Even with regional specificity and micro-circuit modeling, two-dimensional cultures fail to recapitulate the three-dimensional organization of the brain and circuits therein. The ongoing development of three dimensional neural culture (alternatively called brain organoids or cortical spheroids) shows significant promise for modeling network activity and circuit organization. Paşca et al. (2015) derived cortical spheres containing non-reactive astrocytes and functional cortical neurons with laminated organization. Qian et al. (2016) designed a miniature bioreactor system to ensure proper circulation of nutrients in media and produced region-specific organoids that mimicked forebrain, midbrain, and hypothalamus expressing appropriate markers and resembling respective cytoarchitecture. Most recently, Birey et al. (2017) generated and fused together pallium- and subpallium-resembling organoids to model development and migration of inhibitory neurons. After 3 weeks of contact between the pallium and subpallium (ventral forebrain) organoids, inhibitory neurons from the subpallium sphere migrated into the pallium sphere, yielding functional excitatory and inhibitory post-synaptic connections. Creation of such chimeric organoids is an exciting prospect for modeling developmental cellular migration and connectivity in a 3D system.
