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Neurogenesis is a Whole Life Process
Posted on: September 4, 2003

Process of neurogenesis is known to proceed in newborns. Adults, it was thought, have their finite number of neuronal cells, which doesn't change until death. So because of their degeneration with age and inability to renovate we have neurodegenerative diseases (Alzheimer's, Parkinson's etc.). Recent studies with stem cells opened new gates of cell's renovation possibilities. Human body is not as rigid as it was thought earlier; cells responsible for regeneration processes are present in all human tissues without any exception and these cells are called stem cells. But let's start from neurons and neurogenesis.

The majority of neurons are born before or around birth. The first indications of neurogenesis in the adult mammalian brain were presented four decades ago, but it is only during the last years that it has been firmly established that new neurons are generated continuously from stem cells in certain regions of the adult brain in all studied mammals, including man. The most active neurogenic regions are the dentate gyrus (DG) of the hippocampus and the olfactory bulb. It has been estimated that about 10,000 new neurons are added each day to the adult rat DG, and the rate of neurogenesis in the olfactory bulb is likely to be several fold higher. In retrospect, it is quite remarkable that such pronounced processes went unnoticed for so long time and it raises the question whether there may be a low level of neurogenesis in other brain regions, which has not yet been detected.

In addition to the neurogenesis in the olfactory bulb and DG, low numbers of new neurons have been suggested to be generated in other parts of the hippocampus as well as in the cortex, although the latter remains controversial. Moreover, neurogenesis has been demonstrated in several additional regions in response to injury. Whether new neurons are generated also in the substantia nigra pars compacta (SNpc) of the midbrain, the region where dopamine-producing neurons lost in Parkinson's disease reside.

The advantage of in vivo labeling techniques employed allowed tracing of labeled cells showing the slow turnover of dopaminergic projection neurons in the adult rodent brain, and that neurogenesis is increased after a partial injury.

Analysis of total number of neurons in the SNpc containing the rate-limiting enzyme for dopamine synthesis showed that dopaminergic neurons are dying, whereas total nigral neuronal numbers remain constant over a large part of the life span of an adult mouse, suggested that new neurons might be added. Indeed, neurons are generated in the adult substantia nigra. Most new neurons were found in the medial-rostral part of the substantia nigra, where the neuronal density is highest, whereas they were never observed in the most caudal SNpc. Nerve cells were individually dispersed, rarely occurred in clusters, and never displayed an apoptotic, condensed morphology.

Neural stem cells lining the ventricular system of the adult rodent give rise to olfactory bulb interneurons and have been found to reside both in the ependymal and subependymal layer of the lateral ventricle wall. Labeled cells proliferated in vitro to form clonal aggregates, i.e., neurospheres. When passaged, single cells generated new neurospheres, which when induced to differentiate, generated both neurons and glia. However, the cells did not spontaneously acquire a dopaminergic phenotype, which indicates the presence of signals for phenotypic differentiation in vivo.

Neutral stem cells in the midbrain give rise to the observed new neurons in the adult substantia nigra. Nigral dopaminergic neurons generated in the adult mouse derive from stem cells lining the ventricular system. Adult-born neurons in the substantia nigra participated in defined multisynapse network connections with the cortex – they innervate their appropriate target. Thus newly generated neurons project to the striatum and integrate into synaptic circuits (Fig. 1).

Fig. 1. Newborn substantia nigra neurons project to the striatum. Schematic drawing showing the right intraventricular injection of DiI (red, cell marker) to label cells lining the ventricular system, and left intrastriatal fluorogold (cell marker) injection (blue) to retrogradely trace nigrostriatal projections.

In agreement with the lesion-induced effects on neurogenesis observed in other brain regions, a systemic dose of MPTP (lesion inducer), known to kill approximately half of the nigral dopaminergic nerve cell population, led to a 2-fold increase of newborn nigral neurons 3 weeks after the lesion. Labeled neurons in SNpc did not display pyknotic nuclei or other signs of apoptosis. These data suggest a significant increase in nigral neurogenesis after a partial lesion.

These data support the presence of neurogenesis in the adult substantia nigra. SNpc did not lose newborn neurons during aging; new nerve cells were added during adulthood to maintain homeostasis. Indeed, markers for proliferation were demonstrated in nuclei of cells with nerve cell characteristics. In agreement with functional integration of the adult-born neurons in other regions, the newly generated nigral neurons projected axons to the appropriate terminals in striatum and were integrated into multisynapse circuits to cortex (Fig. 1).

Furthermore, these data suggest that the newly generated dopaminergic projection neurons derive from stem cells lining the cerebroventricular system in the midbrain. Although the number of neurons generated is orders of magnitude lower than in the hippocampus or the olfactory bulb, the estimated turnover rate implies, provided the rate is constant, that the entire population of dopaminergic substantia nigra neurons could be replaced within the life span of the mouse.

It is believed that a gradual decline in the number of nigral dopamine neurons occurs with normal aging in humans, and that Parkinson's disease is caused by an abnormally rapid rate of cell death. Interestingly, apoptotic neurons have been found in the normal human substantia nigra. Neural stem cells and neurogenesis have been demonstrated in the adult human brain. If there is neuronal turnover also in the human substantia nigra, it is possible that Parkinson's disease could be caused, at least in some cases, by decreased neurogenesis, rather than an increased cell death. Interestingly, studies of nigral tissue from patients with neurodegenerative disorders affecting nigral neurons, including Parkinson's and Lewy-body disease, show that a surprisingly large proportion (5-11%) of the neuronal population displays signs of apoptosis. Based on this, and taking into account the rapid kinetics of apoptosis, one would assume that the neurons would rapidly run out. This paradox could be explained by a parallel production of neurons, though it would not keep up with the degenerative processes, leading to net loss of cells in the Parkinsonian patients. Indeed, transient processes observed during neuronal cell death, e.g., glial activation, support the presence of ongoing neuronal loss as the disease progresses over several years. Our data imply that disturbances in the finely tuned equilibrium of cell genesis and cell death could result in neurodegenerative disorders.

The presence of a slow physiological turnover of neurons in the adult substantia nigra points to a functional role for neural stem cells in the midbrain. Moreover, the increased neuronal replacement observed after a partial nigral MPTP-induced lesion indicates that the rate of neurogenesis can be regulated. Unveiling the molecular mechanisms controlling neurogenesis may enable the development of strategies to increase the generation of dopaminergic neurons in the adult brain, and potentially offer an attractive way to treat Parkinson's disease.

Source: Ming Zhao, Stefan Momma, Kioumars Delfani, Marie Carlén, Robert M. Cassidy, Clas B. Johansson, Hjalmar Brismar, Oleg Shupliakov, Jonas Frisén, and Ann Marie Janson; Evidence for neurogenesis in the adult mammalian substantia nigra. PNAS June 24, 2003 vol. 100 no. 13 7925-7930.
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