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。与其他健忘症或痴呆症相关的疾病一样，间脑性健忘症伴有胆碱能功能障碍。利用间脑性健忘症的动物模型，我们记录了内侧隔/斜角带(MS/DB)的胆碱能丢失和海马区的低胆碱能输出，这与行为障碍有关，这可以通过类胆碱药物来缓解。这些结果可以归因于两个潜在的相互正交的机制：(1)在学习过程中，MS/DB区的胆碱能细胞丢失导致海马区的低胆碱能输出；(2)丘脑和下丘脑核团的损伤降低了边缘区域的神经激活，这反映在认知加工过程中ACh的输出受损。这项拟议的研究使用了两种间脑性遗忘症的啮齿动物模型，对间脑性遗忘症中出现的神经自律性、神经化学和行为功能障碍之间的关系进行了系统水平的分析。目的：利用动物模型，我们将：(A)应用体视学显微镜技术，结合免疫细胞化学，充分记录几条重要的上升胆碱能通路中胆碱能细胞的丢失；(B)通过一种新的体内微透析/高效液相色谱法的应用，评估功能性乙酰胆碱的破坏，以评估在一系列任务和与间脑性遗忘症受损的核团相连的大脑区域(海马体、杏仁核和背侧纹状体)的认知处理过程中ACh的外流；(C)测试海马或隔区给药增加脑ACh水平是否会不同地导致学习/记忆功能的恢复；(D)利用离散的神经毒素诱导的损害绘制间脑核团的功能多样性图，以确定这种损害是否导致关键记忆结构中ACh输出的减少。意义：间脑性健忘症的神经机制仍未确定。在间脑性遗忘症动物模型的认知测试中使用在体微透析是一种新颖的方法，它将加深我们对间脑和其他边缘结构之间相互依赖的理解。这样的实验对于理解乙酰胆碱功能障碍在健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.