Mice with visual cortex damage became better at distinguishing fine, low-contrast patterns after receiving lab-grown human neural tissue and stimulation matched to its own rhythm
Mice with visual cortex damage became better at distinguishing fine, low-contrast patterns after receiving lab-grown human neural tissue and stimulation matched to its own rhythm
On November 6, Cell Stem Cell published a study by Xiaohong Li’s group at Tianjin University. The researchers removed part of the visual cortex in immunocompromised mice and replaced it with an organoid, a piece of neural tissue grown from human stem cells. They first used an electrode to stimulate the tissue throughout its depth, then restricted stimulation to the region where its own electrical rhythm was strongest.
A stroke or injury can leave a cavity where cortical tissue has been destroyed. Organoids can survive transplantation: in 2023, researchers at the University of Pennsylvania showed that an organoid transplanted into a rat responded to visual stimuli. Transplanted neurons extend processes without predefined targets. In 2024, Xiaohong Li’s team wrote that electrical stimulation might allow researchers to “guide neurons toward preselected targets.”
Visual signals travel from the eye through the thalamus, a relay station in the brain, to the fourth layer of the visual cortex. During brain development, this input helps cells in that layer specialize in processing visual signals. In mice, this layer has particularly strong gamma oscillations, an electrical rhythm of about 60 cycles per second driven by thalamic neurons. The authors set out to reproduce this rhythm with electrical stimulation to guide the organoid’s specialization.
The electrode was implanted during a period of rapid organoid maturation. For eight days, the researchers delivered 70 pulses per second through five sites spanning the organoid’s depth while showing the mice patterns on a screen. Regions with gamma oscillations emerged in the organoid after this stimulation. Following a two-week break, the researchers delivered 60 pulses per second through five adjacent electrode contacts in the region with the strongest gamma rhythm. In three control groups, they changed one feature of this second stage: they randomized the intervals between pulses, reduced the frequency to 20 pulses per second, or stimulated a region with a weak gamma rhythm. The gamma rhythm grew stronger under the targeted protocol and remained unchanged in these control groups. The authors concluded that both the rhythm and the stimulation site were necessary.
Organoids in the targeted group contained more neurons expressing NECAB1, a protein characteristic of the fourth cortical layer, than organoids stimulated throughout their depth. Processes from organoid neurons reached visual centers in the thalamus. A virus capable of passing between connected neurons was injected into the thalamus and subsequently detected in the organoid, revealing a pathway in the reverse direction as well, from the thalamus to the transplanted tissue. These bidirectional connections were denser than those formed after transplantation without stimulation or with stimulation throughout the organoid’s depth.
The researchers showed the mice stripes moving in eight directions and recorded organoid responses without applying electrical stimulation. The targeted group had a higher proportion of neurons that responded more strongly to one direction of motion than to the others compared with the other groups; this proportion fell when the screen was obscured. Oscillations in the organoid and thalamus became more closely aligned in time, and organoid neurons fired more often at particular phases of the gamma rhythm.
Five months after transplantation, the researchers tested vision in a water maze. The mice were trained to swim toward a platform in front of a screen displaying a striped pattern; a second screen was gray. The researchers then made the stripes finer or reduced the pattern’s contrast until the mice began making errors. Mice in the targeted group could distinguish finer patterns and patterns with lower contrast than mice that received transplants without stimulation or with stimulation throughout the organoid’s depth. Each group contained six mice. The differences in both measures were statistically significant.