The best-recognized obstacles to effective clinical translation in psychiatry include the complexity of the brain and the associated challenge of connecting levels of analysis from molecules to cells, synapses, circuits, and thence to higher cognition, emotion regulation, and executive function. The relative uniqueness of the human brain creates high hurdles for development of animal models. Anatomically, much of the neural circuitry involved in psychiatric symptoms—for example, that of the prefrontal cerebral cortex—is new or vastly expanded in humans, and gene expression patterns in the human cerebral cortex also appear to be newly evolved, even compared with nonhuman primates (24). That said, for neural circuits that are conserved in evolution—those involved in basic emotions such as fear and reward as well as some basic cognitive functions—rodents and other organisms can potentially provide useful preclinical models (16, 25). Transgenic mice constructed with highly penetrant genetic variants that cause rare monogenic disorders have also proven informative (26), and in the case of fragile X syndrome they have predicted drug efficacy against a subset of symptoms (27). However, most psychiatric disorders are highly heterogeneous and polygenic (28), casting doubt about the utility of existing genetic mouse models. Overall, industry has come to the justifiable view that with few exceptions, valid disease models do not exist for psychiatric disorders. - stm.sciencemag.org