Motor neuronal and glial apoptosis in the adult facial nucleus after intracranial nerve transection.

OBJECT: Intracranial lesions affecting the facial nerve are usually associated with significant morbidity and poor functional restitution, despite the fact that a peripheral nerve injury normally recovers well. Mechanistic explanations are needed to direct future therapies. Although neonatal motor neurons are known to die as a result of apoptosis after axotomy, this cell death mechanism has not been explicitly demonstrated after peripheral cranial nerve transection in adult mammals. METHODS: The authors induced substantial retrograde neuronal death in the adult rodent by transecting the facial nerve during its intracranial course. Neuronal apoptosis was demonstrated as shrunken facial motor neurons, retrogradely labeled with fluorogold and with nuclei positively labeled by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL). Glial apoptosis was demonstrated by double labeling with respect to cell type. On postinjury Days 7 and 14, the intracranial axotomy led to neuronal apoptosis, corresponding to a neuronal loss that was observed quantitatively in cresyl violet-stained tissue sections obtained using a stereological method. In contrast, no neuronal apoptosis was observed after creating a distal lesion of the facial nerve, which causes less neuronal loss. In addition, glial apoptosis was seen in the facial nucleus after both distal and proximal axotomy. Whereas the proximal intracranial axotomy led to TUNEL-positive nuclei in cells showing markers for oligodendrocytes and microglia, only the latter glial cell population was double labeled with TUNEL-positive nuclei after distal lesioning. CONCLUSIONS: These findings may ultimately lead to new therapeutic strategies in patients suffering from facial nerve palsy due to an intracranial lesion.

Aging of the nigrostriatal system in the squirrel monkey.

Increasing incidence of Parkinson's disease with advancing age suggests that age-related processes predispose the nigrostriatal dopaminergic system to neurodegeneration. Several hypotheses concerning the effects of aging on nigrostriatal neurons were assessed in this study using a non-human primate model. First, we examined the possibility that the total number of dopaminergic neurons decline in the substantia nigra as a function of age. Stereological counting based on both tyrosine hydroxylase immunoreactivity (TH-ir) and neuromelanin (NM) content revealed no difference in cell number between young, middle-aged and old squirrel monkeys. We then determined whether advancing age changed the relative proportion of neurons characterized by 1) TH-ir in the absence of NM, 2) the presence of both TH-ir and NM, or 3) NM without TH-ir. Indeed, a progressive age-related depletion of TH only cells was paralleled by an increase in NM only neurons. The possibility that these changes could underlie a functional impairment of the nigrostriatal system was supported by striatal dopamine measurements showing a decrease in older monkeys. Finally, we tested the hypotheses that aging may enhance cell vulnerability to injury and that different dopaminergic subpopulations display varying degrees of susceptibility. When monkeys were exposed to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, cell loss was markedly more pronounced in older animals, and the ranking of vulnerability was TH only < TH/NM < NM only cells. The data indicate that, even in the absence of an overall neuronal loss, changes in the characteristics of dopaminergic cells reflect functional deficits and increased vulnerability to injury with age. NM content appears to be an important marker of these age-related effects.

Evidence for neurogenesis in the adult mammalian substantia nigra.

New neurons are generated from stem cells in a few regions of the adult mammalian brain. Here we provide evidence for the generation of dopaminergic projection neurons of the type that are lost in Parkinson's disease from stem cells in the adult rodent brain and show that the rate of neurogenesis is increased after a lesion. The number of new neurons generated under physiological conditions in substantia nigra pars compacta was found to be several orders of magnitude smaller than in the granular cell layer of the dentate gyrus of the hippocampus. However, if the rate of neuronal turnover is constant, the entire population of dopaminergic neurons in substantia nigra could be replaced during the lifespan of a mouse. These data indicate that neurogenesis in the adult brain is more widespread than previously thought and may have implications for our understanding of the pathogenesis and treatment of neurodegenerative disorders such as Parkinson's disease.