Birth Time of Dopaminergic Neurons Determines Function

New neural pathways are constantly forming and changing within developing brains. With so many neurons fighting for synaptic connections, how do these specialized cells know what their function will be later down the line?

Typically, a standard neural "hierarchy" plays out in developing brains. During the development of the cerebral cortex, neural stem cells generate neurons within six cortical layers. The first developed neurons are in layers 6 and 5, followed by layers 4, 3, 2, and 1. Within each layer, these cells will begin to aggregate in different brain areas, and neural stem cells will differentiate into the specific cell type appropriate for that location.

But how do these neuronal cells know where to migrate, and how does this impact cell signaling in surrounding brain areas? Researchers at the University of Bonn set out to answer this question in their recent paper, published in the journal eNeuro.

In their study, the team examined a specific type of neuronal cell – dopaminergic neurons located within the midbrain in mice. As the name suggests, these cells are responsible for the production of dopamine, which is integral for cellular communication and signal transmission. The loss of dopaminergic neurons is associated with diseases such as Parkinson's and results in characteristic tremors and other movement deficits.

"We wanted to know how these progenitors develop into the different groups of dopaminergic cells without which the brain would not function, " states Prof. Dr. Sandra Blaess of the Institute for Reconstructive Neurobiology at the University Hospital Bonn.

While it has been known for a while that nerve cells' careers depend on the time of their emergence, the team wanted to see whether this was the case in dopaminergic neurons, whose functions in the midbrain are not all the same.

"In mice, it takes four to five days for all the progenitor cells to convert to dopaminergic neurons," says Alessandro Petese, doctoral student in Dr. Blaess' lab. "We wanted to know: Are the neurons that form on day one different from those that form on day two, three, or four?"

To assess these cellular mechanisms, the team fluorescently labeled precursor cells at different times so that the neurons emerging from those precursors lit up green under the microscope. This allowed neurons that appeared previously from unlabeled precursors to remain dark.

"In this way, we found that cells born early can still develop into all types of dopaminergic neurons in the midbrain," says Dr. Blaess' collaborator, Franca Fries. Theoretically, these cells can still follow very different career paths. "However, the later they are born, the more their options narrow. So they become more specialized."

Now, the researchers want to investigate which signals force progenitor cells in a particular direction. "In reconstructive neurobiology, efforts are now being made to create neurons from stem cells," says Dr. Blaess. "This is because it allows for targeted reproduction of nerve cell types in the laboratory, which could potentially be used to reverse the loss of cells that occurs in Parkinson's disease, for example."

This work suggests strategies to switch off and on specific dopaminergic neurons in mice. These findings provide new insight into the various disease mechanisms, inducing alterations in the dopaminergic system for conditions like chronic depression, Parkinson's, and more.