Mature Nervous Tissue Research Articles

Comparative model of minimal spinal cord injury reveals a rather anti-inflammatory response in the lesion site as well as increased proliferation in the central canal lining in the neonates compared to the adult rats.

Spinal cord injury (SCI) resulting from trauma decreases the quality of human life. Numerous clues indicate that the limited endogenous regenerative potential is a result of the interplay between the inhibitory nature of mature nervous tissue and the inflammatory actions of immune and glial cells. Knowledge gained from comparing regeneration in adult and juvenile animals could draw attention to factors that should be removed or added for effective therapy in adults. Therefore, we generated a minimal SCI (mSCI) model with a comparable impact on the spinal cord of Wistar rats during adulthood, preadolescence, and the neonatal period. The mechanism of injury is based on unilateral incision with a 20ga needle tip according to stereotaxic coordinates into the dorsal horn of the L4 lumbar spinal segment. The incision should harm a similar amount of gray matter on a coronal section in each group of experimental animals. According to our results, the impact causes mild injury with minimal adverse effects on the neurological functions of animals but still has a remarkable effect on nervous tissue and its cellular and humoral components. Testing the mSCI model in adults, preadolescents, and neonates revealed a rather anti-inflammatory response of immune cells and astrocytes at the lesion site, as well as increased proliferation in the central canal lining in neonates compared with adult animals. Our results indicate that developing nervous tissue could possess superior reparative potential and confirm the importance of comparative studies to advance in the field of neuroregeneration.

Newly Generated and Non-Newly Generated "Immature" Neurons in the Mammalian Brain: A Possible Reservoir of Young Cells to Prevent Brain Aging and Disease?

Brain plasticity is important for translational purposes since most neurological disorders and brain aging problems remain substantially incurable. In the mammalian nervous system, neurons are mostly not renewed throughout life and cannot be replaced. In humans, the increasing life expectancy explains the increase in brain health problems, also producing heavy social and economic burden. An exception to the “static” brain is represented by stem cell niches leading to the production of new neurons. Such adult neurogenesis is dramatically reduced from fish to mammals, and in large-brained mammals with respect to rodents. Some examples of neurogenesis occurring outside the neurogenic niches have been reported, yet these new neurons actually do not integrate in the mature nervous tissue. Non-newly generated, “immature” neurons (nng-INs) are also present: Prenatally generated cells continuing to express molecules of immaturity (mostly shared with the newly born neurons). Of interest, nng-INs seem to show an inverse phylogenetic trend across mammals, being abundant in higher-order brain regions not served by neurogenesis and providing structural plasticity in rather stable areas. Both newly generated and nng-INs represent a potential reservoir of young cells (a “brain reserve”) that might be exploited for preventing the damage of aging and/or delay the onset/reduce the impact of neurological disorders.

Is the modulation of retinoid and retinoid‐associated signaling a future therapeutic strategy in neurological trauma and neurodegeneration?

The complex molecular pathways that mediate the effects of vitamin A and its derivatives, are increasingly recognized as a component of the repair capacity that could be activated to induce protection and regeneration in the mature nervous tissue. Retinoid and retinoid-associated signaling plays an essential role in normal neurodevelopment and appears to remain active in the adult CNS. In this paper, we review evidence which supports the hypothesis of an activation of retinoid-associated signaling molecular pathways in the mature nervous tissue and its significance in the context of neurodegenerative, trauma-induced and psychiatric disorders, at spinal and supra-spinal levels. Finally, we summarize the potential therapeutic avenues based on the modulation of retinoid targets undergoing reactivation under conditions of acute injury and chronic degeneration in the central nervous system, and discuss some of the unresolved issues linked to this treatment strategy.

Engraftment and differentiation of neocortical progenitor cells transplanted to the embryonic brain in utero.

Transplantation of neural progenitors or stem cells is a most useful tool to investigate the relative contribution of cell-autonomous mechanisms and environmental cues in the regulation of cell specification and differentiation during CNS development. To assess the capability of neocortical progenitor cells to integrate into foreign brain regions, here we examined the fate of precursor cells isolated from the dorsal telencephalon of E12 ss-actin-EGFP transgenic mouse embryos after heterotopic/heterochronic transplantation to the E16 rat brain in utero. Our observations show that donor cells were able to penetrate, survive and produce mature cell types into wide regions of the host CNS. Namely, EGFP-positive cells acquired site-specific neuronal identities in many telencephalic regions, including neocortex, hippocampus, olfactory bulb and corpus striatum. In contrast, incorporation into more caudal sites was much less efficient. A fraction of donor cells formed large aggregates that remained segregated from the host milieu. Such aggregates contained mature neurons and glia, including some EGFP-negative elements of host origin, and developed the complex organization of the mature nervous tissue. On the other hand, transplanted cells that engrafted in the parenchyma of extratelencephalic regions predominantly generated glial types. The few neurons failed to acquire obvious site-specific phenotypic traits and did not integrate into the local host architecture. Altogether, our observations indicate that E12 neocortical progenitors are already committed towards regional identities and are unable to modify their phenotypic choices when exposed to heterotopic environmental conditions along different rostro-caudal domains of the embryonic CNS.

Glia-independent chains of neuroblasts through the subcortical parenchyma of the adult rabbit brain.

In the brains of adult mammals long-distance cell migration of neuronal precursors is known to occur in the rostral migratory stream, involving chains of cells sliding into astrocytic glial tubes. By combining immunocytochemistry for polysialylated neural cell adhesion molecule (PSA-NCAM), neuronal and glial antigens, endogenous and exogenously administered cell-proliferation markers, and light and electron microscopy 3D reconstructions, we show that chains of newly generated neuroblasts exist both inside and outside the subventricular zone of adult rabbits. Two groups of chains were detectable within the mature brain parenchyma: anterior chains, into the anterior forceps of the corpus callosum, and posterior chains, close to the external capsule. Parenchymal chains were not associated with any special glial structures, thus coming widely in contact with the mature nervous tissue, including unmyelinated/myelinated fibers, astrocytes, neurons, and oligodendrocytes. These chains of cells, unlike those in the subventricular zone, do not display cell proliferation, but they contain BrdUrd administered several weeks before. Telencephalic areas, such as the putamen, amygdala, claustrum, and cortex, adjacent to the chains harbor numerous PSA-NCAM-positive cells. The counting of newly generated cells in these areas shows small differences in comparison with others, and a few cells double-labeled for BrdUrd/PSA-NCAM (after 1-month survival) and for BrdUrd/NeuN (after 2 months) were detectable. These results demonstrate the occurrence of glial-independent chains of migrating neuroblasts, which directly contact the mature brain parenchyma of adult mammals. These chains could provide a possible link between the adult germinative layers and a very low-rate/long-term process of cell addition in the telencephalon.

Human neuroblastoma cell lines as models for the in vitro study of neoplastic and neuronal cell differentiation.

Neuroblastoma is a childhood solid tumor composed of primitive cells derived from precursors of the autonomic nervous system. This neoplasm has the highest rate of spontaneous regression of all cancer types and has been noted to undergo spontaneous and chemically induced differentiation into elements resembling mature nervous tissue. As such, neuroblastoma has been a prime model system for the study of neuronal differentiation and the process of cancer cell maturation. In this paper we review those agents that have been described to induce the differentiation of neuroblastoma, with an emphasis on the effects and possible mechanisms of action of a group of related compounds, the retinoids. With this model system and the availability of subclones that are both responsive and resistant to chemically induced differentiation, fundamental questions regarding the mechanisms and processes underlying cell maturation have become more amenable to in vitro study.

Rescue of embryonic cells homozygous for a lethal haplotype of the T/t complex: tw12

A series of recessive mutations which arrest embryonic development are located within the T/t region of chromosome 17 in the mouse. To assess whether these mutations cause death in specific differentiating cells or in all cells of the embryo, we removed the embryonic cells from normal developmental constraints and attempted to grow them ectopically in vivo and in vitro. We have succeeded in producing teratomas and teratocarcinomas by transplantation of inner cell masses from blastocysts of t w12 + and t w12 t w12 genotypes. The ability of embryonic cells to grow as tumors was not affected by their genotype; 7 of the 17 tumors were homozygous for t w12 , 7 were heterozygous, and 3 could not be analyzed. Virtually all the tumors of both genotypes contained derivatives of all three germ layers. Neuroepithelial and mature nervous tissue was present in all homozygous tumors and all except one heterozygous tumor. However, no cartilage or bone was found in 5 of 5 t w12 homozygous tumors, while both tissues were present in 3 of 4 t w12 heterozygous tumors. This observation is compatible with the abnormalities characteristic of t w12 t w12 embryos, which show very localized effects in nervous tissue and more general effects on bone and cartilage formation. Cells derived from homozygous tumors were capable of at least limited growth in culture and a cell line has been derived from one of them. The p63/6.9a marker protein was used to determine the presence of the t w12 haplotype in the tumor and cultured cells. We conclude that the lethality associated with the t w12 haplotype is due to lethality of specific cells, and not all cell types.

Effect of Radiation on the RNA Metabolism of the Central Nervous System

In spite of numerous studies on the effects of radiation on the central nervous system, the pathogenesis and mechanism of radiation injury to the nervous tissue are still little understood (1-4). Furthermore, the great discrepancy of dose requirements leading to physiological responses on the one hand and, on the other, to pathomorphological changes in the central nervous system has not been satisfactorily explained (5-8). The recent advances of cytochemical techniques have drawn particular attention to the relationship between Nissl substance and ribonucleic acid (RNA). Alteration of RNA content and chromatolysis of Nissl substance in the neuron, under pathological conditions, were observed by several investigators to precede obvious histomorphological changes indicative of neuronal changes (9-12). The application of microautoradiographic techniques can lead to an extension of these observations. Autoradiographically labeled substances can be followed within the single cell and its compartments, resulting in direct information on the dynamics of physiochemical activity in cells. Tritium-labeled cytidine has been used in various laboratories to study the rate and time course of RNA synthesis on a single-cell level with autoradiographic techniques (13-16). Deoxyribonucleic acid synthesis in the mature nervous tissue, with tritiated thymidine as a specific precursor, was identified only in microglias, astrocytes, oligodendron glias, and subependymal cells and not in any neurons nor in the choroid plexus cells (17-19). In the present study, therefore, tritiated cytidine was used to detect changes in

Partition of adenosine triphosphatase in intracellular fractions of mature and immature rat cerebrum.

Experiments in which infant and adult rat cerebrum were fractionated by differential centrifugation afford evidence that differences exist between comparable fractions from immature and mature nervous tissue with respect to a number of properties. These include differences in layering characteristics, and in the partition of total nitrogen and of calcium and magnesium activated adenosine triphosphatase (ATPase) activities. The total nitrogen content and Ca and Mg ATPase contents of the supernatant fraction of infant cerebrum are strikingly higher than those of the comparable fraction from adult cerebrum. Also, the "specific activity" of ATPase in two of the larger cytoplasmic particle fractions from infant cerebrum is higher than in comparable adult fractions.