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: 7457880
• 负责人: Marilyn J. Duncan
• 金额: $ 29.43万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7457880
• 关键词: Affect; Age; Aging; Agonist; Attenuated; Autoradiography; Brain region; Circadian Rhythms; Disruption; Dorsal; Employee Strikes; Environment; Exhibits; Funding; Gastrin releasing peptide; Generations; Genetic; Glutamates; Hamsters; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Length; Lesion; Longevity; Maintenance; Malignant Neoplasms; Mediating; Memory; Memory Loss; Memory impairment; Messenger RNA; Metabolic Diseases; Microinjections; Mus; Nerve Degeneration; Neural Pathways; Neurites; Neurodegenerative Disorders; Neurons; Neuropeptides; Organ; Output; Pedunculopontine Tegmental Nucleus; Peptides; Peripheral; Phase; Process; Prosencephalon; Rattus; Receptor Activation; Research; Research Personnel; Role; Serotonin; Serotonin Agents; Signal Transduction; Site; Sleep; Structure; Synapses; System; Time; Vasoactive Intestinal Peptide; Work; age related; aged; attenuation; base; cardiovascular disorder risk; cardiovascular risk factor; chemotherapy; circadian pacemaker; dorsal raphe nucleus; extracellular; gamma-Aminobutyric Acid; in vivo; mRNA Expression; nerve supply; neuromechanism; neuropeptide Y; neurotransmission; novel; programs; raphe nuclei; receptor; relating to nervous system; serotonergic regulation; serotonin 7 receptor; serotonin transporter; suprachiasmatic nucleus; transmission process

DESCRIPTION (provided by applicant): Aging leads to deficits in many functions,including circadian timekeeping, which has been the focus of our on-going research. Circadian rhythm disruption is associated with increased risk of cardiovascular disease and cancer as well as impaired memory. Our previous studies revealed age-related changes in serotonergic regulation of the suprachiasmatic nucleus (SON), the site of the master circadian pacemaker, and the dorsal raphe nucleus (DRN), which also regulates circadian rhythms. We expanded our studies to include the hippocampus, which regulates memory, and observed aging changes in serotonergic regulation of this structure as well. In the SCN, aging increases serotonin transporter sites and decreases VIP mRNA expression. VIP is a key peptide involved in circadian rhythm generation, phase resetting, and transmission of circadian output. We propose to investigate if the increase in transporter sites causes the age-related decrease in VIP mRNA, since serotonin depletion attenuates VIP mRNA levels. Our previous studies also showed that aging decreases 5-HT7 receptors in the DRN and hippocampus. The age-related loss of 5-HT7 receptors in the DRN attenuates phase shifts to serotonergic drugs. We propose to investigate the neural pathways mediating DRN 5-HT7 receptor induction of phase shifts, by exploring the role of the GABAergic and glutamatergic neurotransmission, which are modulated by DRN 5-HT7 receptors in vitro. Finally, the age-related loss of 5-HT7 receptors in the hippocampal CA1 may be related to age-related memory loss, because genetic deletion of 5-HT7 receptors induces memory deficits. Exciting new studies of hippocampal neurons in vitro show that activation of 5-HT7 receptors stimulates neurite extensions critical process for synaptic connectivity. Decreased dendritic length is associated with memory impairments during aging and neurodegenerative diseases. Therefore, we propose to further investigate the intriguing but relatively little explored effect of 5-HT7 receptor stimulation of neurite length. The specific aims are to investigate: 1) the role of age-related changes in serotonin transporter sites in regulating SCN VIP and GRP expression, 2) the mechanisms by which 5-HT7 receptors in the dorsal raphe, which are decreased with aging, mediate nonphotic circadian phase shifts and 3) the effect of 5-HT7 receptors on neurite length in the hippocampus, SCN and DRN and whether this effect decreases during aging.

描述（由申请人提供）：老化会导致许多功能的缺陷，包括昼夜节时间，这一直是我们正在进行的研究的重点。昼夜节律破坏与心血管疾病和癌症的风险增加以及记忆受损有关。我们先前的研究表明，与年龄相关的血清素能调节变化，圆形核心核（SON），昼夜节奏起搏器的部位和背侧raphe核（DRN），这也调节了昼夜节律。我们扩大了研究，以包括调节记忆的海马，并观察到该结构的血清素能调节的老化变化。在SCN中，衰老会增加5-羟色胺转运蛋白位点并降低VIP mRNA的表达。 VIP是参与昼夜节律产生，相位和昼夜节律输出传播的关键肽。我们建议研究转运蛋白位点的增加是否导致与年龄相关的VIP mRNA降低，因为5-羟色胺耗竭会减轻VIP mRNA水平。我们以前的研究还表明，衰老降低了DRN和海马中的5-HT7受体。 DRN中与年龄相关的5-HT7受体的损失减弱了相对的血清素能药物。我们建议通过探索GABA能和谷氨酸能神经传递的作用来研究介导DRN 5-HT7受体诱导相移的神经途径，这些神经传递在体外受到DRN 5-HT7受体的调节。最后，海马CA1中与年龄相关的5-HT7受体的损失可能与年龄相关的记忆丧失有关，因为5-HT7受体的遗传缺失会诱导记忆缺陷。在体外对海马神经元的令人兴奋的新研究表明，5-HT7受体的激活刺激神经突扩展突触连通性的关键过程。树突长度的减小与衰老和神经退行性疾病期间的记忆障碍有关。因此，我们建议进一步研究5-HT7受体刺激神经突长的有趣但相对较少的探索作用。 The specific aims are to investigate: 1) the role of age-related changes in serotonin transporter sites in regulating SCN VIP and GRP expression, 2) the mechanisms by which 5-HT7 receptors in the dorsal raphe, which are decreased with aging, mediate nonphotic circadian phase shifts and 3) the effect of 5-HT7 receptors on neurite length in the hippocampus, SCN and DRN and whether this effect衰老期间减少。