The Role of Acetylcholine Dysfunction in Diencephalic Amnesia

描述（由申请人提供）：大量证据表明胆碱能传递在认知、记忆和行为状态控制中具有重要作用。与其他遗忘或痴呆相关疾病一样，间脑性遗忘症伴有胆碱能功能障碍。使用间脑性遗忘症的动物模型，我们已经记录了内侧隔/斜角带（MS/DB）的胆碱能损失和与行为障碍相关的海马胆碱能输出减少，这可以通过拟胆碱药物来缓解。这些结果可以归因于2种潜在的正交机制：（1）MS/DB区域中的胆碱能细胞损失导致学习期间海马中的胆碱能输出减少;（2）丘脑和下丘脑核的损伤降低边缘区的神经激活，这反映在认知处理期间受损的ACh输出中。拟议的研究使用2种间脑性遗忘症的啮齿动物模型，对间脑性遗忘症中观察到的神经解剖学、神经化学和行为功能障碍之间的关系进行系统水平的分析。目的：使用动物模型，我们将：（A）结合免疫细胞化学，应用体视学显微镜技术，充分记录几个重要的胆碱能上行通路中胆碱能细胞的损失;（B）通过体内微透析/HPLC的新应用评估功能性乙酰胆碱破坏，以评估在一系列任务和脑区域的认知处理期间的ACh流出（C）测试增加脑ACh水平的药物的海马或隔区给药是否将差异性地导致学习/记忆功能的恢复;（D）使用离散的神经毒素诱导的损伤来绘制间脑核的功能多样性，以确定这些损伤是否导致关键记忆结构中ACh输出的减少。意义：间脑性遗忘症的神经机制尚未确定。在间脑性遗忘症动物模型的认知测试过程中使用体内微透析在线是新颖的，将增强我们对间脑和其他边缘结构之间相互依赖性的理解。这些实验对于理解乙酰胆碱功能障碍在遗忘症中的作用以及药物治疗的发展至关重要。

DESCRIPTION (provided by applicant): A considerable body of evidence has demonstrated an important role for cholinergic transmission in cognition, memory and behavioral state control. Like other amnestic or dementia-related disorders, diencephalic amnesia is accompanied by cholinergic dysfunction. Using an animal model of diencephalic amnesia we have documented cholinergic loss in the medial septum/diagonal band (MS/DB) and hypo-cholinergic output in the hippocampus that correlates with behavioral impairment, which can be alleviated by cholinomimetic drugs. These results can be attributed to 2 potentially orthogonal, mechanisms: (1) Cholinergic cell loss in the MS/DB region causes hypocholinergic output in the hippocampus during learning; (2) Lesions to thalamic and hypothalamic nuclei degrade neural activation in limbic regions and this is reflected in impaired ACh output during cognitive processing. The proposed research uses 2 rodent models of diencephalic amnesia to conduct a systems level analysis of the relationships between neuroantomical, neurochemical and behavioral dysfunctions seen in diencephalic amnesia. Aims: Using animal models we will: (A) Apply stereological microscopy techniques, in combination with immunocytochemistry, to fully document cholinergic cell loss in several important ascending cholinergic pathways; (B) Assess functional acetylcholine disruption by a novel application of in-vivo microdialysis/HPLC to assess ACh efflux during cognitive processing on a range of tasks and brain regions (hippocampus, amygdala, and dorsal striatum) connected to nuclei damaged in diencephalic amnesia; (C) Test whether hippocampal or septal administration of drugs that increase brain ACh levels will differentially lead to recovery of learning/memory function; (D) Map the functional diversity of diencephalic nuclei using discrete neurotoxin-induced lesions to determine if such lesions cause decreased ACh output in key memory structures. Significance: The neural mechanisms of diencephalic amnesia remain undetermined. Using in-vivo microdialysis on-line during cognitive testing in animal models of diencephalic amnesia is novel and will enhance our understanding of the interdependence between diencephalic and other limbic structures. Such experiments are critical to understanding the role of acetylcholine dysfunction in amnesia and thus the development of pharmacotherapeutics.