1. The great tragedy of Science - the slaying of a beautiful hypothesis by an ugly fact. Thomas Henry Huxley (1825-1895) I will listen to any hypothesis but on one condition - that you show me a method by which it can be tested. August William von Hoffman (1818-1894)

2. A model in which: 1.normative biology or behavior can be studied 2.a spontaneous or induced pathological process can be investigated 3.the phenomenon in one or more respects resembles the same phenomenon in humans. U.S. National Research Committee on Animal Models for Research on Aging What is an animal model?

3. Two very important animal models 1. Genetic variations, mutations, knock outs etc. Very cool technologies - conditional KOs 2. Lesioning chemical, surgical “A good means to discovery is to take away certain parts of a system and to find out how the rest behaves.” George Christoph Lichtenberg (1742-1799) Occam's razor: the simplest solution is the best

4. Willner, 1984, Willner, 1986 and Willner, 1991 Face validity  Phenomenological similarity Predictive validity  Performance in the test predicts performance in the modeled condition  Similar response to treatment Construct validity  Modeled behavior and behavior share a similar physiological basis, and pathophysiological picture  Difficult to obtain in many disorders where altered perceptions are part of the diagnosis (e.g. RLS has a subjective component - limb dysesthesias)  Putative subcortical neural circuits engaged are easier to define Validity of Animal Models

5. Matthysse (1986) Symptom similarity how closely the model approximates the human condition Pharmacological isomorphism how well drugs that work in humans also work in the model and how well effects of drugs in model predict clinical effects Theory-driven models do not rely on a priori assumptions about the validity of the theory; rather, they are developed to test the theory Joel, D. Prog Neuropsychopharmacol Biol Psychiatry. 2006 30:374-88 McKinney (1988) Behavioral similarity models designed to simulate a specific sign or symptom of the human disorder Empirical validity models designed to permit preclinical drug evaluations Theory-driven models designed to evaluate a specific etiological theory Criteria for assessing animal models

6. “It is widely agreed that a common physiological basis of the model and the modeled condition contributes greatly to the model's validity. A critical component … is the demonstration of a similar response to treatment, because the latter suggests similarity in the neurotransmitter systems involved.” Joel, D. Prog Neuropsychopharmacol Biol Psychiatry. 2006 30:374-88 Some models may not fit the data but may help sharpen the question