title: Reverse-translational biomarker validation of Abnormal Repetitive Behaviors in mice: an illustration of the 4P's modeling approach.
abstract: The NIMH's new strategic plan, with its emphasis on the "4P's" (Prediction, Pre-emption, Personalization, and Populations) and biomarker-based medicine requires a radical shift in animal modeling methodology. In particular 4P's models will be non-determinant (i.e. disease severity will depend on secondary environmental and genetic factors); and validated by reverse-translation of animal homologues to human biomarkers. A powerful consequence of the biomarker approach is that different closely related disorders have a unique fingerprint of biomarkers. Animals can be validated as a highly specific model of a single disorder by matching this 'fingerprint'; or as a model of a symptom seen in multiple disorders by matching common biomarkers. Here we illustrate this approach with two Abnormal Repetitive Behaviors (ARBs) in mice: stereotypies and barbering (hair pulling). We developed animal versions of the neuropsychological biomarkers that distinguish human ARBs, and tested the fingerprint of the different mouse ARBs. As predicted, the two mouse ARBs were associated with different biomarkers. Both barbering and stereotypy could be discounted as models of OCD (even though they are widely used as such), due to the absence of limbic biomarkers which are characteristic of OCD and hence are necessary for a valid model. Conversely barbering matched the fingerprint of trichotillomania (i.e. selective deficits in set-shifting), suggesting it may be a highly specific model of this disorder. In contrast stereotypies were correlated only with a biomarker (deficits in response shifting) correlated with stereotypies in multiple disorders, suggesting that animal stereotypies model stereotypies in multiple disorders.
authors.affiliation: Purdue University, Department of Animal Sciences, 125 South Russell Street, West Lafayette, IN 47907, USA. jgarner@purdue.edu
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Garner
authors.forename: Collette M
authors.initials: CM
authors.lastname: Thogerson
authors.forename: Brett D
authors.initials: BD
authors.lastname: Dufour
authors.forename: Hanno
authors.initials: H
authors.lastname: Würbel
authors.forename: James D
authors.initials: JD
authors.lastname: Murray
authors.forename: Joy A
authors.initials: JA
authors.lastname: Mench
mesh_terms: D000339:Affect / Q000502:physiology; D000818:Animals; D001321:Autistic Disorder / Q000523:psychology; D015415:Biomarkers; D003192:Compulsive Behavior / Q000523:psychology; D003463:Cues; D004192:Discrimination, Psychological / Q000502:physiology; D004195:Disease Models, Animal; D005247:Feeding Behavior / Q000187:drug effects; D005715:Gambling / Q000523:psychology; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009771:Obsessive-Compulsive Disorder / Q000523:psychology; D011597:Psychomotor Performance / Q000502:physiology; D012201:Reward; D012718:Set, Psychology; D013239:Stereotyped Behavior / Q000187:drug effects*; D014256:Trichotillomania / Q000523:psychology
chemical_list: D015415:Biomarkers