Defective hippocampal neurogenesis underlies cognitive impairment by carotid stenosis-induced cerebral hypoperfusion in mice

Frontiers in Cellular Neuroscience

Neuroscience

Juan Manuel Garcia-Segura¹  María Ángeles Moro²  María Isabel Cuartero³  Violeta Medina³  Enrique Fraga³  Alicia García-Culebras⁴  Olivia Hurtado⁵  Macarena Hernández-Jiménez⁵  Isabel Bravo-Ferrer⁵  Ignacio Lizasoain⁶  Jesus Miguel Pradillo⁶ 

[1] Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid (UCM), Madrid, Spain;ICTS Bioimagen Complutense, Universidad Complutense de Madrid (UCM), Madrid, Spain;Neurovascular Pathophysiology Group, Cardiovascular Risk Factor and Brain Function Programme, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain;Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain;Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain;Neurovascular Pathophysiology Group, Cardiovascular Risk Factor and Brain Function Programme, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain;Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain;Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain;Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid (UCM), Madrid, Spain;Neurovascular Pathophysiology Group, Cardiovascular Risk Factor and Brain Function Programme, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain;Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain;Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain;Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid (UCM), Madrid, Spain;Departamento de Biología Celular, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain;Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain;Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain;Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain;Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid (UCM), Madrid, Spain;

关键词: hypoperfusion;    carotid stenosis;    neurogenesis;    hippocampus;    vascular cognitive impairment;    dementia;    aberrant neurogenesis;    maladaptive remodeling;   

DOI  :  10.3389/fncel.2023.1219847

 received in 2023-05-09, accepted in 2023-07-31,  发布年份 2023

来源: Frontiers

【 摘 要 】

Chronic cerebral hypoperfusion due to carotid artery stenosis is a major cause of vascular cognitive impairment and dementia (VCID). Bilateral carotid artery stenosis (BCAS) in rodents is a well-established model of VCID where most studies have focused on white matter pathology and subsequent cognitive deficit. Therefore, our aim was to study the implication of adult hippocampal neurogenesis in hypoperfusion-induced VCID in mice, and its relationship with cognitive hippocampal deficits. Mice were subjected to BCAS; 1 and 3 months later, hippocampal memory and neurogenesis/cell death were assessed, respectively, by the novel object location (NOL) and spontaneous alternation performance (SAP) tests and by immunohistology. Hypoperfusion was assessed by arterial spin labeling-magnetic resonance imaging (ASL-MRI). Hypoperfused mice displayed spatial memory deficits with decreased NOL recognition index. Along with the cognitive deficit, a reduced number of newborn neurons and their aberrant morphology indicated a remarkable impairment of the hippocampal neurogenesis. Both increased cell death in the subgranular zone (SGZ) and reduced neuroblast proliferation rate may account for newborn neurons number reduction. Our data demonstrate quantitative and qualitative impairment of adult hippocampal neurogenesis disturbances associated with cerebral hypoperfusion-cognitive deficits in mice. These findings pave the way for novel diagnostic and therapeutic targets for VCID.

【 授权许可】

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Copyright © 2023 Fraga, Medina, Cuartero, García-Culebras, Bravo-Ferrer, Hernández-Jiménez, Garcia-Segura, Hurtado, Pradillo, Lizasoain and Moro.