Aging, sleep, and kynurenic acid

衰老、睡眠和犬尿酸

• 批准号: 10574749
• 负责人: Ana Pocivavsek
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574749
• 关键词: Acute; Address; Age-associated memory impairment; Aging; Animals; Astrocytes; Attention; Behavior; Behavioral; Brain; Brain region; Catabolism; Cholinergic Antagonists; Chronotherapy; Cognition; Cognitive; Data; Deterioration; Elderly; Electroencephalography; Endocrine; Enzymes; Experimental Designs; Fatigue; Functional disorder; Gene Transfer; Headache; Homeostasis; Hypothalamic structure; Immunohistochemistry; Impaired cognition; Impairment; Kynurenic Acid; Kynurenine; Kynurenine-oxoglutarate aminotransferase; Lateral; Link; Mediating; Microdialysis; Molecular; Neurons; Organism; Outcome; Pathway interactions; Periodicity; Pharmacological Treatment; Phase; Physiological; Play; REM Sleep; Rattus; Regulation; Role; Signal Transduction; Sleep; Sleep Architecture; Sleep Deprivation; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Source; Testing; Time; Tryptophan; Virus; Wakefulness; age related; aged; aging brain; basal forebrain; cholinergic; circadian; combat; design; extracellular; hypocretin; improvement on sleep; in vivo; inhibitor; interest; neurotransmission; non rapid eye movement; novel; novel therapeutic intervention; pharmacologic; prevent; response; sleep quality; sleep quantity; sleep regulation; small molecule; tool; transmission process; treatment duration

Advanced age presents challenges that increase the likelihood of poor quality and reduced duration of sleep. Disruptions in sleep that come with aging may result in effects such as fatigue, irritability, headaches, and deteriorating cognition. These disruptions are presumed to result from alterations in brain regions that underlie endocrine, behavioral and cognitive responses to homeostatic challenges in the organism. Unraveling common molecular mechanisms between aging and sleep disturbances – which may lead to new therapeutic strategies to alleviate these outcomes – is of great importance. Aging pathophysiology points to dysfunctional cholinergic transmission, which may be driven, in part, by altered hypothalamic orexin neurons. We hypothesize that kynurenic acid (KYNA), an endogenous antagonist of cholinergic neurotransmission, plays a mechanistic role in age-related sleep dysfunction and orexin activation. The small molecule KYNA is of particular interest because (i) KYNA and its synthesizing enzymes kynurenine aminotranferases (KATs) are increased in the aging brain and (ii) an excess of KYNA may be especially involved in sleep deficits that are seen with advanced age. We propose the novel hypothesis that accumulated KYNA activates orexin neurons, thereby disrupting sleep, a circumstance that is exacerbated with aging or a homeostatic sleep deprivation (SD) challenge wherein KYNA accumulates in the brain. A specific inhibitor of KAT II, main enzyme responsible for brain KYNA formation, will be used as an experimental tool to mechanistically test the hypothesis. There are two specific aims to test our hypothesis. Aim #1: To examine the relationship of KYNA to orexinergic activation in the lateral hypothalamus of young rats (3-4 months) and old rats (26-28 months). Hypothesis: Accumulation of KYNA, as a result of aging or acute sleep deprivation (SD), in the lateral hypothalamus activates orexin neurons. Aim #2: To evaluate the impact of KYNA synthesis inhibition in improving sleep quality in old rats and young rats with reduced orexin expression. Hypothesis: KAT II inhibition serves as an efficacious strategy to overcome sleep architecture deficits in old rats and young rats with reduced orexinergic signaling.

高龄带来的挑战增加了质量差的可能性， 睡眠时间。随着年龄的增长而出现的睡眠中断可能会导致疲劳， 易怒头痛和认知能力下降据推测，这些中断是由于 改变大脑区域的基础内分泌，行为和认知反应， 体内平衡的挑战。揭示了 衰老和睡眠障碍-这可能导致新的治疗策略，以减轻这些 结果-非常重要。衰老的病理生理学指向胆碱能功能障碍 这可能部分由改变的下丘脑食欲素神经元驱动。我们 假设犬尿烯酸（KYNA）是一种内源性胆碱能拮抗剂， 神经传递，在与年龄相关的睡眠功能障碍和食欲素中起着机械作用 activation.小分子KYNA是特别令人感兴趣的，因为（i）KYNA和其 合成酶犬尿氨酸氨基转移酶（KAT）在老化的大脑中增加， (ii)过量的KYNA可能特别涉及睡眠不足， 年龄我们提出了一个新的假设，即积累的KYNA激活食欲素神经元， 扰乱睡眠，这种情况会随着年龄的增长或缺乏稳态睡眠而加剧 (SD)其中KYNA在脑中积累的挑战。KAT II的特异性抑制剂，主要 负责大脑KYNA形成的酶，将被用作实验工具， 机械地检验假设。有两个具体的目的来检验我们的假设。目标一： 研究KYNA与下丘脑外侧区食欲素能激活的关系， 年轻大鼠（3-4个月）和老年大鼠（26-28个月）。假设：KYNA的蓄积，作为 由于老化或急性睡眠剥夺（SD），在外侧下丘脑激活食欲素 神经元目的#2：评估KYNA合成抑制对改善睡眠质量的影响 在老年大鼠和食欲素表达减少的年轻大鼠中。假设：KAT II抑制作用 一种有效的策略来克服老年大鼠和年轻大鼠的睡眠结构缺陷， 减少食欲素能信号传导。