Adult Neurogenesis in Mammals: An Identity Crisis

Rakić, Paško

doi:10.1523/jneurosci.22-03-00614.2002

Cited by 271 publications

(173 citation statements)

References 50 publications

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“…Our results simply indicate that the incorporation of BrdU alone cannot be taken as sufficient evidence of neurogenesis in models of brain injury and that multiple markers using a variety of independent methods are needed to reach definite conclusions as to whether new neurons have been born in adult mammalian brain (Rakic, 2002;van Praag et al, 2002).…”

Section: Discussionmentioning

confidence: 85%

Hypoxia-Ischemia Induces DNA Synthesis without Cell Proliferation in Dying Neurons in Adult Rodent Brain

et al. 2004

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Recent studies suggest that postmitotic neurons can reenter the cell cycle as a prelude to apoptosis after brain injury. However, most dying neurons do not pass the G 1 /S-phase checkpoint to resume DNA synthesis. The specific factors that trigger abortive DNA synthesis are not characterized. Here we show that the combination of hypoxia and ischemia induces adult rodent neurons to resume DNA synthesis as indicated by incorporation of bromodeoxyuridine (BrdU) and expression of G 1 /S-phase cell cycle transition markers. After hypoxia-ischemia, the majority of BrdU-and neuronal nuclei (NeuN)-immunoreactive cells are also terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL)-stained, suggesting that they undergo apoptosis. BrdU ϩ neurons, labeled shortly after hypoxia-ischemia, persist for Ͼ5 d but eventually disappear by 28 d. Before disappearing, these BrdU ϩ /NeuN ϩ / TUNEL ϩ neurons express the proliferating cell marker Ki67, lose the G 1 -phase cyclin-dependent kinase (CDK) inhibitors p16INK4 and p27Kip1 and show induction of the late G 1 /S-phase CDK2 activity and phosphorylation of the retinoblastoma protein. This contrasts to kainic acid excitotoxicity and traumatic brain injury, which produce TUNEL-positive neurons without evidence of DNA synthesis or G 1 /S-phase cell cycle transition. These findings suggest that hypoxia-ischemia triggers neurons to reenter the cell cycle and resume apoptosis-associated DNA synthesis in brain. Our data also suggest that the demonstration of neurogenesis after brain injury requires not only BrdU uptake and mature neuronal markers but also evidence showing absence of apoptotic markers. Manipulating the aberrant apoptosis-associated DNA synthesis that occurs with hypoxia-ischemia and perhaps neurodegenerative diseases could promote neuronal survival and neurogenesis.

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Section: Discussionmentioning

confidence: 85%

Hypoxia-Ischemia Induces DNA Synthesis without Cell Proliferation in Dying Neurons in Adult Rodent Brain

et al. 2004

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“…Third, the inside-to-outside settling pattern of isochronously generated neurons in primates is more precise than in rodents (3,6) and thus, the tolerance for malpositioning may be smaller. In addition, different functional areas in the primate cortex are generated by different schedules (43) so that exposure to USW may potentially affect selective cortical areas and different layers, depending on the time of exposure, potentially causing a variety of symptoms.…”

Section: Discussionmentioning

confidence: 99%

Prenatal exposure to ultrasound waves impacts neuronal migration in mice

Ang

Glunčić

Duque

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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243

172

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Neurons of the cerebral neocortex in mammals, including humans, are generated during fetal life in the proliferative zones and then migrate to their final destinations by following an inside-tooutside sequence. The present study examined the effect of ultrasound waves (USW) on neuronal position within the embryonic cerebral cortex in mice. We used a single BrdU injection to label neurons generated at embryonic day 16 and destined for the superficial cortical layers. Our analysis of over 335 animals reveals that, when exposed to USW for a total of 30 min or longer during the period of their migration, a small but statistically significant number of neurons fail to acquire their proper position and remain scattered within inappropriate cortical layers and͞or in the subjacent white matter. The magnitude of dispersion of labeled neurons was variable but systematically increased with duration of exposure to USW. These results call for a further investigation in larger and slower-developing brains of non-human primates and continued scrutiny of unnecessarily long prenatal ultrasound exposure.brain malformations ͉ cerebral cortex ͉ embryonic development A fundamental feature of cerebral cortical organization is that positions of its neuronal constituents into horizontal (laminar) and vertical (radial) arrays ultimately define their connectivity and function (1). Cortical neurons acquire appropriate positions by migration from the site of their origin in the proliferative zones lining the cerebral ventricle, according to a precise schedule (2, 3) and along well defined pathways (4-6). When the rate of neuronal migration and the sequence of arrival are altered because of genetic and͞or environmental factors, various consequences, including abnormal behavior, have been observed (7-13). In terms of orientation and directionality of movement, neuronal migration to the cerebral cortex can be classified into radial (proceeding radially from the ventricular to the pial surface) (5, 14) and tangential (running parallel to the brain surface) (15)(16)(17). Contact interaction between migrating neurons and the surfaces of neighboring cells plays a decisive role in selecting the migratory pathway and determining their final position (18,19). Neuronal migration involves translocation of the nucleus and the surrounding cytoplasm with the leading process, which requires rearrangement of the cytoskeleton (20, 21). As a consequence of these complex cellular and molecular interactions, the process of neuronal migration is highly sensitive to a variety of biological, physical, and chemical agents, as well as to specific genetic mutations (7-13). For example, repeated exposure of the rodent and primate fetal brain to environmental agents, such as alcohol (9), drugs (22), neurotrophic viruses (23), and ionizing irradiation (24, 25), causes misplacement of neurons and behavioral deficits.To our knowledge, the effect of ultrasound waves (USW) on the rate of migration in the cerebral cortex has never been tested, although it has been reported ...

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“…2e). IddU incorporation reflects DNA duplication, but it is not a marker for cell division (Rakic, 2002). Thus, control and EAE mice at 20 dpi were injected for either 1 or 12 h, and the numbers of total labeled cells per section were compared with those obtained from 10 h experiments.…”

Section: Activated Microglia Reproduces the Synaptic Defects Of Eae Mmentioning

confidence: 99%

Inflammation Triggers Synaptic Alteration and Degeneration in Experimental Autoimmune Encephalomyelitis

Centonze¹,

Muzio²,

Rossi³

et al. 2009

J. Neurosci.

349

420

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Neurodegeneration is the irremediable pathological event occurring during chronic inflammatory diseases of the CNS. Here we show that, in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, inflammation is capable in enhancing glutamate transmission in the striatum and in promoting synaptic degeneration and dendritic spine loss. These alterations occur early in the disease course, are independent of demyelination, and are strongly associated with massive release of tumor necrosis factor-␣ from activated microglia. CNS invasion by myelin-specific blood-borne immune cells is the triggering event, and the downregulation of the early gene Arc/Arg3.1, leading to the abnormal expression and phosphorylation of AMPA receptors, represents a culminating step in this cascade of neurodegenerative events. Accordingly, EAE-induced synaptopathy subsided during pharmacological blockade of AMPA receptors. Our data establish a link between neuroinflammation and synaptic degeneration and calls for early neuroprotective therapies in chronic inflammatory diseases of the CNS.

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Adult Neurogenesis in Mammals: An Identity Crisis

Cited by 271 publications

References 50 publications

Hypoxia-Ischemia Induces DNA Synthesis without Cell Proliferation in Dying Neurons in Adult Rodent Brain

Hypoxia-Ischemia Induces DNA Synthesis without Cell Proliferation in Dying Neurons in Adult Rodent Brain

Prenatal exposure to ultrasound waves impacts neuronal migration in mice

Inflammation Triggers Synaptic Alteration and Degeneration in Experimental Autoimmune Encephalomyelitis

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