Neurovascular coupling and oxygenation are decreased in hippocampus compared to neocortex because of microvascular differences

Abstract

The hippocampus is essential for spatial and episodic memory but is damaged early in Alzheimer’s disease and is very sensitive to hypoxia. Understanding how it regulates its oxygen supply is therefore key for designing interventions to preserve its function. However, studies of neurovascular function in the hippocampus in vivo have been limited by its relative inaccessibility. Here we compared hippocampal and visual cortical neurovascular function in awake mice, using two photon imaging of individual neurons and vessels and measures of regional blood flow and haemoglobin oxygenation. We show that blood flow, blood oxygenation and neurovascular coupling were decreased in the hippocampus compared to neocortex, because of differences in both the vascular network and pericyte and endothelial cell function. Modelling oxygen diffusion indicates that these features of the hippocampal vasculature may restrict oxygen availability and could explain its sensitivity to damage during neurological conditions, including Alzheimer’s disease, where the brain’s energy supply is decreased.

Strategic Modification of Gut Microbiota through Oral Bacteriotherapy Influences Hypoxia Inducible Factor-1α: Therapeutic Implication in Alzheimer’s Disease

“…Gastrointestinal-tract microbiota-derived LPS is an important contributor to inflammatory neurodegeneration in the brain of AD patients [ 20 ], contributing to neuronal loss and impaired memory. Considering that, in AD subjects, specific cerebral regions are more susceptible to damages due to BBB dysfunction, impaired vascularization, and hypoxic insult [ 12 ], it is crucial to identify new strategies to improve neuronal function by modulating the expression level of key molecular agents that can finely modulate the gut–brain axis, reduce nitric oxide and ROS production, and counteract neuronal cell loss. In particular, during hypoxia the oxygen-regulated subunit HIF-1α forms a heterodimer with the constitutively expressed HIF-1β, influencing the transcription of important regulators of glucose homeostasis, cellular stress, inflammation, and apoptosis [ 21 ].…”

“…Considering that blood oxygenation is especially reduced in the hippocampus of AD subjects and that the decreased neurovascular function contributes to AD damages [ 12 ], hypoxia conditioning has been described as a promising strategy to cure diseases of the central nervous system [ 13 , 14 ].…”

Neurovascular Coupling in Development and Disease: Focus on Astrocytes

“…More information on the regional variety of astrocyte properties and function, particularly in subcortical and brain stem regions, have yet to be discovered. Likewise, whether heterogeneity of astrocytes contributes to regional variations in neurovascular coupling ( Ekstrom, 2021 ), such as that reported between the visual cortex and hippocampus ( Shaw et al, 2021 ), is also unknown and a question that demands further attention.…”

Hypoxia-Induced Neuroinflammation in Alzheimer’s Disease: Potential Neuroprotective Effects of Centella asiatica

“…Since AD is clinically manifested by memory loss and cognitive decline, these hypoxic insults are considered as predisposing factors of ageing brain towards AD ( Zhang et al, 2019 ). A spatial and episodic memory of AD patients is progressively deteriorated over time as the brain processes in their hippocampus become dysfunctional and very sensitive to hypoxia ( Shaw et al, 2021 ). The changes in vascular structures and functions are commonly observed as early features of developing AD, as the dysfunction of blood–brain barrier and inadequate cerebral perfusion can promote accumulation of Aβ as well as hyperphosphorylation of tau proteins ( Montagne et al, 2016 ).…”