Chronic heart failure in forebrain circuit dementias

摘要 心力衰竭(HF)是一个主要的健康问题，是心脏综合征的终末期表现，是 是美国老年人住院的主要原因。慢性心力衰竭伴发 由大脑中神经回路的改变引起的认知缺陷，并使个人容易患上 血管性痴呆和阿尔茨海默病的发展。这项建议的主要目标是 描述慢性心衰小鼠模型前脑神经通路的变化。中环 这一建议的假设是，慢性心力衰竭导致皮质丘脑和 皮质通路。预计这将导致前脑功能连接的变化，并 这是慢性心力衰竭患者认知功能障碍发展的基础。这个项目的具体目标是 小鼠皮层丘脑第5层通路与第2/3层通路的变化 慢性心力衰竭的检查：1)第5层和第2/3层神经元的神经解剖联系的变化 2)丘脑高阶核团和皮质区神经生理反应的改变 通过激活来自这些层的通路。预计拟议中的实验将确定这些变化 通过这些不同途径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心衰和慢性心力衰竭患者的认知障碍直接联系起来 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5层皮质丘脑通路在以下认知缺陷中的重要作用 慢性心力衰竭，这将导致对这种后遗症和相关后遗症的加强诊断和前瞻性治疗， 尤其是血管性痴呆症和阿尔茨海默病。

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.