In an unanticipated finding, researchers at the UC Davis School of Medicine have discovered that, during early adulthood, the brain produces new excitatory neurons, and that these neurons arise from non-neuronal support cells in an area of the brain that processes smell.
The study, conducted in mice, is the first to demonstrate that pyramidal neurons in the mature brain stem are generated by precursors of glial cells - non-neuronal support cells - and that these new neurons likely are capable of transmitting information to widespread regions of the brain, said David Pleasure, a professor of neurology and pediatrics at the UC Davis School of Medicine and the study's author.
"Pyramidal Neurons are Generated from Oligodendroglial Progenitor Cells in Adult Piriform Cortex," is published online this week in the Journal of Neuroscience.
"We used to think that the sole destiny of oligodendroglial progenitor cells was to become myelin-forming oligodendroglia," Pleasure said. "Later it was shown that they also can generate other kinds of glial cells as well. We now have demonstrated that these oligodendroglial progenitor cells, which are widely distributed in the brain, and persist throughout life, also give rise to a group of large cerebral cortical neurons. Thus, oligodendroglial progenitor cells are truly multipotent."
The researchers found that precursors of glial cells, called proteolipid promoter-expressing NG2 progenitors (PPEPs, pronounced Pee-peps), give rise to glutamatergic pyramidal neurons, an important type of brain cell that sends long-range excitatory signals. PPEPs belong to a class of glial precursor cells called oligodendroglial progenitor cells (OPCs). These cells have been discovered only recently, and they hold tremendous promise for stem-cell regenerative medicine. They are the largest proliferating population of cells in the mammalian brain and spinal cord, and they could replace or repair injured cells.
"This study shows very definitively that PPEPs generate new neurons, that these new neurons have all the morphological and structural features which suggest that they are functionally integrated into the existing circuitry," said Fuzheng Guo, the study's lead author and a postdoctoral fellow in the Department of Neurology in the UC Davis School of Medicine.
"For the past two decades, we have known that there are two small regions that continue to give rise to newborn neurons," said study co-author Joyce Ma, a student at the UC Davis School of Medicine and doctoral candidate in neuroscience. "The new neurons in those known regions are small interneurons or small granule neurons that modulate existing circuitry or relay signals generated by other neurons, respectively. Unlike these neurons, the new pyramidal neurons are likely the main players in processing and integrating olfactory memories."
The study identified the new pyramidal neurons in a part of the brain not typically associated with neurogenesis, the piriform cortex. The piriform cortex receives not only olfactory information, but also inputs from regions of the brain that are involved in emotion regulation and memory formation. Because of its privileged access to diverse brain regions, the piriform cortex is capable of tying odor representations to other types of information that are important for a wide range of behaviors. In animals and humans, activation in the piriform cortex is linked to odor memory and the emotional qualities of odors. In rodents, activity in this region is related to sexual behavior.
Earlier studies have found that precursors to neural cells can give rise to neurons in two mature brain regions: the subventricular zone and the subgranular zone in the hippocampus, a structure crucial for memory formation. The new neurons in those regions were only capable of influencing neuronal activity within localized areas of the brain rather than sending far-reaching signals, said Pleasure, who also is the research director at Shriners Hospitals for Children - Northern California and the director of the UC Davis-Shriners Institute for Pediatric Regenerative Cures.
The current study follows findings published in 2009 that PPEPs in the immature mouse brain generate neurons in multiple regions, including the hippocampus and piriform cortex, and that these neurons survive into adulthood. They also found that PPEPs produced GABA-ergic interneurons in the immature brain. Prior to that study, scientists had assumed that the general class of glial precursor cells, called oligodendroglial progenitor cells (OPCs), could produce only glial cells, which create insulating sheets that wrap around neuronal projections and ensure speedy and reliable signal transmission. Instead, their results showed that these cells generate all three major cell types in the brain and spinal cord.
"Whether or not OPCs could form new neurons was not at all clear until our prior study," Pleasure said.
The researchers focused on the piriform cortex in the current study because it was found to be a "hot spot" for PPEPs in the earlier study. The study was conducted using a genetic fate-mapping technique to track the lineage, or cell fates, of OPCs in the young adult brains of genetically-engineered mice. These cells and their progeny glow fluorescent yellow after being injected with the drug tamoxifen. The scientists then extracted tissue samples from their piriform cortex and analyzed the data using a confocal microscope at different time points for six months.