Rescue of dormant brain circuits in neurodegenerative disease

 描述（由申请人提供）： 该提案的目标是测试重新激活休眠或抑制的食欲素回路是否可以减少内质网应激（ERS），改善神经变性小鼠模型的神经保护和认知表现。这项工作的长期目标是确定一种新的治疗策略，以改善神经退行性疾病，如嗜睡症，帕金森病，阿尔茨海默病和亨廷顿病的认知。这些疾病有不同的原因和病因，但下丘脑细胞的一个特定亚群，含食欲素的神经元的损失，发生在所有。下丘脑食欲素神经元投射到海马体，海马体是对学习和记忆很重要的大脑区域。食欲素在海马体中的作用改善了认知能力，最近被证明可以防止神经退行性变。在神经退行性疾病期间，神经保护信号减少，ERS被激活，这提示了一种共同的潜在机制。总之，这些数据表明，神经退行性疾病中食欲素信号传导的减少可能会减少神经保护作用并增加ERS，导致进一步的神经退行性疾病和认知能力下降。 确定治疗干预是否可以对抗神经退行性疾病中食欲素损失的影响的必要步骤是测试大脑中的食欲素反应通路是否可以重新激活。食欲素/共济失调蛋白-3小鼠是一种转基因模型，最初开发用于研究发作性睡病中的食欲素损失，其中食欲素神经元在发育过程中特异性地逐渐下降，认知过程恶化。然而，我们的初步数据显示，食欲素受体水平在年轻和年老的小鼠中保持不变，并且用食欲素刺激这些受体可以恢复认知能力。这些新的令人兴奋的数据提供了概念证明，即使在食欲素神经元丢失的情况下，刺激食欲素通路也可以用作改善认知的策略。我们计划在食欲素共济失调（O/A3）小鼠和α突触核蛋白病小鼠（帕金森病的经典模型）中确定这种策略的全部潜力。我们将研究是否增加海马增食欲素的紧张局势，拯救这些动物的认知缺陷。我们还建立了一个设计药物食欲素激活模型（DREADD），这是一个转基因小鼠，其中食欲素神经元已被修改，以特异性激活，否则代谢惰性药物。这些小鼠将与食欲素共济失调和帕金森病（α突触核蛋白病）小鼠杂交，以确定刺激残余的食欲素神经元是否也可以拯救休眠的食欲素反应通路。为了了解操纵食欲素通路导致的认知变化的潜在基础，我们将测量海马中的神经保护和ERS标记物。 我们的总体假设是，食欲素促进神经保护和减少ERS，并重新激活食欲素反应通路将改善神经退行性疾病相关的认知障碍。为了测试这一点，我们将确定食欲素替代疗法和食欲素神经元刺激是否改善1）具有轻度、中度和重度食欲素神经元损失的小鼠;和2）经典PD模型中的认知表现、神经保护标志物和ERS。我们预测，增强食欲素张力将通过改善神经保护和降低ERS来改善认知能力。这些研究的结果将确定食欲素救援是否是对抗认知能力下降的重要策略，并最终提供一种治疗神经退行性疾病的治疗途径。

 DESCRIPTION (provided by applicant): The goal of this proposal is to test whether reactivating dormant or depressed orexin circuits can reduce endoplasmic reticulum stress (ERS), improve neuroprotection and cognitive performance in mouse models of neurodegeneration. The long-term goal of this work is to identify a novel therapeutic strategy for improving cognition in neurodegenerative diseases such as narcolepsy, Parkinson's disease, Alzheimer's disease, and Huntington's disease. These diseases have differing causes and etiology, but loss of a specific subset of hypothalamic cells, the orexin-containing neurons, occurs in all. Hypothalamic orexin neurons project to the hippocampus, a brain area important to learning and memory. Orexin action in the hippocampus improves cognitive performance and was recently shown to protect against neurodegeneration. Neuroprotective signals are reduced and ERS is activated during neurodegenerative disease, suggestive of a common underlying mechanism. Together, these data suggest reduced orexin signaling in neurodegenerative disease may reduce neuroprotection and increase ERS, causing further neurodegeneration, and cognitive decline. A necessary step in determining whether therapeutic intervention can counter the effect of orexin loss in neurodegenerative disease is to test whether orexin-responsive pathways in the brain can be reactivated. The orexin/ataxin-3 mouse, first developed to study orexin loss in narcolepsy, is a transgenic model in which orexin neurons specifically and gradually decline during development, and cognitive processing deteriorates. Yet our preliminary data show that orexin receptor levels remain intact in young and old mice, and that stimulating these receptors with orexin restores cognition. These novel exciting data provide proof-of- concept that stimulation of orexin pathways, even when orexin neurons are lost, can be used as a strategy to improve cognition. We plan to determine the full potential of this strategy in the orexin ataxin (O/A3) mouse and in the alpha synucleinopathy mouse, a classic model of Parkinson disease. We will examine whether increasing hippocampal orexin tone rescues the cognitive deficit noted in these animals. We also have an established designer drug orexin activation model (DREADD), which is a transgenic mouse in which orexin neurons have been modified to be specifically activated by an otherwise metabolically inert drug. These mice will be crossed with the orexin ataxin and the Parkinson's disease (alpha synucleinopathy) mouse to determine whether stimulating remnant orexin neurons can also rescue dormant orexin-responsive pathways. To gain understanding of the underlying basis for observed cognitive changes resulting from manipulation of orexin pathways, we will measure markers of neuroprotection and ERS in hippocampus. Our overall hypothesis is that orexin promotes neuroprotection and reduces ERS, and that reactivating orexin-responsive pathways will ameliorate neurodegeneration-related cognitive disturbances. To test this, we will determine whether orexin replacement therapy and orexin neuron stimulation improves cognitive performance, markers of neuroprotection and ERS in 1) mice with mild, moderate, and severe orexin neuron loss; and 2) in a classic model of PD. We predict that enhancing orexin tone will improve cognitive performance by improving neuroprotection and decreasing ERS. The results of these studies will determine if orexin rescue is an important strategy in countering cognitive decline, and could ultimately provide a therapeutic pathway to target in neurodegenerative disease.