title: 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<0.05) and a shorter latency to death (p<0.01) 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 10weeks of age. Furthermore, we identified significant dysregulation of circadian rhythmicity of corticosterone release measured over a 24h period compared to wild-type controls. Unexpectedly, we found that R6/2 transgenic mice show a blunted corticosterone response to restraint stress, compared to wild-type mice. Together, these data provide further evidence that HPA-axis activity is abnormal in R6/2 mice, and highlight 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.
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA; Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, 97006, USA.
authors.forename: Brett D
authors.initials: BD
authors.lastname: Dufour
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA; Department of Neurology, Oregon Health and Science University, Portland, OR, USA; Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, 97006, USA. Electronic address: mcbridej@ohsu.edu.
authors.forename: Jodi L
authors.initials: JL
authors.lastname: McBride
mesh_terms: D000315:Adrenalectomy; D000367:Age Factors; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001835:Body Weight / Q000502:physiology; D003345:Corticosterone / Q000008:administration & dosage / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005106:Exploratory Behavior / Q000187:drug effects; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D006854:Hydrocortisone; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D003345:Corticosterone; D006854:Hydrocortisone
keywords: Circadian dysfunction; Corticosterone; Cortisol; HPA-axis; Huntington's disease; R6/2 transgenic mice