Hypocretin/orexin modulation of cognitive correlates of brain aging

阿尔茨海默病（AD）的主要神经递质标志是乙酰胆碱的丧失，乙酰胆碱是由基底前脑胆碱能系统（BFCS）的神经元产生的。胆碱能细胞的丧失或功能障碍也是路易体痴呆和血管性痴呆的重要组成部分。因此，BFCS有助于认知功能的几个方面，这些方面在AD和相关痴呆中受到负面影响，包括注意力、学习和记忆。包括下丘脑在内的传入输入对BFCS的调节对于体内平衡和认知功能的整合是重要的。由于稳态和生理障碍，如食物摄入或睡眠-觉醒周期的改变，经常先于和预测AD的认知能力下降，了解这些相互作用可能会导致新的干预点，以治疗或延缓AD等疾病的认知能力下降。这种传入调节的一个重要来源是下丘脑食欲素/下丘脑分泌素神经肽系统，该系统激活胆碱能神经元以响应信号生理价的刺激。我们之前已经表明，衰老是阿尔茨海默病的最大危险因素，它与促食欲素表达减少有关。最近，食欲素传递已被证明在限制神经炎症中发挥作用，这表明衰老过程中食欲素系统的减少可能会促进神经炎症过程，从而进一步对胆碱能依赖性信号传导和认知产生负面影响。在这一更新应用中，我们将使用病毒介导的基因转移、神经化学、药理学和认知行为方法，在老年啮齿动物模型中分析食欲素信号丧失、神经炎症和随后的胆碱能功能障碍和神经退行性变之间的关联机制。我们将进一步验证这一假设，即从衰老早期开始的食欲素功能的慢性恢复和维持将通过调节局部小胶质细胞动力学来保持BFCS的完整性。拟议的研究将开始描述与年龄相关的食欲素信号丧失驱动胆碱能功能障碍和认知能力下降的机制，并提出食欲素靶向治疗预防或改善阿尔茨海默病或相关痴呆的潜力，所有这些都以神经炎症和胆碱能功能障碍为特征。

The primary neurotransmitter hallmark of Alzheimer’s Disease (AD) is a loss of acetylcholine, produced by neurons of the basal forebrain cholinergic system (BFCS). Cholinergic cell loss or dysfunction is also a prominent component of Lewy Body Dementia and vascular dementia, respectively. Thus the BFCS contributes to several aspects of cognitive function that are negatively impacted in AD and related dementias, including attention, learning and memory. Regulation of the BFCS by afferent inputs, including those from the hypothalamus, is important for integration of homeostatic and cognitive functions. Because homeostatic and physiological disturbances, such as altered food intake or sleep-wake cycles, often precede and predict cognitive decline in AD, understanding these interactions may lead to novel points of intervention to treat or delay cognitive decline in conditions such as AD. An important source of this afferent regulation is the hypothalamic orexin/hypocretin neuropeptide system, which activates cholinergic neurons in response to stimuli that signal physiological valence. We have previously shown that aging, the strongest risk factor for AD, is associated with reduced orexin expression. Recently, orexin transmission has been shown to play a role in limiting neuroinflammation, suggesting that a diminished orexin system in aging may promote neuroinflammatory processes that further negatively impact cholinergic-dependent signaling and cognition. In this renewal application, we will dissect the mechanisms underlying the association between loss of orexin signaling, neuroinflammation and subsequent cholinergic dysfunction and neurodegeneration in an aged rodent model using virus-mediated gene transfer, neurochemical, pharmacological and cognitive behavioral approaches. We will further test the hypothesis that chronic restoration and maintenance of orexin function beginning in early aging will preserve the integrity of the BFCS by modulating local microglial dynamics. The proposed studies will begin to delineate the mechanisms by which age-related loss of orexin signaling drives cholinergic dysfunction and cognitive decline and suggest the potential for orexin-targeted therapies in preventing or ameliorating AD or related dementias, all of which are characterized by neuroinflammation and cholinergic dysfunction.