Chronic heart failure in forebrain circuit dementias

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.