Advancing preclinical models of psychiatric disorders with human brain organoid cultures

Abstract

Psychiatric disorders are often distinguished from neurological disorders in that the former do not have characteristic lesions or findings from cerebrospinal fluid, electroencephalograms (EEGs), or brain imaging, and furthermore do not have commonly recognized convergent mechanisms. Psychiatric disorders commonly involve clinical diagnosis of phenotypic behavioral disturbances of mood and psychosis, often with a poorly understood contribution of environmental factors. As such, psychiatric disease has been challenging to model preclinically for mechanistic understanding and pharmaceutical development. This review compares commonly used animal paradigms of preclinical testing with evolving techniques of induced pluripotent cell culture with a focus on emerging three-dimensional models. Advances in complexity of 3D cultures, recapitulating electrical activity in utero, and disease modeling of psychosis, mood, and environmentally induced disorders are reviewed. Insights from these rapidly expanding technologies are discussed as they pertain to the utility of human organoid and other models in finding novel research directions, validating pharmaceutical action, and recapitulating human disease.

Fig. 1. Comparison of in vitro and animal modelling platforms for preclinical research.

Schematic illustrating commonalities and differences between preclinical research platforms of in vitro human cell platforms (left, blue) and animal modeling (right, yellow), with shared analyses (center, green). Ongoing developments in human cell platforms (bottom left), animal modelling (bottom right), and shared research goals (bottom center). Individual boxes described from left to right, all content generalized and streamlined for ease of depiction. (Left) Human cell-based platforms use punch biopsies from patients and controls to derive dermal fibroblasts, then differentiated in directed methods to specified 3D organoids, which can be cultured in standardized and controlled tissue culture. Developments including multi-electrode array recording and cocultured fused organoids (‘assembloids’) are among the more recent advances in the field toward increased complexity of culture and analysis (bottom left). Human cell based and animal modeling platforms use several shared analytic techniques for similar readouts (center), and have similar goals of understanding neurodevelopment mechanistically, as well as novel treatment development (bottom center). Animal models use common model species which can be induced to disease states with specific treatments or genetic programming (right). Behavioral tests are used as experimental methods for phenotypic readouts, and optogenetics and other tissue based methods represent newer developments in the use of animal models for preclinical and basic research (bottom right). Schematic created with BioRender.com.

Fig. 2. Comparison of neural layers found in development of the mammalian cerebral cortex.

Simplified illustration of human, rodent, and organoid model systems expanding cortical neural layers, with cell types distinguished by color and morphology with legend on left. The human neural layers (left) are marked by an expanded subventricular zone with a unique outer layer, named the outer subventricular zone, where intermediate progenitors, outer radial glia, and migrating neuroblasts populate an expanding tissue layer, which will contribute to human neocortex. The corresponding neural tissue layers found in rodent developing cortex (middle) are depicted with analogous cell types and tissue layers labelled. Cortical organoid expanding neural cell layers include regions resembling the outer and inner subventricular zones termed ‘-like regions’ as they represent a model system rather than a fully functional characterized in vivo tissue. Illustration created with BioRender.com.