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The development of the human brain is a highly self-organizing process that involves cell proliferation, differentiation, migration, and connectivity to form functional neural circuits.
Due to the limitations of the difficulty of obtaining human brain tissue, human pluripotent stem cells are mainly used to induce the formation of organoids
.
Despite defects such as immature cells, human cortical organoids (hCOs) mimic the early development of the cortex, but hCO cannot be
integrated into mature functional neural circuits.
Transplantation of hCO may solve these problems: it has been shown that transplanting human neurons into the cerebral cortex of rodent adult animals survives and forms synaptic and axonal connections
with neurons in animals.
On October 12, 2022, the research team of Sergiu P.
Pașca of Stanford University transplanted human neural stem cell-derived brain-like organs into the rat cortex to form functional neural circuits and regulate reward-related behaviors
.
1
hCO can be successfully integrated into rat neural networks
Three-dimensional hCO was transplanted into the primary somatosensory cortex of immunodeficient young mice on days 3-7 after birth (mature neural circuits were not formed during this period), and the 1-year survival rate of rats after transplantation exceeded 74%, the motor function was normal, and there was no impairmentin learning and memory function.
The results of magnetic resonance imaging showed that the volume of three-dimensional hCO increased by about 9 times after three months, and immunofluorescence experiments showed that the transplantation of three-dimensional hCO included glutamatergic neurons, GABAergic neurons, neural progenitor cells, oligodendrocytes and other cells
.
Figure 1: hCO can be successfully integrated into rat neural networks
2
Morphological features of hCO transplantation
.
Compared with human cortical neurons differentiated at the same time, the electrophysiological and morphological characteristics of transplanted hCO neurons are closer to those of cortical layer 2/3 pyramidal neurons
.
In addition, single-cell sequencing revealed enhanced gene expression in terms of three-dimensional hCO activity, and these transcriptomics, electrophysiological, and morphological features suggest that transplanted hCO is more mature
than ex vivo cultured hCO.
Figure 2: Integration of hCO neurons into the mature neural circuits of the brain after transplantation
3
Transplanted hCO regulates reward behavior in rats
Are these transplanted hCO neurons integrated into the rat neural circuit? The researchers first infected hCO neurons with retrograde tracers carrying green fluorescent protein, and then transplanted into the rat primary somatosensory cortex where there were dense green-fluorescent protein-tagged neural projectionsin regions such as the ventral basal nucleus of the thalamus.
Photoactivation of this neural projection can cause a transient excitatory postsynaptic current in hCO neurons, which can be blocked by AMPA receptor antagonists
.
These results suggest that hCO neurons can be integrated into rat neural circuits
.
After the researchers further transplanted hCO neurons infected with optogenetic virus into the primary somatosensory cortex of rats, hCO neurons could project to the auditory cortex, visual cortex, hippocampus, striatum, thalamus and other regions
after about 3 months.
It was found that continuous 2 weeks of photostimulation of hCO neurons promoted the behavior
of licking water in rats.
Figure 3: The neural circuit formed by hCO is functional
summary
In this paper, human-derived brain-like organs cultured in vitro were transplanted into rats, which can be successfully integrated into existing neural circuits and can play the function
of regulating behavior.
Despite the ethical issues, this one is cool!
【References】
1.
https://doi.
org/10.
1038/s41586-022-05277-w
The images in the article are from references
