TY - JOUR
KW - Development of the nervous system
KW - Diseases of the nervous system
KW - Experimental models of disease
KW - Stem-cell differentiation
KW - Stem-cell research
AU - Daniel Reumann
AU - Christian Krauditsch
AU - Maria Novatchkova
AU - Edoardo Sozzi
AU - Sakurako Nagumo Wong
AU - Michael Zabolocki
AU - Marthe Priouret
AU - Balint Doleschall
AU - Kaja I. Ritzau-Reid
AU - Marielle Piber
AU - Ilaria Morassut
AU - Charles Fieseler
AU - Alessandro Fiorenzano
AU - Molly M. Stevens
AU - Manuel Zimmer
AU - Cedric Bardy
AU - Malin Parmar
AU - Jürgen A. Knoblich
AB - Ventral midbrain dopaminergic neurons project to the striatum as well as the cortex and are involved in movement control and reward-related cognition. In Parkinson’s disease, nigrostriatal midbrain dopaminergic neurons degenerate and cause typical Parkinson’s disease motor-related impairments, while the dysfunction of mesocorticolimbic midbrain dopaminergic neurons is implicated in addiction and neuropsychiatric disorders. Study of the development and selective neurodegeneration of the human dopaminergic system, however, has been limited due to the lack of an appropriate model and access to human material. Here, we have developed a human in vitro model that recapitulates key aspects of dopaminergic innervation of the striatum and cortex. These spatially arranged ventral midbrain–striatum–cortical organoids (MISCOs) can be used to study dopaminergic neuron maturation, innervation and function with implications for cell therapy and addiction research. We detail protocols for growing ventral midbrain, striatal and cortical organoids and describe how they fuse in a linear manner when placed in custom embedding molds. We report the formation of functional long-range dopaminergic connections to striatal and cortical tissues in MISCOs, and show that injected, ventral midbrain-patterned progenitors can mature and innervate the tissue. Using these assembloids, we examine dopaminergic circuit perturbations and show that chronic cocaine treatment causes long-lasting morphological, functional and transcriptional changes that persist upon drug withdrawal. Thus, our method opens new avenues to investigate human dopaminergic cell transplantation and circuitry reconstruction as well as the effect of drugs on the human dopaminergic system.
BT - Nature Methods
DA - 2023-12
DO - 10.1038/s41592-023-02080-x
LA - en
N2 - Ventral midbrain dopaminergic neurons project to the striatum as well as the cortex and are involved in movement control and reward-related cognition. In Parkinson’s disease, nigrostriatal midbrain dopaminergic neurons degenerate and cause typical Parkinson’s disease motor-related impairments, while the dysfunction of mesocorticolimbic midbrain dopaminergic neurons is implicated in addiction and neuropsychiatric disorders. Study of the development and selective neurodegeneration of the human dopaminergic system, however, has been limited due to the lack of an appropriate model and access to human material. Here, we have developed a human in vitro model that recapitulates key aspects of dopaminergic innervation of the striatum and cortex. These spatially arranged ventral midbrain–striatum–cortical organoids (MISCOs) can be used to study dopaminergic neuron maturation, innervation and function with implications for cell therapy and addiction research. We detail protocols for growing ventral midbrain, striatal and cortical organoids and describe how they fuse in a linear manner when placed in custom embedding molds. We report the formation of functional long-range dopaminergic connections to striatal and cortical tissues in MISCOs, and show that injected, ventral midbrain-patterned progenitors can mature and innervate the tissue. Using these assembloids, we examine dopaminergic circuit perturbations and show that chronic cocaine treatment causes long-lasting morphological, functional and transcriptional changes that persist upon drug withdrawal. Thus, our method opens new avenues to investigate human dopaminergic cell transplantation and circuitry reconstruction as well as the effect of drugs on the human dopaminergic system.
PY - 2023
SP - 2034
EP - 2047
T2 - Nature Methods
TI - In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain–striatum–cortex assembloids
UR - https://www.nature.com/articles/s41592-023-02080-x
VL - 20
Y2 - 2024-08-13
SN - 1548-7105
ER -