It could now become possible to control metabolism and sex aggression through embryonic neuron transplant. The transplant in mice repaired defective brain circuits, enabling them to respond to leptin, a hormone that regulates metabolism. The mutant mice that usually become morbidly obese experienced substantially less weight gain after the transplant.
It was a collaborative effort of scientists at Harvard University, Massachusetts General Hospital, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS).
They successfully transplanted normally functioning embryonic neurons at a carefully selected stage of their development into the hypothalamus of mice. The hypothalamus is a critical and complex region of the brain that regulates phenomena such as hunger, metabolism, body temperature, and basic behaviors such as sex and aggression.
The successful neuronal transplant indicates the possibility of new therapeutic approaches to even higher level conditions such as spinal cord injury, autism, epilepsy, ALS (Lou Gehrig's disease), Parkinson's disease, and Huntington's disease.
"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," said Jeffrey Macklis, Harvard University professor of stem cell and regenerative biology and HMS professor of neurology at Massachusetts General Hospital, and one of three corresponding authors on the paper. "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."
The two other senior authors on the paper are Jeffrey Flier, dean of Harvard Medical School, and Matthew Anderson, HMS professor of pathology at BIDMC.
The findings are to appear Nov. 25 in Science
The researchers used a mouse model in which the brain lacks the ability to respond to leptin. Flier and his lab have long studied this hormone, which is mediated by the hypothalamus. Deaf to leptin's signaling, these mice become dangerously overweight.
Prior research had suggested that four main classes of neurons enabled the brain to process leptin signaling. 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" — like the animals with mixed features from Greek mythology.
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.
The new neurons integrated functionally into the circuitry, responding to leptin, insulin, and glucose. Treated mice matured and weighed approximately 30 percent less than their untreated siblings or siblings treated in multiple alternate ways.
"The finding that these embryonic cells are so efficient at integrating with the native neuronal circuitry makes us quite excited about the possibility of applying similar techniques to other neurological and psychiatric diseases of particular interest to our laboratory," said Anderson.
The researchers call their findings a proof of concept for the broader idea that new neurons can integrate specifically to modify complex circuits that are defective in a mammalian brain.
"The next step for us is to ask parallel questions of other parts of the brain and spinal cord, those involved in ALS and with spinal cord injuries," Macklis said. "In these cases, can we rebuild circuitry in the mammalian brain? I suspect that we can."