptide; voltage gated channel

DESCRIPTION: (Application abstract) The long-term goal of this research is to determine the cellular and molecular mechanisms in the aging brain that disrupt circadian behaviors. During aging, the circadian pacemaker loses its ability to respond to serotonin, one of the neurotransmitters that shifts the phase of circadian rhythms in locomotor behavior and regulates the expression of vasoactive intestinal peptide (VIP), a neuropeptide which alters the phase of the circadian pacemaker. The specific aims and methodologies are: (1) to test the hypothesis that aging alters synaptic release of serotonin, by using microdialysis and HPLC, (2) to test the hypothesis that aging leads to a loss of 5HT7 receptors, by using quantitative autoradiography, (3) to test the hypothesis that aging attenuates serotonergic stimulation of cAMP, by using short-term in vitro studies and radioimmunoassays, and (4) to test the hypothesis that aging reduces basal and/or serotonin-stimulated VIP mRNA expression, by using in situ hybridization. The initial studies will focus on the suprachiasmatic nucleus (SCN). Subsequent studies will investigate whether these age-related changes are unique to the SCN or also occur in other brain regions. The findings will provide a rational basis for therapeutic amelioration of the fragmented sleep-wake cycles that occur in the elderly and are especially severe in Alzheimer's patients. Also, because 5HT7 receptors have a high affinity for many anti-psychotic drugs, these studies will benefit the development of treatments for schizophrenia in the elderly.

描述：（应用摘要）这项研究的长期目标是 确定衰老大脑中的细胞和分子机制 破坏昼夜节律的行为。 在衰老期间，昼夜节奏起搏器失败了 它对5-羟色胺的反应能力，这是神经递质之一 改变运动行为中昼夜节律的阶段并调节 血管活性肠肽（VIP）的表达，一种神经肽，该肽的表达 改变了昼夜节奏起搏器的阶段。 具体目的 方法论是：（1）检验衰老改变突触的假设 通过使用微透析和HPLC释放5-羟色胺，（2）测试 假设衰老会导致5HT7受体的丧失，通过使用 定量自显影术，（3）测试衰老的假设 通过使用短期体外，可以减轻cAMP的血清素能刺激 研究和放射免疫测定，以及（4）测试衰老的假设 通过使用 原位杂交。 最初的研究将重点放在界面上 核（SCN）。 随后的研究将调查是否 与年龄相关的变化是SCN独有的，或者在其他大脑中也发生 地区。 这些发现将为治疗提供合理的基础 在老年人中的碎片睡眠效果周期的改善 并且在阿尔茨海默氏症患者中特别严重。 另外，因为5HT7 受体对许多抗精神药物具有很高的亲和力，这些研究 将有利于老年人精神分裂症治疗的发展。