Chronic heart failure in forebrain circuit dementias

前脑回路痴呆引起的慢性心力衰竭

基本信息

批准号：
10276214
负责人：
CHARLES C LEE
金额：
$ 14.8万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-17 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10276214
关键词：
Affect Alzheimer&apos s Disease Anatomy Applications Grants Area Behavior Behavioral Biological Assay Biological Models Brain Cardiac Cells Cognitive Cognitive deficits Congestive Heart Failure Dementia Development Diagnosis Diagnostic Electrophysiology (science)Flavoproteins Foundations Future Glutamates Goals Health Healthcare Systems Heart failure Hospitalization Image Impaired cognition In Vitro Individual Investigation Knowledge Lasers Lesion Link Mediating Methods Mission Molecular Mus Neural Pathways Neurobehavioral Manifestations Neurologic Neurons Outcome Pathway interactions Perception Physiological Play Preparation Productivity Prosencephalon Public Health Quality of life Research Role Route Scanning Slice Societies Symptoms Syndrome Testing Thalamic Nuclei Thalamic structure United States United States National Institutes of Health Vascular Dementia associated symptom experience experimental study improved in vivo innovation mouse model neural circuit neuromechanism neurophysiology novel optogenetics prevent prospective relating to nervous system response therapeutic target

项目摘要

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.

抽象的心力衰竭（HF）是一个主要的健康问题，是心脏综合征的终末期表现，是一种严重的健康问题。这是美国老年人住院的主要原因。慢性心力衰竭伴有由于大脑神经回路的改变而引起的认知缺陷，并使个体容易陷入血管性痴呆和阿尔茨海默病的发展。该提案的主要目标是描述慢性心衰小鼠模型中前脑神经通路的改变。中央该提议的假设是，慢性心力衰竭导致皮质丘脑与皮质丘脑的差异性变性皮质通路。预计这将导致前脑和大脑功能连接的变化是慢性心力衰竭认知缺陷进展的基础。该项目的具体目标是表征小鼠模型中第 5 层皮质丘脑通路与第 2/3 层皮质丘脑通路的变化慢性心力衰竭通过检查：1）第 5 层和第 2/3 层神经元的神经解剖学连接发生变化 2）高阶丘脑核和皮质区域介导的神经生理反应的改变通过激活这些层的通路。拟议的实验预计将确定这些变化由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途径的改变与慢性心力衰竭和认知障碍患者的认知缺陷直接联系起来最终恢复该模型系统的正常行为。这些实验将产生积极影响阐明第 5 层皮质丘脑通路在认知缺陷中的重要作用慢性心力衰竭，这将导致对该病及相关后遗症的诊断和前瞻性治疗的加强，尤其是血管性痴呆和阿尔茨海默病。