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Brain cells capable of "early-career" switch

Scientists at the Salk Institute have discovered that the role of neurons–which are responsible for specific tasks in the brain–is much more flexible than previously believed.

By studying sensory neurons in mice, the Salk team found that the malfunction of a single molecule could prompt the neuron to make an “early-career” switch, changing a neuron originally destined to process sound or touch, for example, to instead process vision.

The finding, reported May 11, 2015 in PNAS, will help neuroscientists better understand how brain architecture is molecularly encoded and how it can become miswired. It may also point to ways to prevent or treat human disorders (such as autism) that feature substantial brain structure abnormalities.

“We found an unexpected mechanism that provides surprising brain plasticity in maturing sensory neurons,” says the study’s first author, Andreas Zembrzycki, a senior research associate at the Salk Institute.

How Neurons Mature
Scientists at the Salk Institute discovered new details into how certain master proteins dictate neuron’s specialties. This new work could help better understand–and ultimately prevent or treat–diseases like Rett syndrome, schizophrenia and autism.

Images: Courtesy of the Salk Institute for Biological Studies

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Neighboring neurons in the area of the brain known as the thalamus are shown making connections to the visual cortex (red) and the somatosensory cortex (green). Visible are the cell bodies (star-like cells in the lower right) and axons (arm-like extensions moving downward). Click here for a high-resolution image.
In the neocortex, neighboring cells are shown making connections to the visual cortex (red) and the somatosensory cortex (green). Click here for a high-resolution image.
In this developing mouse brain, green staining at the top indicates neurons; red staining at the bottom reveals cortical stem cells; and orange/yellow staining in the middle shows neurons that are transitioning from stem cells to neurons. Click here for a high-resolution image.
An embryonic mouse forebrain shows the genetically modified neurons in the neocortex (orange/yellow). Cortical stem cells and neurons in other brain regions remain unaltered. Click here for a high-resolution image.
In this section of the mouse brain, single cell bodies in the thalamus (center: red and green cells) were labeled by adding dyes into different neocortical (top: green, red, and yellow) regions. Click here for a high-resolution image.

The mechanism, a transcription factor called Lhx2 that was inactivated in neurons, can be used to switch genes on or off to change the function of a sensory neuron in mice. It has been known that Lhx2 is present in many cell types other than in the brain and is needed by a developing fetus to build body parts. Without Lhx2, animals typically die in utero. However, it was not well known that Lhx2 also affects cells after birth.

“This process happens while the neuron matures and no longer divides. We did not understand before this study that relatively mature neurons could be reprogrammed in this way,” says senior author Dennis O’Leary, Salk professor and holder of the Vincent J. Coates Chair in Molecular Neurobiology. “This finding opens up a new understanding about how brain architecture is established and a potential therapeutic approach to altering that blueprint.”

Scientists had believed that programming neurons was a one-step process. They thought that the stem cells that generate the neurons also programmed their functions once they matured. While this is true, the Salk team found that another step is needed: the Lhx2 transcription factor in mature neurons then ultimately controls the fate of the neuron.

In the mouse study, the scientists manipulated Lhx2 to make the switch in neuronal fate shortly after birth (when the mouse neurons are fully formed and considered mature). The team observed that controlling Lhx2 let them instruct neurons situated in one sensory area to process a different sense, thus enlarging one region at the expense of the other. The scientists don’t know yet if targeting Lhx2 would allow neurons to change their function throughout an organism’s life.

“This study provides proof that the brain is very plastic and that it responds to both genetic and epigenetic influences well after birth,” says O’Leary. “Clinical applications for brain disorders are a long way away, but we now have a new way to think about them.”