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（通过应用程序证明）：与年龄相关的神经退行性认知下降的老化。神经递质的系统和脑部介导了适当的行为和认知反应，对衰老有影响，我们表明，与体面的低渗性低螺旋蛋白/OREXIN神经元A细胞相关。张力，学习和记忆我们假设与年龄相关的认知能力下降的thysololololololololololoil lololololololloction。 将允许在AIM 1中使用Presese功能。对衰老模型进行慢性操作。 e整个生命都跨越了急性和慢性操纵性降压素 /奥雷蛋白的传播，这是对年龄相关的神经功能障碍的认知表现的主要因素与年龄有关的认知下降。