Modeling Human Brain Circuitry Using Pluripotent Stem Cell Platforms

Abstract

Neural circuits are the underlying functional units of the human brain that govern complex behavior and higher-order cognitive processes. Disruptions in neural circuit development have been implicated in the pathogenesis of multiple neurodevelopmental disorders such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and schizophrenia. Until recently, major efforts utilizing neurological disease modeling platforms based on human induced pluripotent stem cells (hiPSCs), investigated disease phenotypes primarily at the single cell level. However, recent advances in brain organoid systems, microfluidic devices, and advanced optical and electrical interfaces, now allow more complex hiPSC-based systems to model neuronal connectivity and investigate the specific brain circuitry implicated in neurodevelopmental disorders. Here we review emerging research advances in studying brain circuitry using in vitro and in vivo disease modeling platforms including microfluidic devices, enhanced functional recording interfaces, and brain organoid systems. Research efforts in these areas have already yielded critical insights into pathophysiological mechanisms and will continue to stimulate innovation in this promising area of translational research.

Keywords: brain organoid; cerebral organoid; human induced pluripotent stem cell (hiPSC); microfluidic; neural circuit; neurodevelopment.

Figure 1

In vitro-based platforms to investigate human brain circuitry. Schematic illustrating different approaches to investigate human brain circuitry in vitro. Patient-specific somatic cells such as skin fibroblasts or peripheral blood mononuclear cells (PBMCs) that are easily isolated can be reprogrammed into hiPSCs using the Yamanka factors (OCT3/4, SOX2, c-MYC, and KLF4). hiPSCs can then be used as a source for generating multiple cell types in various platforms to investigate human brain circuitry.