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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.

Spontaneously occurring abnormal behaviors in animals have recently received considerable attention, both in veterinary medicine and as a potential model for abnormal behavior in several human mental disorders. Stereotypies are abnormal repetitive, unvarying, and functionless behaviors that are often performed by captive and domesticated animals housed in barren environments. They closely resemble the stereotypies of autistic and mentally retarded patients, stereotypies of unmedicated chronic schizophrenic patients, certain classes of simple tic in Tourette's syndrome, and several drug-induced behaviors. However, evidence for a common mechanism has been lacking. Stereotypies in human mental disorders are indicative of profound brain dysfunction involving the basal ganglia, and are associated with pervasive voluntary-motor impairments and psychological distress. Here we show that stereotypy in captive Orange-Wing Amazon Parrots (Amazona amazonica) is correlated with poor performance on the same psychiatric task (the 'gambling task') as stereotypy in autistic and schizophrenic patients. The task measures recurrent perseveration-the tendency to inappropriately repeat responses. Thus, the more stereotypy a parrot performed, the more likely it was to inappropriately repeat itself from trial-to-trial on the task; and the more rapidly it made repeated, but not switched, responses. These results parallel the executive motor impairments seen in human patients, and therefore suggest that, like in human patients, stereotypy in caged parrots reflects a general disinhibition of the behavioral control mechanisms of the dorsal basal ganglia. If this result holds true in other laboratory species, stereotypic animals are likely to be of questionable utility in behavior, neuroscience, and neuropharmacological experiments. In humans, stereotypies and obsessive-compulsive behaviors are considered to be mutually exclusive categories of behavior, with different neural substrates, and different treatment strategies. These results, therefore, suggest that the pharmacological treatment of stereotypies in veterinary medicine based on the assumption that they are equivalent to human Obsessive-Compulsive Disorder may be inappropriate. As stereotypies in captive animals develop in response to the captive environment, these results also emphasize the role that the environment may play in eliciting or exacerbating stereotypy in human patients. Finally, by parallel to human patients, there is a potential psychological distress in animals showing these behaviors.

The avian hippocampal formation has been proposed to play a critical role in the neural regulation of a navigational system used by homing pigeons to locate their loft once in the familiar area near home. In support of this hypothesis, the homing performance of pigeons with target lesions of either the hippocampus or parahippocampus was found to be impaired compared to controls following releases of about 10 km. Further, radio tracking revealed that the in-flight behavior of the hippocampal lesioned homing pigeons was characterized by numerous direction changes and generally poor orientation with respect to the home loft. The results identify a local navigational impairment on the part of the hippocampal lesioned pigeons in the vicinity of the loft where landmark cues are thought to be important. Additionally, target lesions of the hippocampus or parahippocampus were found to be similarly effective in causing homing deficits.

Research in animal neuropsychology is providing an exciting new generation of behavioral tests for mice that promise to overcome many of the limitations of current high-throughput testing, and provide direct animal homologues of clinically important measures in human research. Set shifting tasks are some of the best understood and widely used human neuropsychological tasks, with clinical relevance to traumatic brain injury, schizophrenia, autism, obsessive compulsive disorder, trichotillomania, and many other disorders. Here we report the first successful modification of a human set shifting neuropsychological task, the Intra-Dimensional Extra-Dimensional (IDED) task, for use with mice. We presented mice with a series of compound discrimination and reversal tasks where one stimulus dimension consistently cued reward. Task performance improved with a new set of compound stimuli, as did reversal performance--indicating the formation of a cognitive-attentional set. We then overtrained a subset of the mice, and presented control and overtrained mice with a new compound discrimination where a novel stimulus dimension cued reward. As is the case in human control subjects, control mice persisted in responding to the now-incorrect stimulus dimension, performing poorly on this extra-dimensional shift compared with the previous intra-dimensional shift, thereby validating the task as a measure of set shifting. Furthermore, overtrained mice were impaired on this extra-dimensional shift compared with controls, further validating the task. The advantages and disadvantages of the IDED task compared to high-throughput approaches are discussed.