Hypertension promotes hippocampal inflammation and cognitive impairment via sympathetic activation of peripheral immune system
Hypertension (HTN) has been associated with cerebrovascular dysfunction and cognitive impairment. To understand how HTN affects the brain, the coupling between oxygen consumption and cerebral blood flow in multiple brain regions was firstly analyzed using functional MRI, in patients with HTN and healthy controls. It indicated less functional hyperemia in the cortical areas of HTN group, but showed no difference in their hippocampus. We then used deoxycorticosterone acetate (DOCA)-salt model, in which HTN is developed via sympathetic overactivity, and confirmed HTN-associated cognitive decline and reduction in functional hyperemia of pia arterioles in both male and female mice. Notably, maze test-based cognitive function was partially protected in female mice. In the sensory cortex and hippocampus of male HTN mice, we detected higher reactiveness of glial cells, compared to sham controls. But microglia in the hippocampus reacted more to DOCA-salt, showing a sub-population characterized by high expression of Apoe, B2m, Ramp1, and S100a8/a9, which was not detected in the cortex. With further analyzing the gene profile of immune cells, it revealed disease-associated types of monocyte and macrophage only in the hippocampus, and pinpointed an involvement of peripheral reservoir of immune cells. Next, to determine possible contribution from sympathetic agitation of the peripheral immune system, we tested mice lacking neuron-expressed type 1 angiotensin-II receptors (AT1R), a line that previously showed blunted sympathoexcitation under DOCA-salt treatment. In addition to improved cognitive function, DOCA-salt-induced upregulation of glial reactiveness and pro-inflammatory markers were not seen, and Bdnf expression was preserved in the hippocampus of those mice. To test the role of spleen, which deployed leukocytes upon splenic sympathoexcitation in DOCA-salt HTN, splenectomy was performed and it attenuated hippocampal inflammation and cognitive impairment, in a similar manner as neuronal AT1R knockout. Together, our data provide evidence that the cortex and hippocampus were differently affected by HTN, and proposed a neural mechanism for HTN-associated cognitive impairment that involves sympathoexcitation-induced immune response, thus highlighting that autonomic regulation of the immune system could be a therapeutic target for improving hippocampal health during HTN. Overall design: The hippocampus and sensory cortex of DOCA-salt- or sham-treated WT mice were rapidly isolated and  analysed by Single-cell RNA sequencing (scRNA-seq).