Adult neurogenesis : from stem cell to functional neuron

Abstract

The adult mammalian central nervous system harbors a population of neural stem cells with the ability to generate neurons, astrocytes and oligodendrocytes. These pluripotent cells can be enriched in vitro, and by directing their differentiation it would be possible to generate populations of specific neural cell types to use for transplantation. Alternatively, gene therapies stimulating stem cells directly in the brain to produce more neurons of a desired type could be an attractive treatment. It has proven difficult to express genes in stem cells. We have therefore established and evaluated different gene delivery methods, both viral and nonviral, for introduction of genes into adult neural stem cells in vitro and in vivo. Using these different techniques, we show that it is possible to target gene expression to stem cells in the adult brain, and also that it is feasible to direct the differentiation of the stem cells to neurons in vitro.

In the adult mammalian brain stem cells give rise to new neurons in the olfactory bulb and the hippocampus. A question has been whether neurons born in the adult integrate into the existing neuronal network of the brain. Using a transsynaptically transported virus, we have shown that adult-born neurons in both the olfactory bulb and the hippocampus do integrate into existing circuit. Moreover, markers for neuronal activity show that a high degree of the neurons born in the adult olfactory bulb participate in odor processing, showing that adult-born neurons not only integrate, they also function as they respond to relevant environmental stimuli.

The finding that ongoing neuronal cell death in the substantia nigra does not alter the total number of neurons in the same area indicates that new neurons are continuously added and compensate for the cell loss. We have therefore investigated the neurogenic potential in the substantia nigra of the midbrain, the region where dopamine-producing neurons lost in Parkinson's disease reside. Two different mitotic markers were found in dopaminergic neurons of the substantia nigra, and we identified ependymal cells lining the ventricles of the midbrain as the most likely origin for the newborn neurons. The adult-born dopaminergic neurons were found to project to their appropriate target and also to integrate into the existing synaptic network. Additionally, we could show that the rate of neurogenesis is increased after a selective lesion of dopaminergic neurons. This indicates that the rate of adult neurogenesis can be altered, a finding with implications for cellular therapies of Parkinson's disease.

The regulation of neurogenesis from stem cells in the adult brain is largely unknown. Notch receptor signaling has been suggested to be involved. We found several Notch receptors and ligands, as well as downstream genes, to be expressed in the stem cell niche in the adult neurogenic lateral ventricle wall. Genetic manipulations in transgenic mice have shown that inhibition of Notch signaling in ependymal cells leads to differentiation of ependymal cells into neurons. These neurons migrate and mature similarly to neurons normally born in the lateral ventricle wall. This demonstrates that Notch signaling keeps ependymal cells in a quiescent state and that ablation of this signaling pathway induces neurogenesis by ependymal cells in vivo. This further supports the finding of ependymal cells acting as neural stem cells in the adult brain.