Hypocretin/orexin modulation of cognitive correlates of brain aging

下丘脑分泌素/食欲素对大脑衰老认知相关性的调节

• 批准号: 8937397
• 负责人: JIM R FADEL
• 金额: $ 28.65万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8937397
• 关键词: Acetylcholine; Acute; Age-Months; Age-associated memory impairment; Aging; Alzheimer' s Disease; Animal Model; Animals; Arousal; Attention; Behavior; Behavioral; Biological Preservation; Body Composition; Brain region; Cells; Chronic; Clinical; Clinical Research; Cognition; Cognitive; Cognitive aging; Cognitive deficits; Designer Drugs; Disease; Eating; Elderly; Functional disorder; Gene Transfer; Glutamates; Hippocampus (Brain); Homeostasis; Hypothalamic structure; Impaired cognition; Insula of Reil; Lead; Learning; Lesion; Link; Literature; Longevity; Maintenance; Mediating; Mediator of activation protein; Memory; Metabolic; Nerve Degeneration; Neurobehavioral Manifestations; Neurobiology; Neurons; Neuropeptides; Neurotransmitters; Parkinson Disease; Pattern; Performance; Physiological; Play; Population; Prevention; Process; Regulation; Resources; Role; Sleep; Sleep Wake Cycle; Stimulus; Support System; Syndrome; System; Testing; Up-Regulation; Virus; Water consumption; Work; age effect; age related; aging brain; basal forebrain; cholinergic; clinically significant; cognitive change; cognitive function; cognitive performance; energy balance; executive function; feeding; frailty; hypocretin; in vivo; juvenile animal; middle age; nervous system disorder; neurobiological mechanism; neurochemistry; neurocognitive disorder; neuron loss; neurotransmission; new therapeutic target; novel; prevent; public health relevance; receptor; relating to nervous system; research study; response; restoration; sustained attention; theories; therapeutic target; therapy development; transmission process

 DESCRIPTION (provided by applicant): The aging U.S. population has led to substantial increases in resources allocated to the prevention and treatment of age-related neurodegenerative conditions, including disorders of cognitive decline. Alterations in homeostatic functions such as energy balance and sleep patterns are also frequently seen in the elderly and these changes often precede and predict subsequent cognitive decline. A novel hypothesis is that some of these seemingly disparate manifestations of age-related deficits may share underlying neurobiological mechanisms; that is, brain regions that are involved in homeostasis regulate the activity of neurotransmitter systems and brain regions that mediate the appropriate behavioral and cognitive responses to physiological challenges, and these interactions may be impacted in aging. We have shown that aging is associated with loss of hypothalamic hypocretin/orexin neurons-a cell population that regulates energy balance and sleep/wake stability. Because hypocretin/orexin neurons also regulate neurotransmission in brain regions that underlie several aspects of attention, learning and memory we hypothesize that these neuropeptides link physiological function with age-related cognitive decline. The testable corollary to this hypothesis is that upregulation of the orexin/hypocretin system in aging will allow for preservation or restoration of these functions. In Aim 1 we will combine DREADD (designer receptors exclusively activated by designer drugs) and in vivo neurochemical approaches to determine the effect of acute orexin/hypocretin activation or inhibition on behavior and neurotransmission in several relevant brain regions. In Aim 2 we will use virus-mediated gene transfer and to perform chronic manipulations of the orexin/hypocretin system in a longitudinal animal model of aging. We will examine how these manipulations alter food and water intake, body composition and markers of neurotransmitter systems and neuronal activation. In Aim 3 we will test the hypothesis that the hypocretin/orexin system supports attentional performance across the life span using both acute and chronic manipulations of hypocretin/orexin transmission. Collectively, these studies will implicate the orexin/hypocretin system as a major contributing factor in cognitive and homeostatic manifestations of age-related neural dysfunction, and suggest a potential new target for development of therapies that prevent, delay or ameliorate age-related cognitive decline.

 描述（由适用提供）：美国老年人口已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的次要增加，包括认知能力下降的疾病。体内平衡功能（例如能量平衡和睡眠模式）的改变也经常出现，这些变化经常在并预测随后的认知能力下降。一个新的假设是，其中一些看似与年龄相关的缺陷的看似不同的表现可能具有潜在的神经生物学机制。也就是说，与体内稳态有关的大脑区域调节了介导适当的行为和认知反应的神经递质系统和大脑区域的活性，并且这些相互作用可能会在衰老中受到影响。我们已经表明，衰老与下丘脑下呼毒素/OREXIN神经元的损失有关，该细胞群可以调节能量平衡和睡眠/唤醒稳定性。由于降钙素/奥甲蛋白神经元还调节了大脑区域的神经递质，这是注意力，学习和记忆的几个方面，因此我们假设这些神经肽将身体功能与年龄相关的认知下降联系起来。该假设的可检验的推论是，衰老中的Orexin/dypocretin系统的上调 在AIM 1中，我们将结合Dreadd（设计器药物专门激活的设计器受体）和体内神经化学方法，以确定急性Orexin/dypocretin激活或抑制对几个相关脑区域的行为和神经传递的影响。在AIM 2中，我们将使用病毒介导的基因转移并在衰老的纵向动物模型中对Orexin/dypocretin系统进行慢性操纵。我们将研究这些操纵如何改变食物和饮水，身体成分以及神经递质系统的标记和神经元激活。在AIM 3中，我们将检验以下假设：低载素/奥雷蛋白系统使用急性和慢性操纵在整个生命周期中支持急性和慢性操纵的假设。总的来说，这些研究将实施Orexin/dypocretin System作为与年龄相关的神经功能障碍的认知和稳态表现的主要因素，并为预防，延迟或改善与年龄相关的认知能力下降的疗法发展潜在的新目标。