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.

Electrophysiological Maturation of Cerebral Organoids Correlates with Dynamic Morphological and Cellular Development

“…COs have shown significant promise as three-dimensional model systems of human brain development and have shaped our current understanding of key neurodevelopmental milestones ( Birey et al., 2017 ; Camp et al., 2015 ; Hartlaub et al., 2019 ; Lancaster et al., 2017 ; Pasca, 2018 ; Qian et al., 2016 ; Yin et al., 2016 ). Here we expanded upon these studies to correlate molecular and morphological features in COs with their EP trajectories.…”

“…Furthermore, our current knowledge of human brain development is largely based on analyses of postmortem or pathological specimens. Although they have provided important fundamental knowledge, these tools are not amenable to experimental manipulation ( Hartlaub et al., 2019 ; Stiles and Jernigan, 2010 ).…”

Unprecedented Potential for Neural Drug Discovery Based on Self-Organizing hiPSC Platforms

“…Organoids can recapitulate discrete brain regions that arise during human brain development such as seen in cortical-plate [24], forebrain [25], midbrain [26] and hypothalamic organoids [27]. These self-assembly platforms can mimic some aspects of human brain development such as topological organization similar to human tissue and can even generate functionally mature brain cells that are synaptically connected [25,28]. As such these region-specific brain organoids are a promising in vitro approach to model brain development [29], understand neurodevelopmental diseases [30], and for personalized drug-screening when an individual's hiPSCs are used [31,32].…”

Three‐dimensional in vitro cell culture devices using patient‐derived cells for high‐throughput screening of drug combinations

“…An advantage of microfluidic networks is their interconnectivity, such that various cell types can be linked through controlled fluid flow to mimic the in vivo environment (Figure 5). Moreover, because microfluidic platforms can deliver soluble growth factors to cells and well‐defined gradients of chemical components, such platforms are particularly suited for sustaining multiple interconnected 3D cell types, for example, for 3D microvascular network models (van Duinen et al, 2015; Polacheck, Zervantonakis, & Kamm, 2013; Shin et al, 2012; Wang, Sun, & Pei, 2018), stem cell‐derived brain models (Hartlaub, McElroy, Maitre, & Hester, 2019; Karimi et al, 2016), 3D liver spheroid models (Trietsch, Israels, Joore, Hankemeier, & Vulto, 2013) and organ‐ and human‐on‐a‐chip operations (van Duinen et al, 2015; Ferretti, Bruni, Dangles‐Marie, Pecking, & Bellet, 2007; Polacheck et al, 2013; Shin et al, 2012; Zhu, Pang, & Yu, 2012).…”