Aging, acetylcholine and the hypothalamus

描述(由申请人提供)：美国人口老龄化导致分配给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。正常的认知和内环境平衡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，如晚年不明原因的体重减轻，经常出现在轻度认知障碍或阿尔茨海默病的后续发展之前，并可能预测随后的发展。一个耐人寻味的假说--部分基于启发式的观察，即对食物或水的匮乏等动态平衡挑战的适当行为反应需要认知成分--是与年龄相关的动态平衡功能变化和认知能力下降可能存在机械联系。这一假说得到了一些研究的支持，这些研究表明，某些经典的与体内平衡功能相关的下丘脑区域与头端脑区之间存在明显的解剖学联系，例如在认知中起关键作用的基底前脑胆碱能系统(BFCS)。依赖于胆碱能系统完整性的认知能力损害是老年性痴呆的早期和一贯的特征，即使没有胆碱能神经元的坦率丢失，这表明BFCS传入调节的变化可能是某些类型的年龄相关性认知下降的基础。我们最近描述了下丘脑增食欲素/下丘脑下克汀神经元对BFCS的密集神经支配，并表明这种输入在老年动物中显著减少。食欲素在动态平衡的多个方面发挥着重要的作用，但激活食欲素输入到基底前脑的条件以及这些相互作用的功能含义在很大程度上是未知的。在这里，我们提出了一个多层次(神经化学、解剖学、行为学、遗传学)的方法来阐明增食欲素-胆碱能相互作用在对内环境平衡挑战和年龄相关认知下降的反应中的作用。目的1将结合损伤和药理学方法来确定增食欲素肽在皮质乙酰胆碱释放中的作用。目的2将研究增食欲素-ACh相互作用在年龄相关性缺陷中激活BFCS的作用，以及通过脑部直接给药或慢病毒介导的基因转移异位给药以恢复正常胆碱能功能的能力。目的3将确定基底动脉注射增食欲素对注意功能的年龄相关影响。总而言之，这些实验将包括对食欲素-乙酰胆碱相互作用在唤醒过程中的重要性以及这些相互作用的变化如何导致与年龄相关的认知功能缺陷和动机行为的系统描述。这些研究的结果将对理解与年龄相关的认知衰退的基础具有重要意义，并可能为这些疾病的治疗提供新的治疗靶点。与公共卫生相关的令人信服的临床数据现在表明，阿尔茨海默病和其他与年龄相关的痴呆症通常在诊断为坦率痴呆症的前几年出现代谢紊乱，包括不明原因的体重减轻。我们的新假设是，体内平衡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年龄的增长而变化。

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.