Corticosterone dysregulation exacerbates disease progression in the R6/2 transgenic mouse model of Huntington's disease

Abstract

Huntington's disease (HD) is a genetic neurological disorder that causes severe and progressive motor, cognitive, psychiatric, and metabolic symptoms. There is a robust, significant elevation in circulating levels of the stress hormone, cortisol, in HD patients; however the causes and consequences of this elevation are largely uncharacterized. Here, we evaluated whether elevated levels of corticosterone, the rodent homolog of cortisol, contributed to the development of symptomology in transgenic HD mice. Wild-type (WT) and transgenic R6/2 mice were given either: 1) adrenalectomy with WT level corticosterone replacement (10ng/ml), 2) adrenalectomy with high HD-level corticosterone replacement (60ng/ml), or 3) sham surgery without replacement. R6/2 mice on HD-level replacement showed severe and rapid weight loss (p<.05) and a shorter latency to death (p<.01) relative to the HD mice on WT-level replacement. We further evaluated basal and stress-induced levels of circulating corticosterone in R6/2 mice throughout the course of their life. We found that R6/2 transgenic HD mice display a spontaneous elevation in circulating corticosterone levels that became significant at 10 weeks of age. Furthermore, we identified significant dysregulation of circadian rhythmicity of corticosterone release measured over a 24 hour period compared to wildtype controls. Unexpectedly, we found that R6/2 transgenic mice show a blunted corticosterone response to restraint stress, compared to wild-type mice. Together, this data provides further evidence that HPA-axis activity is abnormal in R6/2 mice, and highlights the important role that cortisol plays in HD symptom development. Our findings suggest that cortisol-reducing therapeutics may be of value in improving HD patient quality of life.

Normalizing glucocorticoid levels attenuates metabolic and neuropathological symptoms in the R6/2 mouse model of huntington's disease

“…Another cohort of WT and HD mice were given sham surgeries, and provided with vehicle only (no corticosterone replacement) for their drinking water (n=17 HD and n=18 WT). Corticosterone dosing was adjusted from our previously published study (Dufour and McBride, 2016) to reduce the HD-level replacement to a dose that is closer to the levels of hypercortisolinemia normally seen in transgenic R6/2 mice (35μg/ml instead of 60μg/ml). This new 35μg/ml HD-level replacement dose was determined in a pilot (Supplemental Fig.…”

“…This new 35μg/ml HD-level replacement dose was determined in a pilot (Supplemental Fig. 1) with a target plasma corticosterone level of 300 ng/ml, similar to peak corticosterone levels shown by R6/2 HD mice (Dufour and McBride, 2016). The target plasma corticosterone levels for WT-level corticosterone replacement (10μg/ml) was 100 ng/ml, as demonstrated previously (Dufour and McBride, 2016).…”

“…Since R6/2 HD mice show circadian dysregulation in peak plasma corticosterone levels, with individuals peaking at variable times that is idiosyncratic to individual mice, we did not analyze blood samples from sham mice as it would have necessitated a circadian profile that would have been stressful for mice and possibly altered some of the metabolic measures of interest. Instead, we refer readers to our circadian profile of plasma corticosterone published previously in mice form the same colony (Dufour and McBride, 2016).…”

“…However, while these findings provide abundant circumstantial evidence for a role for glucocorticoids in HD metabolic symptoms and neuropathology, there has been little direct evidence to support this speculation. Of the existing HD mouse models, a spontaneous elevation in corticosterone, the rodent homolog of cortisol, has only been described in R6/2 mice (Bjorkqvist et al, 2006a; Dufour and McBride, 2016). R6/2 transgenic mice show robust metabolic symptomology including severe and progressive weight-loss, muscle wasting, and insulin resistance (Bjorkqvist et al, 2005; Luthi-Carter et al, 2002; van der Burg et al, 2009).…”

“…We recently demonstrated that experimental elevation of corticosterone in adrenalectomized R6/2 mice dramatically exacerbates weight loss and shortens the latency to death (Dufour and McBride, 2016). While this provides direct evidence that an elevation in glucocorticoids can exacerbate HD symptomology, it remains unclear whether normalizing glucocorticoids to wild-type (WT) levels in HD mice would conversely attenuate HD symptomology.…”