Human development: Advances in mini-brain technology.

Abstract

Two studies integrate cutting-edge techniques to grow and analyse 3D cultured tissues that resemble human brain structures, enabling examination of how brain regions interact and neurons mature. See Articles p.48 & p.54 Three-dimensional cellular models of the human brain, or organoids, enable the in vitro study of cerebral development and disease, but exactly which cells are generated and how much of the brain's complexity they recreate is undefined. To investigate in depth the nature of cells in human cerebral organoids differentiated from pluripotent stem cells, Paola Arlotta and colleagues carried out droplet-based single-cell expression analysis on cells isolated from over 30 organoids at developmental stages ranging from 3 to 9 months and beyond. They identify a wide diversity of neurons and progenitors and show that the more mature organoids formed dendritic spines as well as electrically active networks, which responded to light stimulation. The authors suggest that organoids may facilitate the study of circuit function using physiological sensory mechanisms. Elsewhere in this issue, Sergiu Pasca and colleagues show that re-assembling ventral and dorsal forebrain spheroids obtained separately in vitro allows the migration of human interneurons and the formation of functional synapses. GABAergic neurons play important roles in brain function and are implicated in numerous psychiatric disorders. They migrate long distances from the ventral to the dorsal forebrain before integrating to cortical circuits. In vitro modelling of GABAergic neuronal differentiation during this interaction would allow us to investigate the cause of human brain disorders associated with defects in neuronal migration, but this has so far been difficult. Sergiu Pasca and colleagues have developed an approach for generating neural three-dimensional spheroids resembling either the ventral or dorsal forebrain. They show that assembling the two types of spheroids separately in vitro allows the saltatory migration of human interneurons into the cortex, as seen in human development, and the formation of functional synapses with the dorsally derived cortical glutamatergic neurons. In this context, they find that interneurons from Timothy syndrome patients exhibit perturbation in migration patterns. Elsewhere in this issue, Paola Arlotta and colleagues carried out single cell expression analysis on cells from human brain organoids to investigate the nature of cells generated by these three-dimensional models.