Aging, acetylcholine and the hypothalamus

衰老、乙酰胆碱和下丘脑

• 批准号: 7675265
• 负责人: JIM R FADEL
• 金额: $ 28.95万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675265
• 关键词: Acetylcholine; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Animals; Anorexia; Arousal; Attention; Attenuated; Automobile Driving; Behavior Control; Behavioral; Behavioral Genetics; Body Weight decreased; Brain region; Classification; Clinical Data; Cognition; Cognitive; Cognitive deficits; Cues; Data; Dementia; Development; Diagnosis; Disease; Elderly; Etiology; Experimental Water Deprivation; Food; Gene Transfer; Homeostasis; Hypothalamic structure; Impaired cognition; Lateral; Lesion; Life; Link; Mediating; Mediator of activation protein; Metabolic; Metabolism; Microdialysis; Motivation; Nature; Neocortex; Nerve Degeneration; Neuraxis; Neurons; Participant; Patients; Peptides; Performance; Phenotype; Physiological; Play; Population; Prevention; Process; Quality of life; Regulation; Research Design; Resources; Rodent; Role; Signal Transduction; Stimulus; System; Task Performances; Testing; Wasting Syndrome; age related; aged; basal forebrain; basal forebrain cholinergic neurons; base; cholinergic; cholinergic neuron; cognitive function; energy balance; experience; feeding; heuristics; hypocretin; in vivo; interest; lentiviral-mediated; mild neurocognitive impairment; motivated behavior; neocortical; nerve supply; neurochemistry; neuromechanism; neurotransmission; new therapeutic target; novel; public health relevance; relating to nervous system; research study; response; transmission process

DESCRIPTION (provided by applicant): The aging U.S. population has resulted in substantial increases in resources allocated to the prevention and treatment of age-related neurodegenerative conditions. Normal cognitive and homeostatic functions are major determinants of the capacity for independence and quality of life in the elderly. A growing body of data suggests that changes in homeostatic function, such as unexplained weight loss late in life, frequently precedes and may predict subsequent development of mild cognitive impairment or Alzheimer's disease. An intriguing hypothesis - based in part on the heuristic observation that proper behavioral responses to homeostatic challenges, such as food or water deprivation, entail a cognitive component - is that age-related changes in homeostatic function and cognitive decline may be mechanistically linked. This hypothesis is supported by studies showing clear anatomical connections between certain hypothalamic regions classically associated with homeostatic function and rostral brain regions, such as the basal forebrain cholinergic system (BFCS), that play crucial roles in cognition. Impairment of cognitive abilities dependent on the integrity of the cholinergic system is an early and consistent feature of age-related dementias, even in the absence of frank loss of cholinergic neurons, suggesting that changes in the afferent regulation of the BFCS may underlie some types of age-related cognitive decline. We have recently described a dense innervation of the BFCS by hypothalamic orexin/hypocretin neurons and shown that this input is dramatically reduced in aged animals. Orexins play prominent roles in multiple aspects of homeostasis but the conditions that activate orexin inputs to the basal forebrain and the functional implications of these interactions are largely unknown. Here, we propose a multi-level (neurochemical, anatomical, behavioral, genetic) approach to elucidate the role of orexin-cholinergic interactions in responses to homeostatic challenges and age-related cognitive decline. Aim 1 will combine lesion and pharmacological approaches to determine the role of orexin peptides in cortical acetylcholine release. Aim 2 will examine the role of orexin-ACh interactions in age-related deficits in activation of the BFCS as well as the ability of ectopic administration of orexins via direct intracranial administration or by lentiviral- mediated gene transfer to restore normal cholinergic function. Aim 3 will determine age-related effects of intra-basalis administration of orexins on attentional function. Collectively, these experiments will comprise a systematic description of the importance of orexin-acetylcholine interactions in arousal and how alterations in these interactions may contribute to age-related deficits in cognitive function and motivated behavior. The results of these studies will have important implications for understanding the basis of age- related cognitive decline and may suggest novel therapeutic targets for the treatment of these disorders. PUBLIC HEALTH RELEVANCE Compelling clinical data now indicate that Alzheimer's disease and other age-related dementias are often preceded by metabolic disturbances, including unexplained weight loss, years prior to diagnosis of frank dementia. Our novel hypothesis is that some aspects of homeostatic changes and cognitive decline may be mechanistically linked at the neural systems level. Accordingly, these studies are designed to investigate how the hypothalamus regulates the basal forebrain cholinergic system and how these interactions change with aging.

描述（由申请人提供）：美国老龄化的人口已大幅增加，分配给预防和治疗与年龄相关的神经退行性状况的资源大幅增加。正常的认知和稳态功能是老年人独立和生活质量能力的主要决定因素。越来越多的数据表明，体内稳态功能的变化（例如生命后期无法解释的体重减轻）经常先于之前，并且可能预测随后的轻度认知障碍或阿尔茨海默氏病的发展。一个有趣的假设 - 部分基于启发式观察结果，即对体内稳态挑战（例如食物或水剥夺）的适当反应需要一种认知成分 - 是与年龄相关的稳态功能的变化和认知下降可能是机械上的。这一假设得到的研究表明，某些与稳态功能和鼻脑区域相关的某些下丘脑区域之间存在明显的解剖联系，例如基础前脑胆碱能系统（BFC）在认知中起着至关重要的作用。认知能力的损害取决于胆碱能系统的完整性是与年龄相关的痴呆症的早期且一致的特征，即使在没有坦率的胆碱能神经元的坦率丧失的情况下，这表明BFC传入调节的变化可能是BFC的某些类型的变化与年龄有关的认知下降。我们最近描述了下丘脑Orexin/pocretin神经元对BFC的致密神经，并表明该输入在老年动物中大大降低。甲蛋白在体内平衡的多个方面起着突出的作用，但是激活奥列甲蛋白输入到基础前脑以及这些相互作用的功能含义的条件在很大程度上是未知的。在这里，我们提出了一种多层次（神经化学，解剖学，行为，遗传）方法，以阐明Orexin-胆碱能相互作用在对体内稳态挑战和与年龄相关的认知能力下降中的作用。 AIM 1将结合病变和药理学方法，以确定Orexin肽在皮质乙酰胆碱释放中的作用。 AIM 2将检查Orexin-ACh相互作用在年龄相关缺陷中的作用在BFC激活中的作用，以及异位施用Orexins通过直接颅内给药或通过慢病毒介导的基因转移到恢复正常胆碱能功能的能力。 AIM 3将确定巴萨利氏菌对Orexins施用对注意功能的年龄相关作用。总的来说，这些实验将构成对唤醒中Orexin-乙酰胆碱相互作用的重要性的系统描述，以及这些相互作用中的变化如何有助于认知功能中与年龄相关的缺陷。这些研究的结果将对理解与年龄相关的认知下降的基础具有重要意义，并可能暗示用于治疗这些疾病的新型治疗靶标。 公共卫生相关性引人注目的临床数据现在表明，阿尔茨海默氏病和其他与年龄有关的痴呆症通常在诊断出弗兰克痴呆症之前的几年之前先于代谢障碍，包括无法解释的体重减轻。我们的新假设是，在神经系统层面上，稳态变化和认知下降的某些方面可能是在机械上联系起来的。因此，这些研究旨在研究下丘脑如何调节基础前脑胆碱能系统以及这些相互作用如何随衰老而变化。