Lean Mice Exposed to Early Life Stress Exhibit Increased Basal Sympathetic Tone and Blunted Parasympathetic Activation in Response to High Salt Diet

Abstract

Previously, we showed that male mice subjected to Maternal Separation and Early Weaning (MSEW), a model of early life stress, exhibit heightened cardiovascular responses to hypertensive stimuli. This study aimed to determine whether MSEW increases blood pressure salt sensitivity. Male C57BL/6J mouse pups were separated daily from their dams for 4-8 h from postnatal Day 2-16. MSEW mice were weaned the following day, while control litters were normally reared and weaned at postnatal Day 21, after which all mice were placed on a low-fat, normal salt diet (LFNS, 10% kcal from fat, 0.4% NaCl) for 20 weeks. Subsequently, mice were randomized to either LFNS or a low-fat, high-salt diet (LFHS, 10% kcal from fat, 4.0% NaCl) for an additional 6 weeks. MSEW induced sympathetic overactivity in mice on the LFNS diet, evidenced by increased urinary NE excretion, reduced low-frequency heart rate variability, and downregulation of cardiac adrenergic receptors compared to control mice. Despite diminished cardiac parasympathetic activation compared to controls, MSEW mice showed enhanced water and electrolyte excretion in response to increased dietary sodium content during daytime hours. Taken together, MSEW increases the basal sympathetic tone and reduces the overall adaptability and responsiveness of the cardiovascular system to increases in dietary sodium content. This impaired autonomic regulation of blood pressure and heart rate variability may favor the development of cardiovascular dysfunction in settings of renal disease where the kidneys lack the capacity to compensate for the excess of sodium intake.

Keywords: circadian regulation; developmental programming; low‐fat diet; spectral analysis of blood pressure; water and electrolytes homeostasis.