Behavioral Assessment of Stress Compensation in Minipigs Transgenic for the Huntington Gene Using Cortisol Levels: A Proof-of-Concept Study

Article type: Research Article

Authors: Schuldenzucker, Verena^{a; b} | Schubert, Robin^a | Muratori, Lisa M.^{a; c} | Freisfeld, Frauke^{a; d} | Rieke, Lorena^{a; e} | Matheis, Tamara^{a; e} | Schramke, Sarah^a | Motlik, Jan^f | Kemper, Nicole^e | Radespiel, Ute^b | Reilmann, Ralf^{a; d; g; *}

Affiliations: [a] George-Huntington-Institute, Technology-Park, Muenster, Germany | [b] Institute of Zoology, University of Veterinary Medicine Hannover, Hannover, Germany | [c] Department of Physical Therapy, School of Health Technology and Management, Stony Brook University, Stony Brook, NY, USA | [d] Department of Clinical Radiology, University of Muenster, Muenster, Germany | [e] Institute of Animal Hygiene, Animal Welfare and Farm Animal Behavior, University of Veterinary Medicine Hannover, Hannover, Germany | [f] Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, v.v.i., AS CR, Libechov, Czech Republic | [g] Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany

Correspondence: [*] Correspondence to: Ralf Reilmann, MD, PhD, FAAN, Founding Director, George-Huntington-Institute, Technology-Park Muenster / Deilmann Building, Johann-Krane-Weg 27, 48149 Muenster, Germany. Tel.: +49 251 788 788 11; Fax: +49 251 788 788 88; E-mail: [email protected].

Abstract: Background:Huntington’s disease (HD) is an autosomal-dominant, progressive neurodegenerative disorder with motor, cognitive, behavioral and metabolic symptoms. HD patients exhibit an altered response to stress which is reflected in changes of cortisol levels. Large animal models of HD such as the Libechov minipig are currently explored in preclinical studies to improve translational reliability and assessing behavior is of interest. Objective:This study aimed to investigate whether cortisol metabolism and response to stress are changed in minipigs transgenic for the Huntington gene (tgHD) compared to wildtype (wt) animals suggesting that cortisol may be used as a marker for stress in minipigs. Methods:Thirty-two Libechov minipigs (14 tgHD and 18 wt) were tested before, during and after a stressor, i.e., a hoof trimming procedure, was applied at baseline and after one year. A total of six saliva samples were collected at each assessment and cortisol was measured. In addition, body temperature and respiratory rate were assessed at three pre-determined points during each hoof trimming procedure. Results:All minipigs showed a rise of cortisol in response to the hoof trimming stressor similarly to cortisol changes induced by stress observed in humans. No relevant differences were detected between tgHD and wt minipigs. Conclusion:Cortisol testing for the assessment of stress compensation, e.g., during hoof trimming, is feasible and well tolerated in wt and tgHD minipigs. To elucidate the time profile of cortisol responses to stressors further studies with assessments at multiple time points and exploration of the diurnal profiles of cortisol in minipigs are recommended.

Keywords: Animal models, minipigs, phenotyping, biomarker, saliva, cortisol, vital signs

DOI: 10.3233/JHD-180285

Journal: Journal of Huntington's Disease, vol. 7, no. 2, pp. 151-161, 2018