Chronic heart failure in forebrain circuit dementias

摘要 心力衰竭（HF）是一个主要的健康问题，作为心脏综合征的终末期表现而出现， 这是美国老年人住院的主要原因。慢性HF伴有 由于大脑神经回路的改变而引起的认知缺陷， 血管性痴呆和阿尔茨海默病的发展。这项建议的主要目的是 表征慢性HF小鼠模型中前脑神经通路的改变。中央 该建议的假设是慢性HF导致皮质丘脑与 皮质皮质通路预计这将导致前脑功能连接的变化， 是慢性HF认知缺陷进展的基础。该项目的具体目标是， 小鼠模型中第5层皮质丘脑与第2/3层皮质皮质通路的改变 慢性HF通过检查：1）第5层和第2/3层神经元的神经解剖学连接的变化 和2）丘脑高级核团和皮层区域介导的神经生理反应的改变 通过激活这些层的通路。预计拟议的实验将确定这些变化 这些不同通路介导的前脑功能连接，并指导我们未来的研究 旨在将这些通路的改变与慢性HF中经历的认知缺陷直接联系起来， 最终恢复这个模型系统的正常行为。这些实验将产生积极的影响， 阐明第5层皮质丘脑通路在以下认知缺陷中的重要作用 慢性HF，这将导致对这种和相关后遗症的增强诊断和前瞻性治疗， 尤其是血管性痴呆和阿尔茨海默病。

ABSTRACT Heart failure (HF) is a major health issue, arising as the end-stage manifestation of cardiac syndromes and is the leading cause of hospitalization among seniors in the United States. Chronic HF is accompanied by cognitive deficits arising from alterations to neural circuitry in the brain and predisposes individuals to the development of vascular dementia and Alzheimer's disease. The primary objective of this proposal is to characterize the alterations to forebrain neural pathways in a mouse model of chronic HF. The central hypothesis of this proposal is that chronic HF results in a differential degeneration of corticothalamic versus corticocortical pathways. This is expected to result in changes to functional connectivity in the forebrain and underlie the progression of cognitive deficits in chronic HF. The specific aims of this project are to characterize the alterations to the layer 5 corticothalamic versus layer 2/3 corticocortical pathways in a mouse model of chronic HF by examining: 1) changes to the neuroanatomical connections of the layer 5 and layer 2/3 neurons and 2) alterations to neurophysiological responses in higher-order thalamic nuclei and cortical areas mediated by activation of pathways from these layers. The proposed experiments are expected to identify the changes to forebrain functional connectivity mediated by these different pathways and guide our future investigations aimed at directly linking alterations to these pathways with the cognitive deficits experienced in chronic HF and ultimately restoring normal behavior in this model system. These experiments will have a positive impact by illuminating the important role of the layer 5 corticothalamic pathways underlying the cognitive deficits following chronic HF, which will lead to enhanced diagnostics and prospective treatments for this and related sequelae, notably vascular dementia and Alzheimer's disease.