Effects of a mild decrease in brain blood or oxygen supply on hippocampal function

Baseline blood flow (CBF), blood oxygen saturation (sO2), and vascular density are lower in the hippocampus than the visual cortex (V1), despite similar oxygen consumption rates. The hippocampus is therefore likely to be especially vulnerable to even mild decreases in brain blood or oxygen supply, as seen in Alzheimer’s disease (AD) and acute mountain sickness (AMS).

We compared the effects of mildly decreasing brain blood and oxygen supply on hippocampal versus V1 function in mice. To achieve this, we either injected N(G)-Nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor that constricts blood vessels and reduces CBF, or mildly reduced the fraction of inspired oxygen (FiO2) using an altitude generator. The generator supplied mice with air of 21-11% FiO2 via a nose cone or tent enclosing the mouse’s cage.

In mice that underwent surgery to place a cranial window over the hippocampus or V1, we recorded haemodynamic changes using an oxy-CBF probe, and neuronal activity using 2-photon microscopy. Baseline CBF and sO2 were lower in hippocampus than V1. L-NAME reduced CBF, sO2, and oxygen consumption, but increased vasomotion in both regions. Mild hypoxia briefly increased CBF but decreased sO2, more in hippocampus, leading to pyramidal cell hyperactivity hippocampus and hypoactivity in V1. Neurovascular coupling was preserved.

We also measured effects of hypoxia on metabolism and nutrient homeostasis in post-mortem brain tissue. After 1hr at 21% or 11% FiO2, mice were culled, and brains collected for biochemical assays or mass spectrometry. Mild hypoxia reduced iron levels only in hippocampus, and there were no changes in cortex or whole brain.

Overall, mild decreases in brain blood or oxygen supply produce lower oxygenation in hippocampus than V1. This causes different effects on neuronal activity and nutrient homeostasis and may help explain why the hippocampus is one of the most affected regions in AD