Rebuilding the brain’s circuitry - Healthy neurons can integrate into diseased areas

Collaborators from HSCI, Massachusetts General Hospital (MGH), Beth Israel Deaconess Medical Center (BIDMC), and the Harvard Medical School have shown that neuronal transplants can repair brain circuitry and substantially normalize function in mice with a brain disorder, an advance indicating that key areas of the mammalian brain are more reparable than was widely believed.

The team transplanted normally functioning embryonic neurons at a carefully selected stage of their development into the hypothalamus of mice which were 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.

“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 Prof. Jeffrey Macklis, Professor of Stem Cell and Regenerative Biology at Harvard, leader of HSCI’s Nervous System Diseases Program, 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, which was published in the journal Science, are Jeffrey Flier, MD, Dean of Harvard Medical School, and Matthew Anderson, MD, PhD, Professor of Pathology at BIDMC.

“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 are interested in further investigating controlled neurogenesis — directing growth of new neurons in the brain from within, potentially creating a route to new therapies.

“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.”