Rapid Single-Step Induction of Functional Neurons from Human Pluripotent Stem Cells

Differentiation of human pluripotent stem cells to small brain-like structures known as brain organoids offers an unprecedented opportunity to model human brain development and disease. To provide a vascularized and functional in vivo model of brain organoids, we established a method for transplanting human brain organoids into the adult mouse brain. Organoid grafts showed progressive neuronal differentiation and maturation, gliogenesis, integration of microglia, and growth of axons to multiple regions of the host brain. In vivo two-photon imaging demonstrated functional neuronal networks and blood vessels in the grafts. Finally, in vivo extracellular recording combined with optogenetics revealed intragraft neuronal activity and suggested graft-to-host functional synaptic connectivity. This combination of human neural organoids and an in vivo physiological environment in the animal brain may facilitate disease modeling under physiological conditions.

An in vivo model of functional and vascularized human brain organoids

The sophisticated circuitry of the neocortex is assembled from a diverse repertoire of neuronal subtypes generated during development under precise molecular regulation In recent years, several key controls over the specification and differentiation of neocortical projection neurons have been identified This work provides substantial insight into the “molecular logic” underlying cortical development, increasingly supporting a model in which individual progenitor-stage and postmitotic regulators are embedded within highly-interconnected networks that gate sequential developmental decisions Here, we provide an integrative account of the molecular controls that direct the progressive development and delineation of subtype and area identity of neocortical projection neurons

/pdf/molecular-logic-of-neocortical-projection-neuron-x1snsrr907.pdf

Molecular logic of neocortical projection neuron specification, development and diversity

Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies.

/pdf/advancing-the-understanding-of-autism-disease-mechanisms-kozleitlsz.pdf

Kimmo A. Michelsen

Papers

Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo.

Area-Specific Reestablishment of Damaged Circuits in the Adult Cerebral Cortex by Cortical Neurons Derived from Mouse Embryonic Stem Cells

Human Pluripotent Stem-Cell-Derived Cortical Neurons Integrate Functionally into the Lesioned Adult Murine Visual Cortex in an Area-Specific Way