Hypocretin/orexin modulation of cognitive correlates of brain aging

 描述（由申请人提供）：美国人口老龄化导致分配用于预防和治疗年龄相关神经退行性疾病（包括认知功能下降疾病）的资源大幅增加。稳态功能的改变，如能量平衡和睡眠模式，也经常出现在老年人中，这些变化往往先于并预测随后的认知能力下降。一个新的假设是，这些看似不同的表现与年龄有关的缺陷可能共享潜在的神经生物学机制;也就是说，参与稳态的大脑区域调节神经递质系统和大脑区域的活动，介导对生理挑战的适当行为和认知反应，这些相互作用可能会受到衰老的影响。我们已经证明，衰老与下丘脑下视丘分泌素/食欲素神经元的丢失有关，下视丘分泌素/食欲素神经元是一种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衰退联系起来。这一假说的可检验的推论是增食欲素/下丘脑泌素系统在衰老中的上调 将允许保存或恢复这些功能。在目标1中，我们将结合联合收割机DREADD（设计师受体专门由设计师药物激活）和体内神经化学方法，以确定急性食欲素/下丘脑泌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，并在纵向衰老动物模型中对食欲素/下丘脑泌素系统进行慢性操作。我们将研究这些操作如何改变食物和水的摄入量，身体成分和神经递质系统和神经元激活的标志物。在目标3中，我们将测试的假设，下丘脑泌素/食欲素系统支持注意力的表现在整个生命周期使用急性和慢性操纵下丘脑泌素/食欲素传输。总的来说，这些研究将暗示食欲素/下丘脑泌素系统作为年龄相关的神经功能障碍的认知和稳态表现的主要贡献因素，并提出了预防，延迟或改善年龄相关的认知下降的治疗开发的潜在新靶点。

 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.