Aging, acetylcholine and the hypothalamus

衰老、乙酰胆碱和下丘脑

• 批准号: 7533192
• 负责人: JIM R FADEL
• 金额: $ 30万
• 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/7533192
• 关键词: Acetylcholine; 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; Cholinergic Agents; Classification; Clinical Data; Cognition; Cognitive; Cognitive deficits; Condition; 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; Public Health; 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; novel; novel therapeutics; relating to nervous system; research study; response; therapeutic target; 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）：美国人口老龄化导致用于预防和治疗与年龄相关的神经退行性疾病的资源大幅增加。正常的认知和稳态功能是老年人独立能力和生活质量的主要决定因素。越来越多的数据表明，体内平衡功能的变化，例如晚年不明原因的体重减轻，经常先于并可能预测随后出现的轻度认知障碍或阿尔茨海默病。一个有趣的假设——部分基于启发式观察，即对食物或水剥夺等稳态挑战的适当行为反应需要认知成分——是与年龄相关的稳态功能变化和认知能力下降可能存在机械联系。这一假设得到了研究的支持，这些研究表明，某些通常与稳态功能相关的下丘脑区域和大脑头端区域（例如在认知中发挥关键作用的基底前脑胆碱能系统（BFCS））之间存在明显的解剖学联系。依赖于胆碱能系统完整性的认知能力受损是年龄相关性痴呆的一个早期且一致的特征，即使胆碱能神经元没有明显丧失，这表明 BFCS 传入调节的变化可能是某些类型的年龄相关认知衰退的基础。我们最近描述了下丘脑食欲素/下丘脑分泌素神经元对 BFCS 的密集神经支配，并表明这种输入在老年动物中显着减少。食欲素在体内平衡的多个方面发挥着重要作用，但激活基底前脑食欲素输入的条件以及这些相互作用的功能影响在很大程度上尚不清楚。在这里，我们提出了一种多层次（神经化学、解剖学、行为、遗传）的方法来阐明食欲素-胆碱能相互作用在应对稳态挑战和与年龄相关的认知衰退中的作用。目标 1 将结合病变和药理学方法来确定食欲素肽在皮质乙酰胆碱释放中的作用。目标 2 将检查食欲素 - 乙酰胆碱相互作用在 BFCS 激活中与年龄相关的缺陷中的作用，以及通过直接颅内给药或通过慢病毒介导的基因转移异位施用食欲素以恢复正常胆碱能功能的能力。目标 3 将确定基础内施用食欲素对注意力功能的年龄相关影响。总的来说，这些实验将系统地描述食欲素-乙酰胆碱相互作用在唤醒中的重要性，以及这些相互作用的改变如何导致与年龄相关的认知功能和动机行为缺陷。这些研究的结果将对理解与年龄相关的认知能力下降的基础具有重要意义，并可能为这些疾病的治疗提出新的治疗靶点。 公共健康相关性 现在令人信服的临床数据表明，阿尔茨海默病和其他与年龄相关的痴呆症通常在诊断为明显痴呆症之前数年就出现代谢紊乱，包括不明原因的体重减轻。我们的新假设是，稳态变化和认知能力下降的某些方面可能在神经系统水平上存在机械联系。因此，这些研究旨在研究下丘脑如何调节基底前脑胆碱能系统以及这些相互作用如何随着衰老而变化。