The neuroendocrine stress response impairs hippocampal vascular function and memory in male and female rats

Chronic psychological stress affects brain regions involved in memory such as the hippocampus and accelerates age-related cognitive decline, including in Alzheimer's disease and vascular dementia. However, little is known about how chronic stress impacts hippocampal vascular function that is critically involved in maintaining neurocognitive health that could contribute to stress-related memory dysfunction. Here, we used a novel experimental rat model that mimics the neuroendocrine and cardiovascular aspects of chronic stress to determine how the neuroendocrine components of the stress response affect hippocampal function. We studied both male and female rats to determine potential sex differences in the susceptibility of the hippocampus and its vasculature to neuroendocrine stress-induced dysfunction. We show that activation of neuroendocrine stress pathways impaired the vasoreactivity of hippocampal arterioles to mediators involved in coupling neuronal activity with local blood flow that was associated with impaired memory function. Interestingly, we found more hippocampal arteriolar dysfunction and scarcer hippocampal microvasculature in male compared to female rats that was associated with greater memory impairment, suggesting the male sex may be at increased risk of neuroendocrine-derived hippocampal dysfunction during chronic stress. Overall, this study revealed the therapeutic potential of targeting hippocampal arterioles to prevent or slow memory decline in the setting of prolonged and/or unavoidable stress.