Hypothalamic–Pituitary–Adrenal Dysfunction inApoe^−/−Mice: Possible Role in Behavioral and Metabolic Alterations

Abstract

Several neurological diseases are frequently accompanied by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis regulates the secretion of glucocorticoids (GCs), which play important roles in diverse brain functions, including cognition, emotion, and feeding. Under physiological conditions, GCs are adaptive and beneficial; however, prolonged elevations in GC levels may contribute to neurodegeneration and brain dysfunction. In the current study, we demonstrate that apolipoprotein E (apoE) deficiency results in agedependent dysregulation of the HPA axis through a mechanism affecting primarily the adrenal gland. Apoe Ϫ/Ϫ mice, which develop neurodegenerative alterations as they age, had an age-dependent increase in basal adrenal corticosterone content and abnormally increased plasma corticosterone levels after restraint stress, whereas their plasma and pituitary adrenocorticotropin levels were either unchanged or lower than those in controls. HPA axis dysregulation was associated with behavioral and metabolic alterations. When anxiety levels were assessed in the elevated plus maze, Apoe Ϫ/Ϫ mice showed more anxiety than wild-type controls. Apoe Ϫ/Ϫ mice also showed reduced activity in the open field. Finally, Apoe Ϫ/Ϫ mice showed age-dependent increases in food and water intake, stomach and body weights, and decreases in brown and white adipose tissues. These results support a key role for apoE in the tonic inhibition of steroidogenesis and HPA axis activity and have important implications for the behavioral analysis of Apoe Ϫ/Ϫ mice.

Apolipoprotein E knockout mice have accentuated malnutrition with mucosal disruption and blunted insulin-like growth factor I responses to refeeding

“…Among extrahepatic tissues, the adrenal gland has one of the highest concentrations of the apoE mRNA and the highest rate of apoE synthesis [40]. In this regard, it is known that apoE-ko mice exhibit dysfunction of the hypothalamic-pituitaryadrenal axis, leading to increased basal adrenal corticosterone levels in these mice with age [41].…”

Role of H3-Receptor-Mediated Signaling in Anxiety and Cognition in Wild-Type and Apoe–/– Mice

“…Anxiety levels were assessed with an elevated, plus-shaped maze consisting of two open arms and two closed arms equipped with rows of infrared photocells interfaced with a computer (Hamilton-Kinder, Poway, CA), as described (Raber et al, 2000). Mice were placed individually in the center of the maze and allowed free access for 10 min.…”

“…Thus, compared to wild-type controls, Apoe -/-mice show an increased sensitivity to the effects of H 1 receptor blockade on measures of anxiety. To determine whether in Apoe -/-the effects of mepyramine on measures of anxiety in the plus maze were associated with an altered HPA axis response (Knigge et al, 1999), we also measured plasma ACTH and corticosterone levels directly after plus maze testing, as described previously (Raber et al, 2000). Compared to saline controls, mepyramine reduced the plasma corticosterone levels in wild-type (saline: 179 7 38 pg/ml, n ¼ 6; mepyramine: 89 7 26 pg/ml, n ¼ 6; po0.05 Tukey-Kramer), but not in Apoe -/-(saline: 206 7 30 pg/ml, n ¼ 8; mepyramine: 224 7 10 pg/ml, n ¼ 9), mice.…”

Changes in anxiety-related behaviors and hypothalamic–pituitary–adrenal activity in mice lacking the 5-HT-3A receptor

“…Mice were killed by decapitation to collect sufficient blood to perform both the ACTH and corticosterone assays. Therefore, separate groups of mice were decapitated immediately following removal from the home cage (the 0-min time point) and at the end of a 30-min period of restraint in a plastic cylindrical tube [34]. For plasma ACTH, the number of mice used were the following: n = 11 for WT and n = 13 for KO under basal conditions, and n = 14 for WT and n = 14 for KO at 30-min restraint.…”