Next-generation strategies in animal model research to translate preclinical discoveries into better treatments for circuit-centered psychiatric dimensions

Abstract

The study of animal models is of key relevance in biomedical research. Animal models of psychiatric disorders have been important tools to gain insight into the presumed mechanisms of psychoses and mood and anxiety disorders in the last several decades. These models have largely focused on the improvement of specific aspects of validity.1 Our current psychopharmacological treatments came from these preclinical models for diverse psychiatric disorders. They provided not only a screening for identifying and further developing these compounds but also helped to clarify neurobiological aspects underlying psychiatric disorders. However, despite these gains, animal models have also contributed to the relatively little progress in developing new and improved therapeutics for human psychiatric disorders --existing medications are largely refinements of older versions and have not been demonstrated to be superior in terms of efficacy.A considerable number of our patients do not benefit from current medications and remain functionally impaired with poor quality of life, severely disabled, and at risk for suicidal behavior. Indeed, despite a critical need for new therapeutic targets for psychiatric disorders, we have been experiencing a period of less investment in drug development for psychiatric disorders than in previous decades. Several new compounds that seemed to satisfactorily improve phenotype in standard animal models were subsequently shown to have little impact in humans (phase I-II studies).2 It is clear that some existing animal models are unable to mimic all symptoms of a specific disease, undoubtedly due in part to the multifaceted aspects of mimicking the subjective nature of human emotions, the complexity of higher human cognition, and the full-blown phenotype of the disorder. We also need to consider the environment and context in which animal model studies are conducted --how representative they are in the environment where humans live and socialize. Furthermore, transgenic animals evaluating specific genetic variants and alleles with small effect have been widely described and associated with specific phenotypes or neurobiological systems, but limited construct validity is still an issue due to the polygenic basis of psychiatric disorders.Thus, some focus has shifted to developing the next generation of animal models. Recent research has highlighted the importance of developing new models based on circuit-centered dimensions (e.g., modeling ''positive and negative affect'' and ''socioaffective function'' for depression) to better understand disease rather than using current models of psychiatric classification. 3Our current psychiatric diagnoses probably represent a heterogeneous collection of disorders, each of which probably consists of many different disorders and etiologies. The use of newer models is likely to lead to a greater understanding of psychiatric disease than the approach which until now has largely relied on the study of behavioral phenotypes. Findings from clinical neuroscience can then...

Translational Research in Bipolar Disorders

“…Animal and preclinical models also represent valuable tools to further studies underlying neurobiological underpinnings of BD, helping to develop the next generation of strategies using circuit-centered psychiatric dimensions [ 11 ]. Findings from clinical neuroscience may be integrated into the next generation of animal models.…”