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In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain-striatum-cortex assembloids

Reumann, Daniel ; Krauditsch, Christian ; Novatchkova, Maria ; Sozzi, Edoardo LU orcid ; Wong, Sakurako Nagumo ; Zabolocki, Michael ; Priouret, Marthe ; Doleschall, Balint ; Ritzau-Reid, Kaja I and Piber, Marielle , et al. (2023) In Nature Methods 20(12). p.2034-2047
Abstract

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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
in
Nature Methods
volume
20
issue
12
pages
2034 - 2047
publisher
Nature Publishing Group
external identifiers
  • scopus:85178437011
  • pmid:38052989
ISSN
1548-7105
DOI
10.1038/s41592-023-02080-x
language
English
LU publication?
yes
id
535d8e59-0ec5-443d-8013-3a98ab6bd518
date added to LUP
2023-12-07 14:09:04
date last changed
2024-04-17 15:01:51
@article{535d8e59-0ec5-443d-8013-3a98ab6bd518,
  abstract     = {{<p>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.</p>}},
  author       = {{Reumann, Daniel and Krauditsch, Christian and Novatchkova, Maria and Sozzi, Edoardo and Wong, Sakurako Nagumo and Zabolocki, Michael and Priouret, Marthe and Doleschall, Balint and Ritzau-Reid, Kaja I and Piber, Marielle and Morassut, Ilaria and Fieseler, Charles and Fiorenzano, Alessandro and Stevens, Molly M and Zimmer, Manuel and Bardy, Cedric and Parmar, Malin and Knoblich, Jürgen A}},
  issn         = {{1548-7105}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{12}},
  pages        = {{2034--2047}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Methods}},
  title        = {{In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain-striatum-cortex assembloids}},
  url          = {{http://dx.doi.org/10.1038/s41592-023-02080-x}},
  doi          = {{10.1038/s41592-023-02080-x}},
  volume       = {{20}},
  year         = {{2023}},
}