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起重要作用。与其他健忘症或痴呆相关疾病一样，间脑性健忘症也伴有胆碱能功能障碍。通过间脑失忆症动物模型，我们证实了中隔/对角带（MS/DB）的胆碱能丧失和海马的低胆碱能输出与行为障碍相关，可通过拟胆碱药物缓解。这些结果可归因于两种可能相互正交的机制：(1)MS/DB区胆碱能细胞的丧失导致学习过程中海马的低胆碱能输出；(2)丘脑和下丘脑核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乙酰胆碱的输出受损。本研究采用2种间脑遗忘症啮齿动物模型，从系统层面分析间脑遗忘症的神经解剖、神经化学和行为功能障碍之间的关系。目的：利用动物模型，我们将：(A)应用立体显微镜技术，结合免疫细胞化学，全面记录几个重要的胆碱能上升通路中的胆碱能细胞损失；(B)通过体内微透析/高效液相色谱的新应用来评估功能性乙酰胆碱破坏，以评估在一系列任务和与间脑失忆症中受损核相关的大脑区域（海马、杏仁核和背纹状体）的认知加工过程中的乙酰胆碱外排；(C)测试海马或间隔给药增加脑乙酰胆碱水平是否会不同程度地导致学习/记忆功能恢复；(D)利用离散神经毒素诱导的病变绘制间脑核的功能多样性图，以确定这些病变是否导致关键记忆结构中乙酰胆碱输出减少。意义：间脑性遗忘的神经机制尚不明确。在间脑失忆症动物模型的认知测试中使用在线体内微透析是新颖的，将增强我们对间脑和其他边缘结构之间相互依赖关系的理解。这些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.