Hypocretin/orexin modulation of cognitive correlates of brain aging

 描述(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，包括认知能力下降的障碍。能量平衡和睡眠模式等体内平衡功能的改变在老年人中也很常见，这些变化往往先于并预测随后的认知能力下降。一种新的假设是，这些与年龄相关的缺陷的一些看似不同的表现可能具有潜在的神经生物学机制；即，参与内稳态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，这些相互作用可能会在衰老中受到影响。我们已经证明，衰老与下丘脑下丘脑下丘脑下肌酸/增食欲素神经元的丧失有关--这是一种调节能量平衡和睡眠/清醒稳定性的细胞群。由于下丘脑泌素/食欲素神经元也调节大脑区域的神经传递，这些区域是注意力、学习和记忆的几个方面的基础，我们假设这些神经肽将生理功能与年龄相关的认知能力下降联系起来。这一假说的可检验推论是增食欲素/下丘脑分泌素系统在衰老过程中上调 将允许保留或恢复这些功能。在目标1中，我们将结合DREADD(设计者受体，由设计者药物独有地激活)和体内神经化学方法来确定急性增食欲素/下丘脑克隆素激活或抑制对几个相关脑区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，并在一个纵向的衰老动物模型中对增食欲素/下克隆素系统进行慢性操作。我们将研究这些手法是如何改变食物和水的摄入量、身体成分、神经递质系统的标志和神经元激活的。在目标3中，我们将使用急性和慢性的下丘脑素/增食欲素传递操作来检验这一假说，即下丘脑泌素/增食欲素系统支持一生中的注意力表现。总而言之，这些研究将表明增食欲素/下丘脑酮系统是年龄相关神经功能障碍的认知和稳态表现的主要促成因素，并提出了一个潜在的新靶点，用于开发预防、延缓或改善年龄相关认知功能下降的治疗方法。

 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.