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Neuronal Transplants Help Rebuild Diseased Brains

Scientists from Harvard University, Harvard Medical School, Massachusetts General Hospital, and Beth Israel Deaconess Medical Center successfully rebuilt diseased brain circuitry in mice by transplanting new neurons. The research, which was published in the November 25 issue of “Science,” indicates that the right type of neuron could successfully integrate and partially restore functionality to areas of the brain that naturally do not regenerate neurons themselves.

Carefully selected embryonic neurons were transplanted into mutant mice that lacked responsive leptin receptors in the hypothalamus, a condition generally leading to symptoms of extreme obesity.

“We asked whether simply adding some neurons carrying these leptin receptors specifically to the hypothalamus can restore feedback signaling to reduce body weight and restore normal glucose levels,” said Matthew Anderson, one of three senior authors of the paper and Harvard Medical School professor of pathology at Beth Israel Deaconess.

“The answer was yes, partially for obesity and more completely for glucose levels.”

The restoration of functionality in areas of such complex circuitry supports the idea that integration of specific neurons from stem cells could offer new therapeutic approaches for complicated conditions ranging from Lou Gehrig’s disease (ALS) and spinal cord injury to Parkinson’s disease.

Together with Anderson, the research was spearheaded by Jeffrey Flier, dean of Harvard Medical School, and Jeffrey Macklis, Harvard University professor of stem cell and regenerative biology and Harvard Medical School professor of neurology at Massachusetts General Hospital.

Artur Czupryn, a postdoctoral fellow in the Macklis laboratory, led the transplantation of new neurons into mice brain circuitry using ultrasound-guided technology. In this way, the researchers created a “chimeric” hypothalamus with both implanted and natural neurons in each treated mouse.

Maggie Chen, a postdoctoral fellow in the Flier laboratory, studied neurotransmitter signaling in these mice and analyzed their metabolic function.

Postdoctoral fellow Yu-Dong Zhou in the Anderson laboratory studied the electrophysiological function of four different neuron types generated from these transplanted neurons.

The results showed that the new neurons functionally integrated and communicated with the brain in both directions, essentially rewiring the hypothalamus to be receptive to leptin, as evidence by an approximately 30 percent drop in weight of the treated mice.

“With [the Flier lab’s] expertise in energy balance and leptin regulation, [the Anderson lab’s] expertise in electrophysiology, and the developmental regenerative expertise of my own lab, we could ask and answer questions that none of us alone could fully address,” Macklis said.

“If we can get the neurons and their development correct, they can rebuild circuitry in the post-developmental brain.”

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