Rebuilding the brain’s circuitry
Neuron transplants have repaired brain circuitry and substantially normalized function in mice with a brain disorder, an advance indicating that key areas of the mammalian brain are more reparable than was widely believed.
Collaborators from Harvard University, Massachusetts General Hospital (MGH), 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. These 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.
Repair at the cellular-level of the hypothalamus — 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 — 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.
In 2005, Harvard Medical School Dean Jeffrey Flier, then the George C. Reisman professor of medicine at BIDMC, published a landmark study showing that an experimental drug spurred the addition of new neurons in the hypothalamus and offered a potential treatment for obesity. File photo by Stephanie Mitchell/Harvard Staff Photographer
“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 MGH, 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.