A new study has found that carefully selected young, healthy neurons can functionally integrate into diseased brain circuitry in mammals.
Collaborators from Harvard University, Massachusetts General Hospital, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS) transplanted normally functioning embryonic neurons at a carefully selected stage of their development into the hypothalamus of mice unable to respond to leptin, a hormone that regulates metabolism and controls body weight.
AdvertisementThese mutant mice usually become morbidly obese, but the neuron transplants repaired defective brain circuits, enabling them to respond to leptin and thus experience substantially less weight gain.
"There are only two areas of the brain that are known to normally undergo ongoing large-scale neuronal replacement during adulthood on a cellular level-so-called 'neurogenesis,' or the birth of new neurons-the olfactory bulb and the subregion of the hippocampus called the dentate gyrus, with emerging evidence of lower level ongoing neurogenesis in the hypothalamus," Jeffrey Macklis, one of three corresponding authors on the paper, said.
"The neurons that are added during adulthood in both regions are generally smallish and are thought to act a bit like volume controls over specific signaling. Here we've rewired a high-level system of brain circuitry that does not naturally experience neurogenesis, and this restored substantially normal function," he said.
The researchers used a mouse model in which the brain lacks the ability to respond to leptin, which causes them to become dangerously overweight.
Postdocs Artur Czupryn and Maggie Chen, from Macklis's and Flier's labs, respectively, transplanted and studied the cellular development and integration of progenitor cells and very immature neurons from normal embryos into the hypothalamus of the mutant mice using multiple types of cellular and molecular analysis.
To place the transplanted cells in exactly the correct and microscopic region of the recipient hypothalamus, they used a technique called high-resolution ultrasound microscopy, creating what Macklis called a "chimeric hypothalamus".
Postdoc Yu-Dong Zhou, from Anderson's lab, performed in-depth electrophysiological analysis of the transplanted neurons and their function in the recipient circuitry, taking advantage of the neurons' glowing green from a fluorescent jellyfish protein carried as a marker.
These nascent neurons survived the transplantation process and developed structurally, molecularly, and electrophysiologically into the four cardinal types of neurons central to leptin signaling.
The new neurons integrated functionally into the circuitry, responding to leptin, insulin, and glucose.
The researchers found that the treated mice matured and weighed approximately 30 percent less than their untreated siblings or siblings treated in multiple alternate ways.
The study has been recently published in Science.