Abstract
Introduction: Comparisons of hypothalamic dysfunction between Huntingtons Disease (HD) patients and rodent models of HD have not always yielded similar results. Cortisol levels in HD patients have been contradictory, with reports ranging from hypo- to hypercorticoidism of morning measurements. Initial reports of major elevations in circulating corticosterone levels in the R6/2 mouse model of HD have only been followed up in one other closely related model, the R6/1 mouse, and the results were not perfectly congruent. To determine if abnormal stress hormones were a characteristic of disease, we examined diurnal and stress-induced corticosterone levels in multiple HD mouse models. Methods: We analyzed serum corticosterone levels from R6/2, Q140 and BACHD mice either diurnally (R6/2) or after restraint stress and subsequent recovery (all 3 models). Glucocorticoid secretion was also examined (R6/2) following dexamethasone suppression and ACTH stimulation. Blood samples were collected either by submandibular puncture or as trunk blood at sacrifice. Plasma corticosterone levels were assayed by RIA. Regional brain glucocorticoid receptor (GR) levels were visualized using immunofluorescence. Results: In the R6/2 mouse, basal levels of corticosterone, exhibited normal, sexually dimorphic diurnal rhythms but eventually became elevated towards end of life, after 13 weeks. The ability of the adrenal gland to produce corticosterone was not altered and the adrenal response to ACTH stimulation was only elevated in male R6/2 mice compared to littermates. Down regulation of GR receptors was only observed in the PVN at 16 weeks. R6/2 mice at both 6 and 12 weeks responded equivalently to littermates in the initial corticosterone response to restraint stress but serum corticosterone recovered from stress significantly more slowly. No differences were found in the initial stress response or in the recovery from stress for Q140 or BACHD mice, examined at 12 and 9 months, respectively. Conclusions: We did not find evidence of major disruption in glucocorticoid signaling in HD mouse models. A significantly slowed recovery from stress observed in the R6/2 mouse suggests such disruptions are context dependent. These results suggest that disruption of the HPA axis was subtle and occurred only at advanced stages of disease represented by comparisons among these HD mouse models.
Competing Interest Statement
The authors have declared no competing interest.