Rodent models for psychiatric disorders: problems and promises

Laboratory Animal Research Baker et al. Laboratory Animal Research (2020) 36:9 https://doi.org/10.1186/s42826-020-00039-z REVIEW Open Access Rodent models for psychiatric disorders: problems and promises Matthew Baker1, Sa-Ik Hong1, Seungwoo Kang1 and Doo-Sup Choi1,2,3* Abstract Psychiatric disorders are a prevalent global health problem, over 900 million individuals affected by a continuum of mental and substance use disorders. Due to this high prevalence, and the substantial direct and indirect societal costs, it is essential to understand the underlying mechanisms of these disorders to facilitate development of new and more effective treatments. Since the advent of recombinant DNA technologies in the early 1980s, genetically modified rodent models have significantly contributed to the genetic and molecular basis of psychiatric disorders. Despite significant advancements, many challenges remain after unsuccessful drug development based on rodent models. Recent human genetics show the polygenetic nature of mental disorders, identifying hundreds of allelic variants that confer increased risk. However, given the complexity of the brain, with many unique cell types, gene expression profiles, and developmental trajectories, proper animal models are needed more than ever to dissect genes and circuits in a cell type-specific manner to advance our understanding and treatment of psychiatric disorders. In this mini-review, we highlight current challenges and promises of using rodent models in advancing science and drug development, focusing on advanced techniques, and their applications to rodent models of psychiatric disorders. Keywords: Rodent models, Psychiatric disorders, Circuits, Genetics, Behaviors Introduction An estimated 970 million people worldwide are affected by substance use or mental disorders. At the individual level, these psychiatric disorders were the leading cause of years lived with disability of any disease group, and were comparable to cardiovascular and circulatory diseases for disability-adjusted life years [1]. In 2010, the estimated global burden of psychiatric illness was an estimated $8.5 trillion [2]. Despite these profound individual and societal costs, substance use and mental disorders still represent a large unmet need in society. Although traditional antipsychotics and antidepressants have improved the lives of many patients, many * Correspondence: 1 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA 2 Neuroscience Program, Rochester, MN, USA Full list of author information is available at the end of the article individuals are resistant or relapse following typical treatments, with new drug development facing a multitude of challenges. Alcohol use disorder, for example, has had the only 3 FDA approved medications available for decades, with mixed effectiveness in promoting cessation of alcohol use. These heterogeneous responses to typical treatments are only further hindered by diagnostic criteria based on symptomology, with reliable biomarkers for disease diagnosis and monitoring yet to be established. This emphasizes the importance of preclinical research and animal models of psychiatric disorders to fully characterize their underlying genetic and neural mechanisms, and facilitate the development of new treatments. In particular, rodent models have been particularly useful towards this end. Regarding genetic architecture, brain structures and behavioral phenotypes, rodent models are more similar to humans than other non-mammalian models such as C. © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Baker et al. Laboratory Animal Research (2020) 36:9 elegans, Drosophila and zebrafish. Additionally, rodent models are cost- and time-effective compared to primate models for drug screening and development. Despite some instances of drugs showing promise in rodents and failing human trials, these model systems are needed to untangle the complexity of the brain and its vast array of cell-types, each with unique gene expression profiles and interconnections in distinct neural circuits, ultimately giving rise to behavioral states. In this review, we focus on newly available forward and reverse genetics models and how these models are useful for neural imaging and modulation techniques, which will give researchers an unprecedented ability to understand the connection between genes, circuits, and behavior, and facilitate the development of new biomarkers and therapies for individuals suffering from substance use and other mental disorders. Cell-specific molecular analysis The genetic and molecular characterization of psychiatric disorders has drastically improved over the last decade with the development of large-scale sequencing technologies. Advances in forward genetics have allowed scientists and physicians to examine the entire genome of patients more quickly and cost-effectively than ever before. Given the profound genetic and environmental interactions in the etiology of psychiatric disorders, other next-generation sequencing technologies are also important to characterize changes in gene expression profiles associated with allelic variants or from epigenetic modifications (e.g. RNA-sequencing, epigenomics). Although blood driven DNA or RNA sequencing may provide correlational etiology, these techniques fundamentally require primary tissue from the brain, and have largely not been feasible outside of post-mortem brain samples in humans. Therefore, rodent models are particularly advantageous for measuring gene expression profiles in behavioral or genetic models of psychiatric disorders. Despite these advances, the brain is composed of thousands of different cell types with diverse gene expression profiles and developmental trajectories. Having considered these limitations, it would be particularly useful to further clarify t (...truncated)