Hippocampal Vascular Dysfunction and Impaired Memory in a Neuroendocrine Model of Stress and Hypertension

Abstract

The hippocampus is a deep brain structure critically involved in learning and memory that is highly susceptible to hypoxic/ischemic injury. Hypertension and psychological stress are major risk factors of dementia; however, their effects on the vasculature of the cognition-centric hippocampus remain unclear. This study investigated hippocampal vascular function and memory in a novel model of neuroendocrine-derived stress and hypertension. This model is induced via vector mediated brain-derived neurotrophic factor (BDNF) overexpression in the paraventricular nucleus of the hypothalamus (PVN) that causes chronic stimulation of the major hypothalamic stress pathways (e.g. hypothalamic-pituitary-adrenal axis), leading to significant long-term elevation of blood pressure. We hypothesized that function of the arterioles supplying the hippocampus and memory would be impaired in this BDNF-PVN model of chronic stress and hypertension. Potential sex differences in the susceptibility of the hippocampus to dysfunction were also investigated. Male and female Sprague Dawley rats received bilateral PVN injections of AAV2 vectors expressing BDNF or GFP for control (n=6-8/group) at 8 weeks of age. Four weeks later, an object recognition task was used to quantify the percent of time spent investigating a novel object as a measure of hippocampal-dependent long-term memory function. Hippocampal arterioles (HAs) from the same rats were then studied isolated and pressurized in an arteriograph chamber. Vasodilator responses of HAs to mediators of functional hyperemia were measured, including small- and intermediate-conductance calcium-activated potassium (SK/IK) channel activation via NS309, and activation of inward rectifier potassium (KIR) channels by increasing extracellular K+ from 3-15mM. Memory function was significantly impaired by PVN-BDNF treatment (two-way ANOVA, Tukey's post hoc test, F1,22=16.53; p=0.001), but sex had no effect (F1,22=1.16; p=0.29). Object recognition was lower in both male and female PVN-BDNF rats that spent 49±3% and 52±6% of the time with the novel object, compared to control male and female rats that spent 66±3% and 72±4% of the time investigating the novel object. HAs from male and female PVN-BDNF rats dilated significantly less to NS309 than controls (F1,20=12.35; p=0.002), suggesting endothelial damage. Surprisingly, activation of KIR channels with 15mM K+ caused a 3-5% vasoconstriction of HAs from both male and female PVN-BDNF rats that was in striking contrast to the 20-30% vasodilation that occurred in response to KIR channel activation in HAs from control rats (F1,19=24.90; p<0.0001). These data show that chronic neuroendocrine stress and hypertension caused hippocampal vascular dysfunction and impaired memory similarly in male and female rats. The blunted vasodilation of HAs from PVN-BDNF rats suggests functional hyperemia may be impaired in the hippocampus that could lead to neuronal dysfunction, memory loss and dementia.