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Scientists rebuild brain circuitry: immature neurons transplanted into the brains of animals were able to connect and function normally.

A team of researchers that included Jl scientists from MGH have collaborated in pioneering work in which they implanted healthy neurons into the brains of laboratory mice with brain deficits, and succeeded in restoring lost connections and normal brain function. The feat has been widely celebrated as a breakthrough that might potentially lead to human treatments in humans for spinal cord injuries and epilepsy, as well as Parkinsons, Lou Gehrig's and Huntington's diseases.

"This is very exciting research," said psychiatrist David Soskin, MD, of the MGH Depression Clinical and Research Program. "It shows us that new neurons can be integrated into complex neural circuits and that they can help to repair abnormal neural functioning. However, it will require many additional studies in animal models before we can assess its potential applicability in humans."



According to the researchers, only two areas of the brain are known to normally undergo full-fledged neurogenesis, the creation of new nerve cells. These regions are the olfactory bulb and an area of the hippocampus called the dentate gyrus. In earlier work, some of the researchers had succeeded in promoting neurogenesis in the cerebral cortex of adult mice by implanting embryonic neurons in that brain region. (Neurogenesis does not normally occur in the cerebral cortex of adult mice.) Other members of the research team had developed a drug that promoted neurogenesis in a brain region called the hypothalamus, which is responsible for the functioning of the autonomic nervous system and basic processes such as temperature, appetite and sleep.

Both approaches seemed to rebuild brain circuitry anatomically, but the research team wanted to assess whether the new cells functioned normally, according to a report published in the November 25, 2011 issue of Science.

The scientists joined together in an investigation using mutant mice that were obese because they lacked the ability to react to the hormone leptin, which regulates metabolism and acts on the hypothalamus to control appetite.

The researchers selected immature neurons from normal mouse embryos and placed them into a specific region of the hypothalamus of the mutant mice using a technique called ultrasound microscopy.

Alter implantation, tne neurons--which were fluorescent--were observed closely to assess the degree to which they integrated themselves into the recipient circuitry. The implanted neurons not only survived, the scientists discovered, but they differentiated into the four types of neuronal cells that are responsible for leptin signaling in the brain.

The use of electron microscopy and other advanced techniques revealed that the new neurons had become fully integrated into the surrounding circuitry, developing normal contacts with surrounding neurons through their synapses (communication points between brain cells) and exchanging signals with the brain. The implanted cells responded normally to glucose, insulin, and leptin, and the obese mice that had received implants eventually weighed 30 percent less than mice that did not receive implants.

"This study was essentially a proof of concept," says Dr. Soskin. "It shows us that it is now possible to go into a dysregulated circuit within the brain and to rewire it in precise, therapeutic ways.

"The researchers used very concrete endpoints to measure how the transplanted neurons were affecting metabolic and behavior abnormalities in the mutant mice. They found significant improvements in obesity, hyperglycemia, and increased levels of the neurohormone leptin."
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Publication:Mind, Mood & Memory
Geographic Code:1USA
Date:Apr 1, 2012
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