Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex

Madison N Wilson; Martin Thunemann; Xin Liu; Yichen Lu; Francesca Puppo; Jason W Adams; Jeong-Hoon Kim; Mehrdad Ramezani; Donald P Pizzo; Srdjan Djurovic; Ole A Andreassen; Abed AlFatah Mansour; Fred H Gage; Alysson R Muotri; Anna Devor; Duygu Kuzum

doi:10.1038/s41467-022-35536-3

Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex

Nat Commun. 2022 Dec 26;13(1):7945. doi: 10.1038/s41467-022-35536-3.

Authors

Madison N Wilson^#¹, Martin Thunemann^#², Xin Liu¹, Yichen Lu¹, Francesca Puppo³, Jason W Adams^{3

4}, Jeong-Hoon Kim¹, Mehrdad Ramezani¹, Donald P Pizzo⁵, Srdjan Djurovic^{6

7

8

9}, Ole A Andreassen^{7

9

10

11

12}, Abed AlFatah Mansour^{13

14}, Fred H Gage¹³, Alysson R Muotri^{3

4

15

16

17}, Anna Devor^{18

19}, Duygu Kuzum²⁰

Affiliations

¹ Department of Electrical and Computer Engineering, University of California San Diego, La Jolla, CA, USA.
² Department of Biomedical Engineering, Boston University, Boston, MA, USA.
³ Department of Pediatrics, University of California San Diego, School of Medicine, La Jolla, CA, USA.
⁴ Department of Cellular and Molecular Medicine, University of California San Diego, School of Medicine, La Jolla, CA, USA.
⁵ Department of Pathology, University of California San Diego, La Jolla, CA, USA.
⁶ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
⁷ NORMENT Center, Oslo, Norway.
⁸ Department of Clinical Science, University of Bergen, Bergen, Norway.
⁹ K. G. Jebsen Center for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway.
¹⁰ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹¹ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹² Oslo University Hospital, University of Oslo, Oslo, Norway.
¹³ Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
¹⁴ Department of Medical Neurobiology, The Hebrew University of Jerusalem, Ein Kerem-Jerusalem, Israel.
¹⁵ Center for Academic Research and Training in Anthropogeny, University of California San Diego, La Jolla, CA, USA.
¹⁶ Archealization Center, University of California San Diego, La Jolla, CA, USA.
¹⁷ Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA, USA.
¹⁸ Department of Biomedical Engineering, Boston University, Boston, MA, USA. adevor@bu.edu.
¹⁹ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA. adevor@bu.edu.
²⁰ Department of Electrical and Computer Engineering, University of California San Diego, La Jolla, CA, USA. dkuzum@eng.ucsd.edu.

^# Contributed equally.

Abstract

Human cortical organoids, three-dimensional neuronal cultures, are emerging as powerful tools to study brain development and dysfunction. However, whether organoids can functionally connect to a sensory network in vivo has yet to be demonstrated. Here, we combine transparent microelectrode arrays and two-photon imaging for longitudinal, multimodal monitoring of human cortical organoids transplanted into the retrosplenial cortex of adult mice. Two-photon imaging shows vascularization of the transplanted organoid. Visual stimuli evoke electrophysiological responses in the organoid, matching the responses from the surrounding cortex. Increases in multi-unit activity (MUA) and gamma power and phase locking of stimulus-evoked MUA with slow oscillations indicate functional integration between the organoid and the host brain. Immunostaining confirms the presence of human-mouse synapses. Implantation of transparent microelectrodes with organoids serves as a versatile in vivo platform for comprehensive evaluation of the development, maturation, and functional integration of human neuronal networks within the mouse brain.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain
Humans
Mice
Neurons* / physiology
Organoids / transplantation
Prostheses and Implants
Visual Cortex* / physiology

Abstract

Publication types

MeSH terms

Grants and funding