Gradual hypertension induction in middle‐aged Cyp1a1‐Ren2 transgenic rats produces significant impairments in spatial learning

Abstract

Hypertension is a major health concern in the developed world, and its prevalence increases with advancing age. The impact of hypertension on the function of the renal and cardiovascular systems is well studied; however, its influence on the brain regions important for cognition has garnered less attention. We utilized the Cyp1a1‐Ren2 xenobiotic‐inducible transgenic rat model to mimic both the age of onset and rate of induction of hypertension observed in humans. Male, 15‐month‐old transgenic rats were fed 0.15% indole‐3‐carbinol (I3C) chow to slowly induce renin‐dependent hypertension over a 6‐week period. Systolic blood pressure significantly increased, eventually reaching 200 mmHg by the end of the study period. In contrast, transgenic rats fed a control diet without I3C did not show significant changes in blood pressure (145 mmHg at the end of study). Hypertension was associated with cardiac, aortic, and renal hypertrophy as well as increased collagen deposition in the left ventricle and kidney of the I3C‐treated rats. Additionally, rats with hypertension showed reduced savings from prior spatial memory training when tested on the hippocampus‐dependent Morris swim task. Motor and sensory functions were found to be unaffected by induction of hypertension. Taken together, these data indicate a profound effect of hypertension not only on the cardiovascular‐renal axis but also on brain systems critically important for learning and memory. Future use of this model and approach may empower a more accurate investigation of the influence of aging on the systems responsible for cardiovascular, renal, and neurological health.

Evolution of Brain Morphology in Spontaneously Hypertensive and Wistar-Kyoto Rats From Early Adulthood to Aging: A Longitudinal Magnetic Resonance Imaging Study

“…The acute effects of hypertension on brain have been recognized for a long time ( Iyonaga et al, 2019 ), while the long-term impacts of chronic hypertension on brain impairment remain incompletely understood. Only a few experiments have evaluated the influence of chronic hypertension ( Willeman et al, 2019 ). SHRs are the most widely used animal model for human essential hypertension.…”

Age-Related Regional Network Covariance of Magnetic Resonance Imaging Gray Matter in the Rat

“…We used the Fischer 344 rat for our study of age-related differences in regional MRI network gray matter, as there have been decades of experience in investigating aging behavior in this rodent model. This work could also be extended to different rodent and other animal models, including those that develop spontaneous health conditions, to evaluate how the development of such comorbid conditions often associated with human aging, like hypertension (Kern et al, 2017 ; Willeman et al, 2019 ; Van Etten et al, 2020 ), impact the aging brain. In this case, further methodological development efforts will be important to help facilitate the harmonization of MRI and other imaging modalities with differing spatial resolutions to support such cross-species comparisons.…”

The new mechanism of cognitive decline induced by hypertension: High homocysteine-mediated aberrant DNA methylation

“…Angiotensin II-treated mice exhibit short-term memory impairment and greater blood–brain barrier (BBB) leakage, microglial activation, and myelin loss than control adult mice ( 29 ). In addition, gradual induction of angiotensin II-dependent hypertension has been shown to produce significant spatial learning impairments in middle-aged cytochrome P450 family 1, subfamily A polypeptide 1 (Cyp1a1)-Ren2 transgenic rats ( 30 ). Furthermore, increased plasma aldosterone impairs cognitive function, whereas spironolactone and eplerenone, mineral corticoid receptor blockers, protect against cardiovascular mortality and cognitive impairment ( 31 , 32 ).…”