Generation Of New Neurons Research Articles

Complete sparing of spatial learning following posterior and posterior plus anterior cingulate cortex lesions at 10 days of age in the rat

Neonatal posterior cingulate cortex lesions spare the spatial deficits that characterize adult lesions. The present experiments examined the possibility that the anterior cingulate cortex mediates the spared spatial behavior. Rats were given bilateral lesions of the posterior cingulate cortex or anterior plus posterior cingulate cortex on postnatal days 4 (P4), 10 (P10), or in adulthood (P120). All groups were tested for spatial learning on the Morris place task in adulthood. Adult animals were impaired on place learning relative to controls whereas place learning was spared in all the neonatal groups and sparing was complete in the group receiving day 10 lesions. The results are discussed in relation to neural mechanisms, including fiber rerouting, synaptic changes and generation of new neurons, that may mediate spared spatial following neonatal posterior cingulate cortex lesions. Also discussed is evidence indicating that the neonatal brain, especially the day 10, has a special ability to compensate for injury.

Genetics of Childhood Disorders: XXXVIII. Stem Cell Research, Part 2: Reconstructing the Brain

An unexpected form of plasticity in the adult brain is the constant generation of new neurons throughout adult life. The addition of thousands of new neurons each day may be a means of sculpting brain circuitry. This turnover has important implications not only for brain function but also for brain repair and pathological conditions such as tumors. This review will cover neurogenesis and the identity of stem cells in the adult brain. The adult brain contains two main types of cells, neurons and macroglia. Macroglia comprise oligodendrocytes and astrocytes. Oligodendrocytes are the cells that form myelin sheaths around the axons of neurons and allow the rapid conduction of electrical impulses. Astrocytes are mysterious cells that have multiple functions, including maintaining homeostasis, absorbing neurotransmitters released by neurons, and providing trophic support. Astrocytes are also induced to divide in response to lesions of the brain resulting in the formation of glial scars. Almost all neurons and glia in the brain are derived from multipotent stem cells located in the germinal layers next to the ventricular cavities of the developing brain. As development proceeds, precursors become progressively more restricted

Is it all DNA repair?: Methodological considerations for detecting neurogenesis in the adult brain

Since the early 1960s, in vivo observations have shown the generation of new neurons from dividing precursor cells. Nevertheless, these experiments suffered from skepticism, suggesting that the prevailing labeling method, which incorporates tagged thymidine analogs, such as [ 3H]-thymidine or bromodeoxyuridine (BrdU), may not be detecting a proliferative event, but could rather mark DNA repair in postmitotic neurons. Even today many scientists outside the field are still skeptical, because the question of specificity for thymidine labeling has not been sufficiently answered. This current paper aims at evaluating the arguments that are used by proponents and skeptics of this method by (i) presenting histological evidence of specificity of BrdU labeling for neural stem cell/progenitor activity in the adult brain; (ii) validating and comparing BrdU labeling with other histological methods; and (iii) combining BrdU and labeling methods for apoptosis to argue against DNA repair being a major contribution of BrdU-positive cells.

Neurogenesis in Adult Subventricular Zone

Much excitement has been generated by the identification of adult brain regions harboring neural stem cells and their continual generation of new neurons throughout life. This is an important departure from traditional views of the germinal potential of the postnatal brain. However, a more profound

Chapter 1 Neuronal changes during development and evolution (an overview)

This overview highlights the presentations made by several authors, with sidelights commentaries on the topics covered in this session. The Neurotropic hypothesis, formulated by Cajal more than one century ago, has been one of the fundamental tenets of modern Neuroscience. Research work is unveiling highly complex molecular mechanisms by means of which neuronal processes grow in the right direction leading to the formation of neural networks. Another interesting topic covered in this session pertains to the remarkably conserved similarity of most parts of the brain between reptiles, birds and mammals. The presence of the neocortex, which occurs in mammals, is discussed on the basis of different migratory behavior during development. The question of neuronal stability throughout the life cycle raises interesting aspects on the generation of new neurons. This is a particularly timely topic because recent evidence, denied by others, has shown the generation of new neocortical neurons in the adult. In another session, it was discussed the evidence showing that pyramidal cells and intrinsic cells of the neocortex have different developmental origins. Finally, several modern analyses show the role of different transcription factors in the formation of brain cortical maps before the arrival of their proper afferent connections.

Making scents of olfactory neurogenesis

Olfaction was long considered to belong more to the realm of art than to that of science. As a result, how the brain perceives, discriminates, and recognizes odorant molecules is still a mystery. Recent progress has nonetheless been made at early stages of the olfactory pathway when olfactory studies entered into the molecular era to elucidate the first contact of an odor molecule with a receptor. Our group focuses on the analysis of odor information in the olfactory bulb, the first processing relay in the mammalian brain. Using this model, we are attempting to decipher the code for odorant information. Furthermore, the olfactory bulb also provides an attractive model to investigate neuronal proliferation, differentiation, migration, and neuronal death, processes involving an interplay between genetic and epigenetic influences. Finally, our goal is to explore the possible consequences of the olfactory bulb plasticity, in olfactory performance. For these purposes, we aim to combine morphological, electrophysiological and behavioral approaches to investigate: (1) how the olfactory bulb processes odor molecule information, (2) how neural precursors differentiate into olfactory bulb interneurons, (3) how these newly-generated neurons integrate into an operational neural network, (4) what role they play in the adult olfactory bulb, and (5) how are basic olfactory functions maintained in such a sensory system subjected to continuous renewal of a large percentage of its neuronal population. These questions should provide new fuel for the molecular and cellular bases of sensory perception and shed light onto cellular bases of learning and memory.

Transcription Factor Expression and Notch-Dependent Regulation of Neural Progenitors in the Adult Rat Spinal Cord

Recent studies have demonstrated that neural stem cells and other progenitors are present in the adult CNS. Details of their properties, however, remain poorly understood. Here we examined the properties and control mechanisms of neural progenitors in the adult rat spinal cord at the molecular level. Adult and embryonic progenitors commonly expressed various homeodomain-type (Pax6, Pax7, Nkx2.2, and Prox1) and basic helix-loop-helix (bHLH)-type (Ngn2, Mash1, NeuroD1, and Olig2) transcriptional regulatory factors in vitro. Unlike their embryonic counterparts, however, adult progenitors could not generate specific neurons that expressed markers appropriate for spinal motoneurons or interneurons, including Islet1, Lim1, Lim3, and HB9. Cells expressing the homeodomain factors Pax6, Pax7, and Nkx2.2 also emerged in vivo in response to injury and were distributed in unique patterns in the lesioned spinal cord. However, neither the expression of the neurogenic bHLH factors including Ngn2, Mash1, and NeuroD1 nor subsequent generation of new neurons could be detected in injured tissue. Our results suggest that signaling through the cell-surface receptor Notch is involved in this restriction. The expression of Notch1 in vivo was enhanced in response to injury. Furthermore, activation of Notch signaling in vitro inhibited differentiation of adult progenitors, whereas attenuation of Notch signals and forced expression of Ngn2 significantly enhanced neurogenesis. These results suggest that both the intrinsic properties of adult progenitors and local environmental signals, including Notch signaling, account for the limited regenerative potential of the adult spinal cord.

Neurogenesis in the olfactory bulb of adult zebrafish

Cell genesis in the adult brain of zebrafish, with specific reference to the olfactory bulbs, was examined using bromodeoxyuridine immunocytochemistry. Mature fish were exposed to a 1% solution of the thymidine analog 5-bromo-2′-deoxyuridine for 1 h and then killed after short (4-h) or long (3–4-week) survival periods. A monoclonal antibody to bromodeoxyuridine allowed visualization of cells that incorporated the drug during the S phase of mitosis. Four hours after administration of the drug, antibody-labeled cells were found almost exclusively in the proliferative zones around the ventricles and in the cerebellum. Very few labeled nuclei were seen in other locations in the brain, indicating that cell genesis occurs in discrete regions in adults. The few labeled profiles in the olfactory bulbs were located in the olfactory nerve layer; these profiles had the morphology of glial nuclei and did not stain with a neuronal marker, the Hu antibody. After longer survival times, labeled cells were present throughout the layers of the olfactory bulb, and many of the immunoreactive profiles in the internal cell layer were also labeled with the Hu antibody, indicating that they are likely adult-formed interneurons. Thus, neurogenesis continues in the olfactory bulb of adult zebrafish. Understanding the process of the generation of new neurons in the brain of adult animals can lead to important insights into neural regeneration and adult plasticity.

Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain

The adult central nervous system was thought to be very limited in its regenerative potential; however, the discovery that stem cell populations produce neurons in the adult brain highlights the dynamics of a previously assumed ‘static’ organ. The continuous generation of new neurons in the adult brain, nevertheless, leads to the question of whether neurogenesis is counterbalanced by an accompanying cell death in the same regions. The objective of this study was to stereologically analyze neurogenesis and programmed cell death in adult brain regions with known neurogenic activity. Using bromodeoxyuridine (BrdU) to identify newborn cells we find that within a few days of BrdU-labeling the adult dentate gyrus and olfactory bulb generate high numbers of newborn neurons. More importantly, dUTP-nick end labeling (TUNEL) reveals that areas of adult neurogenesis also contain high numbers of apoptotic cells. We conclude that programmed cell death may have an important regulatory function by eliminating supernumerous cells from neurogenic regions and may thus contribute to a self-renewal mechanism in the adult mammalian brain.

Increased neurogenesis in a model of electroconvulsive therapy

Background: Electroconvulsive therapy (ECT) is a widely used and efficient treatment modality in psychiatry, although the basis for its therapeutic effect is still unknown. Past research has shown seizure activity to be a regulator of neurogenesis in the adult brain. This study examines the effect of a single and multiple electroconvulsive seizures on neurogenesis in the rat dentate gyrus. Methods: Rats were given either a single or a series of 10 electroconvulsive seizures. At different times after the seizures, a marker of proliferating cells, Bromodeoxyuridine (BrdU), was administered to the animals. Subsequently, newborn cells positive for BrdU were counted in the dentate gyrus. Double staining with a neuron-specific marker indicated that the newborn cells displayed a neuronal phenotype. Results: A single electroconvulsive seizure significantly increased the number of new born cells in the dentate gyrus. These cells survived for at least 3 months. A series of seizures further increased neurogenesis, indicating a dose-dependent mechanism. Conclusions: We propose that generation of new neurons in the hippocampus may be an important neurobiologic element underlying the clinical effects of electroconvulsive seizures.

Origins, functions, and potential of adult neural stem cells.

In recent years, the existence of neural stem cells (NSCs) in the adult mammalian brain has been confirmed. The generation of new neurons from these cells is regulated by growth factors, hormones, and environmental cues; however, the function of newly generated neurons in the adult brain remains elusive. Two recent articles emphasize the impact of motor activity and learning on in situ hippocampal neurogenesis,((1,2)) suggesting a close link to hippocampal function. Adult NSCs can be isolated and expanded in vitro. It was presumed that the origins of the NSCs were within subependyma of the lateral ventricle; however, new evidence suggests that the "real" stem cells may reside in the ependymal lining.((3)) In a related study, these same cells were transplanted into irradiated mice and were able to integrate into the bone marrow and produce various blood cell types,((4)) challenging the limits of neural cell fate determination.

Apparent apoptotic cell death in the olfactory epithelium of adult rodents: death occurs at different developmental stages.

In the olfactory epithelium of adult rodent, receptor neurons are generated continually. Despite the ongoing generation of new neurons, no corresponding increase occurs in the thickness of the mature olfactory epithelium. Thus, epithelial cell death must occur to offset the continual generation of new cells. In the present study, a sensitive method to label nicked DNA in dying cells was combined with immunocytochemistry to determine the identity of dying olfactory cells. In addition, the positions of putative apoptotic cells were mapped to provide additional information about the identity of dying cells. Double labeling experiments revealed that each of the olfactory cell types, i.e., basal cells (keratin-positive), immature neurons (GAP43-positive) and mature receptor neurons (olfactory marker protein (OMP)-positive), were positive for fragmented DNA, suggesting that they undergo apoptotic cell death. The results of the mapping study suggest that apoptotic cell death occurs primarily among GAP43-positive neurons.

Apparent apoptotic cell death in the olfactory epithelium of adult rodents: Death occurs at different developmental stages

In the olfactory epithelium of adult rodent, receptor neurons are generated continually. Despite the ongoing generation of new neurons, no corresponding increase occurs in the thickness of the mature olfactory epithelium. Thus, epithelial cell death must occur to offset the continual generation of new cells. In the present study, a sensitive method to label nicked DNA in dying cells was combined with immunocytochemistry to determine the identity of dying olfactory cells. In addition, the positions of putative apoptotic cells were mapped to provide additional information about the identity of dying cells. Double labeling experiments revealed that each of the olfactory cell types, i.e., basal cells (keratin-positive), immature neurons (GAP43-positive) and mature receptor neurons (olfactory marker protein (OMP)-positive), were positive for fragmented DNA, suggesting that they undergo apoptotic cell death. The results of the mapping study suggest that apoptotic cell death occurs primarily among GAP43-positive neurons. © 1996 Wiley-Liss, Inc.

FGF-2-Responsive Neuronal Progenitors Reside in Proliferative and Quiescent Regions of the Adult Rodent Brain

Neurogenesis is restricted to discrete germinal zones within the developing and the adult central nervous systems. With few exceptions, cells that migrate away from these zones and into the parenchyma no longer participate in the generation of new neurons. In this work, we have found that basic fibroblast growth factor is able to stimulate the proliferation of neuronal and glial progenitors isolated from the septum and striatum of adult rats. These progenitors are indistinguishable from those isolated from the adult hippocampus and subventricular zone, two regions that generate neurons well into adult life. Although a variety of cell types are initially isolated from each brain region, the progenitor-like cells from all four regions are capable of considerable proliferation and, with limited serial passage, can be cultured as enriched populations of immature cells that are capable of differentiating into mature glia and neurons following density arrest and growth factor withdrawal. The fact that cells isolated from the septum and striatum proliferate and have the ability to differentiate into neurons once they are removed from their local environment indicates that neurogenesis may be restricted to discrete areas of the developing and the adult brain by regional differences in regulatory signals rather than from an absence of progenitors capable of responding to neurogenic cues.

Ontogeny of sex differences among newly-generated neurons of the juvenile avian brain

In zebra finches, only males sing and brain regions controlling song exhibit sex differences in neuron number that stem from actions of estrogen during a critical developmental period. In certain song nuclei, these dimorphisms emerge long after neurogenesis and migration are complete, and estrogen promotes masculinization by preventing the death of welldifferentiated neurons. But in another region, the higher vocal center (HVC), cellular mechanisms underlying sex differences in neuron number are not so well understood. In the HVC, neurogenesis continues throughout the post-hatch period of sexual differentiation, and sex differences arise during this time because neuron number increases in males but not females. We used [ 3H]thymidine autoradiography to establish when sex differences in neuron number first develop among a small group of HVC neuronal cohorts. We report that HVC neurons labeled by [ 3H]thymidine on days 15 and 16 after hatching are sexually dimorphic in number within 10 days of their birth, even before all cells in this cohort complete their migration and/or differentiation. This suggests that the cellular mechanisms contributing to sex differences in neuron number in the HVC may differ from those in other sexually dimorphic neural regions of the vertebrate nervous system. In addition, we found that although many thymidine-labeled HVC neurons ultimately project to the robust nucleus of the archistriatum (RA), a sexually dimorphic target, sex differences in their number develop before this efferent projection is established. These results have important implications regarding the site(s) of hormone action, since they suggest that sexual differentiation acts on certain HVC neurons before they establish their efferent projections, and perhaps even before they arrive within the HVC.

Electrical stimulation of lizard brain and behaviour sequences

Reptiles are the only amniotic vertebrates known to be capable of spontaneous regeneration of the central nervous system (CNS). In this study, we analyzed the reactive changes of glial cells in response to a unilateral physical lesion in the cerebral cortex of the lizard Gallotia galloti, at 1, 3, 15, 30, 120, and 240 days postlesion. The glial cell markers glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), S100 protein, and tomato lectin, as well as proliferating cell nuclear antigen (PCNA) were used to evaluate glial changes occurring because of cortical lesions. A transitory and unilateral upregulation of GFAP and GS in reactive radial glial cells were observed from 15 to 120 days postlesion. In addition, reactive lectin-positive macrophage/microglia were observed from 1 to 120 days postlesion, whereas the expression of S100 protein remained unchanged throughout the examined postlesion period. The matricial zones closest to the lesion site, the sulcus lateralis (SL) and the sulcus septomedialis (SSM), showed significantly increased numbers of dividing cells at 30 days postlesion. At 240 days postlesion, the staining pattern for PCNA, GFAP, GS, and tomato lectin in the lesion site became similar to that observed in unlesioned controls. In addition, ultrastructural data of the lesioned cortex at 240 days postlesion indicated a structural repair process. We conclude that restoration of the glial framework and generation of new neurons and glial cells in the ventricular wall play a key role in the successful structural repair of the cerebral cortex of the adult lizard.