Nature Medicine
November 1998 Volume 4 Number 11 p 1207

Take comfort in human neurogenesis
Editorial
Even as children, most of us will have come across the well-rehearsed dogma that our brain cannot replace dying neurons. And as students returning from basic neuroscience classes, we may even have lain awake some nights mulling over the consequences of the inevitable, gradual loss of our precious and predetermined 100 billion neuronal quota. Sleep easy. On this issue, Fred Gage and colleagues in La Jolla and Göteburg report that the adult human brain is capable of neurogenesis.
Most cells are continually dividing, repairing and replenishing organs and other systems. In the developing embryo, cells have a truly prodigious capacity to replicate and neural precursors are no exception. So where did this belief in irreplaceable adult brain cells come from? In the broadest sense, neurons are thought of as unusually large and complicated cells that are highly differentiated. Intuitively, therefore, it seems unlikely that such cells could easily de-differentiate and replicate. In fact, recent work suggests that adult neurogenesis comes from endogenous stem-like cells that persist in the brain, bypassing the need for de-differentiation
Many studies over the last few decades have chipped away at the 'non-diving adult brain cell' edifice. As early as the 1960s, Altman and Das provided good evidence for neurogenesis in the adult rat hippocampus, and in 1967 the same authors, moved beyond 'evidence' and presented a paper simply entitled "Postnatal neurogenesis in the guinea-pig." (The choice of guinea-pig was not trivial as, unlike mice and rats, they are born with relatively mature brains that undergo very little structural change after birth.) Given this precedent, surely humans could match rats and guinea-pigs in regenerative brain capacity. Not so, said the critics, for the simple reason that rodents do not belong to the elite 'higher' animals club. An influential 1985 article by Pasco Rakic (in which he reported an absence of neurogenesis in rhesus monkeys) argued that perhaps neuronal replication could not be tolerated in primates because it might interfere with learning and memory.
 

Nature Reviews Neuroscience 1, 67 -73 (2000)
Neurogenesis in the adult brain: death of a dogma Charles G. Gross
Preface
For over 100 years a central assumption in the field of neuroscience has been that new neurons are not added to the adult mammalian brain. This perspective examines the origins of this dogma, its perseverance in the face of contradictory evidence, and its final collapse. The acceptance of adult neurogenesis may be part of a contemporary paradigm shift in our view of the plasticity and stability of the adult brain
 

Nature Reviews Neuroscience 2, 224 (2001)
LEARNING AND MEMORY
Memories are made of this
Rachel Jones
The human body is constantly producing new cells. Just think about how quickly new skin cells are produced to heal a cut, or the capacity of the bone marrow to produce blood cells. But for many years, neuroscientists believed that neurons in the human brain could not be renewed. Although some issues related to adult neurogenesis remain controversial, it has become increasingly clear that new neurons are constantly being produced even in the adult brain, particularly in the hippocampus.
The well-known association of the hippocampus with memory and learning led naturally to speculation that these newborn neurons were involved in the formation of memories, and studies showed that associative learning could increase the number of newly formed cells that survived for long periods
 

Science 1993 May 21;260(5111):1130-2
GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons.
Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F
A potent neurotrophic factor that enhances survival of midbrain dopaminergic neurons was purified and cloned. Glial cell line-derived neurotrophic factor (GDNF) is a glycosylated, disulfide-bonded homodimer that is a distantly related member of the transforming growth factor-beta superfamily. In embryonic midbrain cultures, recombinant human GDNF promoted the survival and morphological differentiation of dopaminergic neurons and increased their high-affinity dopamine uptake. These effects were relatively specific; GDNF did not increase total neuron or astrocyte numbers nor did it increase transmitter uptake by gamma-aminobutyric-containing and serotonergic neurons. GDNF may have utility in the treatment of Parkinson's disease, which is marked by progressive degeneration of midbrain dopaminergic neurons.
 

Neurobiol Dis 1997;4(3-4):186-200
Studies on neuroprotective and regenerative effects of GDNF in a partial lesion model of Parkinson's disease.
Bjorklund A, Rosenblad C, Winkler C, Kirik D Wallenberg Neuroscience Center, Department of Physiology and Neuroscience, University of Lund, Sweden.
Intrastriatal 6-hydroxydopamine injections in rats induce partial lesions of the nigrostriatal dopamine (DA) system which are accompanied by a delayed and protracted degeneration of DA neurons within the substantia nigra. By careful selection of the dose and placement of the toxin it is possible to obtain reproducible and regionally defined partial lesions which are well correlated with stable functional deficits, not only in drug-induced behaviors but also in spontaneous motoric and sensorimotoric function, which are analogous to the symptoms seen in patients during early stages of Parkinson's disease. The intrastriatal partial lesion model has proved to be particularly useful for studies on the mechanisms of action of neurotrophic factors since it offers opportunities to investigate both protection of degenerating DA neurons during the acute phases after the lesion and stimulation of regeneration and functional recovery during the chronic phase of the postlesion period when a subset of the spared nigral DA neurons persist in an atrophic and dysfunctional state. In the in vivo experiments performed in this model glial cell line-derived neurotrophic factor (GDNF) has been shown to exert neurotrophic effects both at the level of the cell bodies in the substantia nigra and at the level of the axon terminals in the striatum. Intrastriatal administration of GDNF appears to be a particularly effective site for induction of axonal sprouting and regeneration accompanied by recovery of spontaneous sensorimotor behaviors in the chronically lesioned nigrostriatal dopamine system.
 

Ann Neurol 1998 Sep;44(3 Suppl 1):S121-5
Neuroprotective and neurorestorative properties of GDNF.
Gash DM, Zhang Z, Gerhardt G
Department of Anatomy and Neurobiology and Center for Magnetic Resonance Imaging and Spectroscopy, University of Kentucky, College of Medicine, Lexington, USA.
Glial cell line-derived neurotrophic factor (GDNF) promotes recovery of the injured nigrostriatal dopamine system and improves motor functions in both rodent and nonhuman primate models of Parkinson's disease (PD). The neurorestorative effects of a single administration of GDNF last for at least 1 month and can be maintained in rhesus monkeys by monthly injections. Adult midbrain dopamine neurons stimulated by GDNF show increased cell size, neurite extent, and expression of phenotypic markers. In parkinsonian nonhuman primates, GDNF treatment improves three of the cardinal features of PD: bradykinesia, rigidity, and postural instability. Although intracerebral administration is necessary because of the blood-brain barrier, intraventricular, intrastriatal, and intranigral routes of administration have been found to be efficacious in rodents and nonhuman primates. GDNF also induces neuroprotective changes in dopamine neurons which are active within hours after trophic factor administration. The powerful neuroprotective and neurorestorative properties of GDNF seen in preclinical studies suggest that trophic factors may play an important role in treating PD.
 

Ann Neurol 1999 Sep;46(3):419-24
Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson's disease.
Kordower JH, Palfi S, Chen EY, Ma SY, Sendera T, Cochran EJ, Cochran EJ, Mufson EJ, Penn R, Goetz CG, Comella CD
Department of Neurological Sciences, Rush-Presbyterian-St Luke's Medical Center, Chicago, IL 60612, USA.
As part of a safety and tolerability study, a 65-year-old man with Parkinson's disease (PD) received monthly intracerebroventricular injections of glial-derived neurotrophic factor (GDNF). His parkinsonism continued to worsen following intracerebroventricular GDNF treatment. Side effects included nausea, loss of appetite, tingling, L'hermitte's sign, intermittent hallucinations, depression, and inappropriate sexual conduct. There was no evidence of significant regeneration of nigrostriatal neurons or intraparenchymal diffusion of the intracerebroventricular GDNF to relevant brain regions. Alternative GDNF delivery systems should be explored.
 

Beck, K. D., J. Valverde, et al. (1995).
Mesencephalic dopaminergic neurons protected by GDNF from axotomy- induced degeneration in the adult brain.
Nature 373(6512): 339-41.
Glial-cell-line-derived neurotrophic factor (GDNF) promotes survival of embryonic dopaminergic neurons in culture, and its expression pattern suggests a role as a transient target-derived trophic factor for dopaminergic neurons of the substantia nigra. These neurons participate in the control of motor activity, emotional status and cognition, and they degenerate in Parkinson's disease for unknown reasons. To test whether GDNF has a trophic effect on dopaminergic neurons in the adult brain, we used a rat model in which these neurons are induced to degenerate by transecting their axons within the medial forebrain bundle. We report here that axotomy resulted in loss of half the tyrosine hydroxylase-expressing neurons in the substantia nigra. This loss was largely prevented by repeated injections of GDNF adjacent to the substantia nigra. Our findings suggest that GDNF or related molecules may be useful for the treatment of Parkinson's disease.
 

Tomac, A., E. Lindqvist, et al. (1995).
Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo.
Nature 373(6512): 335-9.
Glial-cell-line-derived neurotrophic factor (GDNF), a recently cloned new member of the transforming growth factor-beta superfamily, promotes survival of cultured fetal mesencephalic dopamine neurons and is expressed in the developing striatum. There have, however, been no reports about effects of GDNF in situ. We have used the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces parkinsonian symptoms in man, to determine whether GDNF might exert protective or regenerative effects in vivo in the adult nigrostriatal dopamine system in C57/B1 mice. GDNF injected over the substantia nigra or in striatum before MPTP potently protects the dopamine system, as shown by numbers of mesencephalic dopamine nerve cell bodies, dopamine nerve terminal densities and dopamine levels. When GDNF is given after MPTP, dopamine levels and fibre densities are significantly restored. In both cases, motor behaviour is increased above normal levels. We conclude that intracerebral GDNF administration exerts both protective and reparative effects on the nigrostriatal dopamine system, which may have implications for the development of new treatment strategies for Parkinson's disease.

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