Modeling thought and feelings: the why, what and whereabouts of animals in psychiatry.

Disorders of mood and thought arise from altered functioning of highest human faculties. The idea that meaningful animal models of these disorders can be made seems utterly absurd. Are not we at the top of millennia of evolution, have not we reached levels of complexities that are out of range of any of the animal species populating this planet? Thus, we were caught by surprise when first scientists claimed that drug and gene manipulations apparently elicited disorders of mood and thought remarkably similar to ours, in rats and mice! How it can be true and what it means? And, especially, is it of any use? To begin answering these questions, let me back off. Disorders of thought and emotion like obsessive-compulsive disorder (OCD), schizophrenia, autism, depression, arise from a complex intertwining of genetic factors and our history, including the impact of adverse environmental events. Although there is overwhelming evidence that both genes and environment play crucial roles in disease pathogenesis, how gene/environment interactions occur in any of these disorders is much more difficult to understand. To help reduce the complexity, single-gene mutations have been induced in “simple” organisms such as nematodes, fish and (more relevant for us) mice. This approach has paid off, regardless of whether it was random or targeted to potentially interesting genes. This is because in these organisms it is relatively easy to control for environmental variables, and also because experiments can be done under conditions in which virtually all the other genes in that particular animal strain are invariant, except for the one that is mutated. The null mutation of a single gene, the so-called “gene knockout”, is a remarkably powerful approach. It is a step forward with respect to traditional techniques of biological psychiatry, such as inflicting brain lesions or injecting drugs into the brain. This is because lesions inevitably destroy many cells and pathways. Virtually all pharmacological agents are not perfect agonists or antagonists for a certain receptors, and it is very difficult to manipulate intracellular molecules using drugs. Furthermore, the single gene approach promises to shed light on the ancient question of the specific role played by genes independently of the environment. Hundreds of genes have been knocked out in the mouse genome. Gene knockouts have yielded insights into neurotransmitter receptor subtype contributions to mood and cognition. For example, several investigators reported that mice lacking Modeling thought and feelings: the why, what and whereabouts of animals in psychiatry Editorial (autor convidado)