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Oligodendrocyte precursor cell (OPC) migration is a mechanism involved in remyelination, these cells migrate from niches in the adult CNS. However, age and disease reduce the pool of OPCs, as a result, the remyelination capacity of the CNS decreases over time. Several experimental studies have introduced OPCs to the brain via direct injection or intrathecal administration. In this study, we used the nose-to brain pathway to deliver oligodendrocyte lineage cells (human oligodendroglioma (HOG) cells), which behave similarly to OPCs in vitro. To this end, we administered GFP-labelled HOG cells intranasally to experimental animals, which were subsequently euthanised at 30 or 60 days. Our results show that the intranasal route is a viable route to the CNS and that HOG cells administered intranasally migrate preferentially to niches of OPCs (clusters created during embryonic development and adult life). Our study provides evidence, albeit limited, that HOG cells either form clusters or adhere to clusters of OPCs in the brains of experimental animals.

Resumen Introduccion La esclerosis lateral amiotrofica (ELA) es una enfermedad neurodegenerativa, progresiva y de etiologia desconocida caracterizada por la degeneracion de motoneuronas superiores e inferiores. Aproximadamente el 90% de los casos de ELA son esporadicos, mientras que el 10% restante se consideran familiares. Independientemente de si son familiares o esporadicas, los pacientes desarrollan una debilidad progresiva, atrofia muscular con espasticidad y contracturas. Por lo general, la esperanza de vida en los pacientes de ELA es de 2 a 5 anos. Desarrollo Los modelos in vivo han ayudado a explicar la etiologia y la patogenesis, asi como los mecanismos de la ELA. Sin embargo, estos mecanismos no estan del todo esclarecidos aun, por lo que los modelos experimentales son fundamentales para continuar con el estudio de los mismos, asi como para la busqueda de posibles dianas terapeuticas. A pesar de que el 90% de los casos son esporadicos, la mayoria de los modelos utilizados hasta la actualidad para estudiar la patogenesis estan basados en las mutaciones geneticas asociadas a la enfermedad familiar, lo que provoca que la patogenesis de la ELA esporadica no sea aun conocida. Por tanto, seria fundamental el estudio de la enfermedad en modelos basados en la enfermedad esporadica. Conclusion En el presente articulo se han revisado los principales modelos experimentales, tanto geneticos como esporadicos, utilizados en el estudio de esta enfermedad, enfocandonos en los que se han desarrollado utilizando el roedor como plataforma experimental.

In recent years, the “non-autonomous motor neuron death” hypothesis has become more consolidated behind amyotrophic lateral sclerosis (ALS). It postulates that cells other than motor neurons participate in the pathology. In fact, the involvement of the autonomic nervous system is fundamental since patients die of sudden death when they become unable to compensate for cardiorespiratory arrest. Mitochondria are thought to play a fundamental role in the physiopathology of ALS, as they are compromised in multiple ALS models in different cell types, and it also occurs in other neurodegenerative diseases. Our study aimed to uncover mitochondrial alterations in the sympathoadrenal system of a mouse model of ALS, from a structural, bioenergetic and functional perspective during disease instauration. We studied the adrenal chromaffin cell from mutant SOD1G93A mouse at pre-symptomatic and symptomatic stages. The mitochondrial accumulation of the mutated SOD1G93A protein and the down-regulation of optic atrophy protein-1 (OPA1) provoke mitochondrial ultrastructure alterations prior to the onset of clinical symptoms. These changes affect mitochondrial fusion dynamics, triggering mitochondrial maturation impairment and cristae swelling, with increased size of cristae junctions. The functional consequences are a loss of mitochondrial membrane potential and changes in the bioenergetics profile, with reduced maximal respiration and spare respiratory capacity of mitochondria, as well as enhanced production of reactive oxygen species. This study identifies mitochondrial dynamics regulator OPA1 as an interesting therapeutic target in ALS. Additionally, our findings in the adrenal medulla gland from presymptomatic stages highlight the relevance of sympathetic impairment in this disease. Specifically, we show new SOD1G93A toxicity pathways affecting cellular energy metabolism in non-motor neurons, which offer a possible link between cell specific metabolic phenotype and the progression of ALS.

Introduction: AQP4 (aquaporin-4)–immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve, remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of AQP4–IgG in cell differentiation. Material and Methods: We included three groups—a group of patients with AQP4–IgG-positive neuromyelitis optica, a healthy group, and a sham group. We analyzed differentiation capacity in cultures of neurospheres from the subventricular zone of mice by adding serum at two different times: early and advanced stages of differentiation. We also analyzed differentiation into different cell lines. Results and Conclusions: The effect of sera from patients with NMOSD on precursor cells differs according to the degree of differentiation, and probably affects oligodendrocyte progenitor cells from NG2 cells to a lesser extent than cells from the subventricular zone, however, the resulting oligodendrocytes may be compromised in terms of maturation and possibly limited in their ability to generate myelin. Furthermore, these cells decrease in number with age. It is very unlikely that the use of drugs favoring the migration and differentiation of oligodendrocyte progenitor cells in multiple sclerosis would be effective in the context of neuromyelitis optica, but cell therapy with oligodendrocyte progenitor cells seems to be a potential alternative.

Structural and functional abnormalities in the cerebral microvasculature have been observed in Alzheimer's disease (AD) patients and animal models. One cause of hypoperfusion is the thickening of the cerebrovascular basement membrane (CVBM) due to increased collagen-IV deposition around capillaries. This study investigated whether these and other alterations in the cerebrovascular system associated with AD can be prevented by long-term dietary supplementation with the antioxidant ubiquinol (Ub) stabilized with Kaneka QH P30 powder containing ascorbic acid (ASC) in a mouse model of advanced AD (3 × Tg-AD mice, 12 months old). Animals were treated from prodromal stages of disease (3 months of age) with standard chow without or with Ub + ASC or ASC-containing vehicle and compared to wild-type (WT) mice. The number of β-amyloid (Aβ) plaques in the hippocampus and entorhinal cortex was higher in female than in male 3 × Tg-AD mice. Extensive regions of hypoxia were characterized by a higher plaque burden in females only. This was abolished by Ub + ASC and, to a lesser extent, by ASC treatment. Irrespective of Aβ burden, increased collagen-IV deposition in the CVBM was observed in both male and female 3 × Tg-AD mice relative to WT animals; this was also abrogated in Ub + ASC- and ASC-treated mice. The chronic inflammation in the hippocampus and oxidative stress in peripheral leukocytes of 3 × Tg-AD mice were likewise reversed by antioxidant treatment. These results provide strong evidence that long-term antioxidant treatment can mitigate plasma oxidative stress, amyloid burden, and hypoxia in the AD brain parenchyma.

The presence of the c-Fos protein has been evidenced in the piriform cortex, subiculum, entorhinal and perirhinal cortices, and parietal and occipital cortices at different stages (Sessions 2, 4, and 6) in the acquisition of a trace conditioning in behaving rabbits. c-Fos immunostaining was also measured after a reminder (7th) session. c-Fos immunoreactivity increased significantly across conditioning on the contralateral side of the piriform, entorhinal, perirhinal, and parietal cortices as compared with the ipsilateral side of conditioned animals and the contralateral side of pseudo-conditioned ones. No difference in c-Fos immunostaining was observed between contra- and ipsilateral sides in the subiculum of conditioned animals. c-Fos production decreased significantly across conditioning but presented a noticeable bilateral increase after the reminder session in the piriform, entorhinal, perirhinal, and parietal cortices, but not in the subiculum. Peak production of c-Fos was observed after the 2nd and 7th (reminder) conditioning sessions for the piriform, entorhinal, perirhinal, and parietal cortices, and after the 4th session for the subiculum. It is proposed that different cortical areas process associative learning with different strengths and side dominances.

The medial cerebral cortex of lizards, an area homologous to the hippocampal fascia dentata, shows delayed postnatal neurogenesis, i.e., cells in the medial cortex ependyma proliferate and give rise to immature neurons, which migrate to the cell layer. There, recruited neurons differentiate and give rise to zinc containing axons directed to the rest of cortical areas, thus resulting in a continuous growth of the medial cortex and its zinc-enriched axonal projection. This happens along the lizard life span, even in adult lizards, thus allowing one of their most important characteristics: neuronal regeneration. Experiments in our laboratory have shown that chemical lesion of the medial cortex (affecting up to 95% of its neurons) results in a cascade of events: first, massive neuronal death and axonal-dendritic retraction and, secondly, triggered ependymal-neuroblast proliferation and subsequent neo-histogenesis and regeneration of an almost new medial cortex, indistinguishable from a normal undamaged one. This is the only case to our knowledge of the regeneration of an amniote central nervous centre by new neuron production and neo-histogenesis. Thus the lizard cerebral cortex is a good model to study neuronal regeneration and the complex factors that regulate its neurogenetic, migratory and neo-synaptogenetic events.O córtex cerebral de lagartos, uma área homóloga à fascia dentata hipocampal, exibe neurogênese pós-natal prolongada, isto é, o epêndima do córtex medial prolifera e dá origem a neurônios imaturos, que migram para a camada celular. Nesta camada, neurônios recrutados se diferenciam e dão origem a axônios, ricos em zinco, que se projetam para as demais áreas corticais, do que resulta um crescimento contínuo do córtex medial e sua projeção axonal. Isto acontece por toda a vida do lagarto, mesmo em animais adultos, o que permite uma de suas características mais importantes: a regeneração neuronal. Experimentos em nosso laboratório demonstraram que uma lesão química do córtex medial (afetando até 95% de seus neurônios) resulta em uma cascata de eventos: inicialmente, morte celular e retração dendro-dendrítica maciças, seguidas de proliferação neuroblasto-ependimária e subseqüente neo-histogênese e regeneração de um novo córtex medial, indistingüível de um normal, não danificado. Ao que saibamos, este é o único caso de regeneração de uma estrutura nervosa central por produção de novos neurônios e neo-histogênese em amniotas. Portanto, o córtex cerebral do lagarto é um bom modelo para estudar a regeneração de neurônios e os fatores complexos que regulam os seus eventos neurogenéticos, migratórios e de neo-sinaptogênese.

The molecular layer of the dentate gyrus appears as the main entrance gate for information into the hippocampus, i.e., where the perforant path axons from the entorhinal cortex synapse onto the spines and dendrites of granule cells. A few dispersed neuronal somata appear intermingled in between and probably control the flow of information in this area. In rabbits, the number of neurons in the molecular layer increases in the first week of postnatal life and then stabilizes to appear permanent and heterogeneous over the individuals' life span, including old animals. By means of Golgi impregnations, NADPH histochemistry, immunocytochemical stainings and intracellular labelings (lucifer yellow and biocytin injections), eight neuronal morphological types have been detected in the molecular layer of developing adult and old rabbits. Six of them appear as interneurons displaying smooth dendrites and GABA immunoreactivity: those here called as globoid, vertical, small horizontal, large horizontal, inverted pyramidal and polymorphic. Additionally there are two GABA negative types: the sarmentous and ectopic granular neurons. The distribution of the somata and dendritic trees of these neurons shows preferences for a definite sublayer of the molecular layer: small horizontal, sarmentous and inverted pyramidal neurons are preferably found in the outer third of the molecular layer; vertical, globoid and polymorph neurons locate the intermediate third, while large horizontal and ectopic granular neurons occupy the inner third or the juxtagranular molecular layer. Our results reveal substantial differences in the morphology and electrophysiological behaviour between each neuronal archetype in the dentate molecular layer, allowing us to propose a new classification for this neural population.

Peripheral nerve grafts have shown the ability to facilitate central axonal growth and regenerate the adult central nervous system. However, the detailed description of a technique for atraumatic graft placement within the brain is lacking. We present a stereotactic procedure to implant a peripheral nerve graft within a rat's brain with minimal brain tissue damage. The procedure permits a correct graft placement joining two chosen points, and the survival and integration of the graft in the host tissue with a light glial reaction, with evidence of central axonal growth inside the graft, at least up to 8 weeks after its implantation. (C) 2008 Elsevier B.V. All rights reserved.

Zinc is found in synaptic vesicles in a large number of glutamatergic systems. Its involvement in neurotransmission and neurological disorders has been suggested. There are methods for tracing these circuits, but they do not fill the dendritic tree. In this study, extracellular selenite injections in vivo were combined with intracellular injection of fluorochromes in fixed tissue to reveal the morphology of these zinc-rich neurones. Intraperitoneal and intracerebral injections of sodium selenite alone or intracerebral injections of selenite combined with bisbenzimide were made in the visual cortex of the rat in order to locate the somata of zinc-rich neurones. After 24 h of retrograde transport, animals were killed and fluorescent markers were injected intracellularly into fixed slices to show neuronal morphology: (a) Lucifer Yellow (LY) followed by biocytin, (b) LY coupled to biocytin or (c) micro-ruby (MR) (dextranamines bound to rhodamine and biotin). Double-labelled somata (selenite+fluorochrome) were plotted. Details of the dendritic morphology were then revealed by incubation in avidin–biotin complex and development in 3,3′-diaminobenzidine and H 2 O 2 . Camera lucida drawings showed that zinc-rich neurones in layers II–III involved in cortico-cortical visual projections were typical pyramidal neurones. This technique is noteworthy for its analysis of the morphology (and connections) of zinc-rich neurones.

Apart from iron, zinc is the most abundant oligoelement in the nervous tissue. Although the majority of zinc constitutes a stable fraction that is tightly bound to molecules and molecular complexes (structural or metabolic zinc), a small proportion (10 15% of cerebral zinc) remains as an ion and it is stored inside membranous compartments (ionic vesicular zinc). In neurons, most of this ionic zinc can be found inside synaptic vesicles and it is released outside the neuron during synaptic transmission: this is the synaptic zinc. In the surroundings of the synapse, zinc acts over a variety of neuronal receptors and ionic channels, playing a modulatory role that is not yet fully understood. The prolonged presence of zinc in the vicinity of the synapse allows its translocation to postsynaptic neurons, which lack the defensive mechanisms (membrane transporters that store zinc into vesicles). In this case, zinc acts as a neurotoxic and it can induce neuronal cell death. Neurons and glial cells have very efficient, although not well known, cleaning mechanisms that eliminate synaptic zinc from the extracellular space; it probably is simultaneous with glutamate clearance. It is feasible that dysfunction of these zinc cleaning systems could induce compensatory mechanisms (precipitation induced by amyloid precursor protein) which in turn could potentiate ethiologic factors of Alzheimer s disease.