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（包括认知能力下降疾病）的资源大幅增加。能量平衡和睡眠模式等稳态功能的改变也常见于老年人，这些变化通常先于并预测随后的认知能力下降。一个新的假设是，这些看似不同的年龄相关缺陷表现可能具有共同的神经生物学机制。也就是说，参与体内平衡的大脑区域调节神经递质系统的活动，以及调节对生理挑战的适当行为和认知反应的大脑区域，并且这些相互作用可能会在衰老过程中受到影响。我们已经证明，衰老与下丘脑下丘脑分泌素/食欲素神经元的丧失有关，下丘脑下丘脑分泌素/食欲素神经元是调节能量平衡和睡眠/觉醒稳定性的细胞群。由于下丘脑分泌素/食欲素神经元还调节大脑区域的神经传递，这些神经传递是注意力、学习和记忆多个方面的基础，因此我们假设这些神经肽将生理功能与年龄相关的认知衰退联系起来。该假设的可检验推论是，衰老过程中食欲素/下丘脑分泌素系统的上调 将允许保留或恢复这些功能。在目标 1 中，我们将结合 DREADD（仅由设计药物激活的设计受体）和体内神经化学方法来确定急性食欲素/下丘脑分泌素激活或抑制对几个相关大脑区域的行为和神经传递的影响。在目标 2 中，我们将使用病毒介导的基因转移，并在纵向衰老动物模型中对食欲素/下丘脑分泌素系统进行长期操作。我们将研究这些操作如何改变食物和水的摄入量、身体成分以及神经递质系统和神经元激活的标记。在目标 3 中，我们将测试以下假设：下丘脑分泌素/食欲素系统通过对下丘脑分泌素/食欲素传输的急性和慢性操作来支持整个生命周期的注意力表现。总的来说，这些研究将表明食欲素/下丘脑分泌素系统是与年龄相关的神经功能障碍的认知和稳态表现的主要影响因素，并为开发预防、延迟或改善与年龄相关的认知衰退的疗法提供了潜在的新目标。