Motor Activity-Induced White Matter Repair in White Matter Stroke.

Subcortical white matter stroke (WMS) is a progressive disorder which is demarcated by the formation of small ischemic lesions along white matter tracts in the CNS. As lesions accumulate, patients begin to experience severe motor and cognitive decline. Despite its high rate of incidence in the human population, our understanding of the cause and outcome of WMS is extremely limited. As such, viable therapies for WMS remain to be seen. This study characterizes myelin recovery following stroke and motor learning-based rehabilitation in a mouse model of subcortical WMS. Following WMS, a transient increase in differentiating oligodendrocytes occurs within the peri-infarct in young male adult mice, which is completely abolished in male aged mice. Compound action potential recording demonstrates a decrease in conduction velocity of myelinated axons at the peri-infarct. Animals were then tested on one of three distinct motor learning-based rehabilitation strategies (skilled reach, restricted access to a complex running wheel, and unrestricted access to a complex running wheel) for their capacity to induce repair. These studies determined that unrestricted access to a complex running wheel alone increases the density of differentiating oligodendrocytes in infarcted white matter in young adult male mice, which is abolished in aged male mice. Unrestricted access to a complex running wheel was also able to enhance conduction velocity of myelinated axons at the peri-infarct to a speed comparable to naive controls suggesting functional recovery. However, there was no evidence of motor rehabilitation-induced remyelination or myelin protection.SIGNIFICANCE STATEMENT White matter stroke is a common disease with no medical therapy. A form of motor rehabilitation improves some aspects of white matter repair and recovery.

Reassembly of Excitable Domains after CNS Axon Regeneration.

UNLABELLED: Action potential initiation and propagation in myelinated axons require ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Disruption of these domains after injury impairs nervous system function. Traditionally, injured CNS axons are considered refractory to regeneration, but some recent approaches challenge this view by showing robust long-distance regeneration. However, whether these approaches allow remyelination and promote the reestablishment of AIS and nodes of Ranvier is unknown. Using mouse optic nerve crush as a model for CNS traumatic injury, we performed a detailed analysis of AIS and node disruption after nerve crush. We found significant disruption of AIS and loss of nodes within days of the crush, and complete loss of nodes 1 week after injury. Genetic deletion of the tumor suppressor phosphatase and tensin homolog (Pten) in retinal ganglion cells (RGCs), coupled with stimulation of RGCs by inflammation and cAMP, dramatically enhanced regeneration. With this treatment, we found significant reestablishment of RGC AIS, remyelination, and even reassembly of nodes in regions proximal, within, and distal to the crush site. Remyelination began near the retina, progressed distally, and was confirmed by electron microscopy. Although axons grew rapidly, remyelination and nodal ion channel clustering was much slower. Finally, genetic deletion of ankyrinG from RGCs to block AIS reassembly did not affect axon regeneration, indicating that preservation of neuronal polarity is not required for axon regeneration. Together, our results demonstrate, for the first time, that regenerating CNS axons can be remyelinated and reassemble new AIS and nodes of Ranvier. SIGNIFICANCE STATEMENT: We show, for the first time, that regenerated CNS axons have the capacity to both remyelinate and reassemble the axon initial segments and nodes of Ranvier necessary for rapid and efficient action potential propagation.

Axon initial segment-associated microglia.

Microglia are the brain's resident immune cells and function as the main defense against pathogens or injury. However, in the absence of disease, microglia have other functions in the normal brain. For example, previous studies showed that microglia contribute to circuit refinement and synaptic plasticity in the developing and adult brain, respectively. Thus, microglia actively participate in regulating neuronal excitability and function. Here, we report that in the cortex, but not other brain regions, a subset of microglia extend a single process that specifically associates and overlaps with the axon initial segment (AIS), the site where action potentials are generated. Similar associations were not observed with dendrites or distal axons. Microglia-AIS interactions appear early in development, persist throughout adulthood, and are conserved across species including mice, rats, and primates. However, these interactions are lost after microglial activation following brain injury, suggesting that such interactions may be part of healthy brain function. Loss of microglial CX3CR1 receptors, or the specialized extracellular matrix surrounding the AIS, did not disrupt the interaction. However, loss of AIS proteins by the neuron-specific deletion of the master AIS scaffold AnkyrinG disrupted microglia-AIS interactions. These results reveal a unique population of microglia that specifically interact with the AIS in the adult cortex.

Strain background influences neurotoxicity and behavioral abnormalities in mice expressing the tetracycline transactivator.

The tet-off system has been widely used to create transgenic models of neurological disorders including Alzheimer's, Parkinson's, Huntington's, and prion disease. The utility of this system lies in the assumption that the tetracycline transactivator (TTA) acts as an inert control element and does not contribute to phenotypes under study. Here we report that neuronal expression of TTA can affect hippocampal cytoarchitecture and behavior in a strain-dependent manner. While studying neurodegeneration in two tet-off Alzheimer's disease models, we unexpectedly discovered neuronal loss within the dentate gyrus of single transgenic TTA controls. Granule neurons appeared most sensitive to TTA exposure during postnatal development, and doxycycline treatment during this period was neuroprotective. TTA-induced degeneration could be rescued by moving the transgene onto a congenic C57BL/6J background and recurred on reintroduction of either CBA or C3H/He backgrounds. Quantitative trait analysis of B6C3 F2 TTA mice identified a region on Chromosome 14 that contains a major modifier of the neurodegenerative phenotype. Although B6 mice were resistant to degeneration, they were not ideal for cognitive testing. F1 offspring of TTA C57BL/6J and 129X1/SvJ, FVB/NJ, or DBA/1J showed improved spatial learning, but TTA expression caused subtle differences in contextual fear conditioning on two of these backgrounds, indicating that strain and genotype can interact independently under different behavioral settings. All model systems have limitations that should be recognized and mitigated where possible; our findings stress the importance of mapping the effects caused by TTA alone when working with tet-off models.

Total en bloc spondylectomy for the L5 metastasis of a carcinoid tumor: illustrative case.

BACKGROUND: Total en bloc spondylectomy (TES) was designed to achieve oncological complete tumor resection in a vertebral compartment. Because of the special anatomy of the lumbosacral junction, TES procedure at the L5 level is a challenge, and it has been explained in few reports in the literature. Performing TES in the lower lumbar region, as normal, is accomplished by using a combined approach. OBSERVATIONS: The authors presented the case of a 20-year-old man with an isolated spinal metastasis at the L5 level of carcinoid tumor of jejunum, limited to the vertebral body. Due to good long-term prognosis, after multidisciplinary evaluation the authors decided to treat the patient with TES through a combined posteroanterior approach, with posterior instrumentation and anterior reconstruction. Nine years after surgery, the patient was asymptomatic, with no sign of local recurrence. LESSONS: TES is a feasible technique to provide long-term survival in a select subgroup of patients, reducing the risk of local recurrence. The authors presented some anatomical and biomechanical factors that must be considered at the lumbosacral region. Despite the high rates of complication associated with TES, most patients benefit from local control provided by the technique.

Retinal nerve fiber hypertrophy in ataxia of Charlevoix-Saguenay patients.

PURPOSE: To present full ophthalmologic examination and retinal nerve fiber layer (RNFL) photographs of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) patients showing significant increases in RNFL thickness compared to healthy subjects, but without myelinated retinal fibers. METHODS: The study design was observational case series. Ten eyes of five patients with molecular confirmation of ARSACS underwent a full ophthalmologic examination that included clinical history, visual acuity, biomicroscopy of the anterior segment, gonioscopy, Goldmann applanation tonometry, central corneal ultrasonic pachymetry, ophthalmoscopy of the posterior segment, standard automatic perimetry (Humphrey field), simultaneous stereophotographs of the optic disc after mydriasis, a series of five red-free digital fundus photographs for RNFL evaluation, topographic analysis of the optic disc using the Heidelberg retina tomography, and measurement of peripapillary RNFL thickness with Cirrus optical coherence tomography. RESULTS: All patients showed abnormal visual fields, normal optic discs with a mild to strikingly increased visibility of RNFL in color stereophotographs, normal Heidelberg tomography, and moderate to markedly increased RNFL thickness in Cirrus tomography (average thickness ranging from 119 µm to 220 µm). CONCLUSIONS: We found evidence of RNFL hypertrophy in ARSACS patients that may have been interpreted as hypermyelinated retinal fibers in previous reports. A revision of ARSACS diagnostic criteria, particularly with regard to retinal alterations, is necessary.

Contribution of apical and basal dendrites to orientation encoding in mouse V1 L2/3 pyramidal neurons.

Pyramidal neurons integrate synaptic inputs from basal and apical dendrites to generate stimulus-specific responses. It has been proposed that feed-forward inputs to basal dendrites drive a neuron's stimulus preference, while feedback inputs to apical dendrites sharpen selectivity. However, how a neuron's dendritic domains relate to its functional selectivity has not been demonstrated experimentally. We performed 2-photon dendritic micro-dissection on layer-2/3 pyramidal neurons in mouse primary visual cortex. We found that removing the apical dendritic tuft did not alter orientation-tuning. Furthermore, orientation-tuning curves were remarkably robust to the removal of basal dendrites: ablation of 2 basal dendrites was needed to cause a small shift in orientation preference, without significantly altering tuning width. Computational modeling corroborated our results and put limits on how orientation preferences among basal dendrites differ in order to reproduce the post-ablation data. In conclusion, neuronal orientation-tuning appears remarkably robust to loss of dendritic input.

Tracking the glossopharyngeal nerve pathway through anatomical references in cross-sectional imaging techniques: a pictorial review.

The glossopharyngeal nerve (GPN) is a rarely considered cranial nerve in imaging interpretation, mainly because clinical signs may remain unnoticed, but also due to its complex anatomy and inconspicuousness in conventional cross-sectional imaging. In this pictorial review, we aim to conduct a comprehensive review of the GPN anatomy from its origin in the central nervous system to peripheral target organs. Because the nerve cannot be visualised with conventional imaging examinations for most of its course, we will focus on the most relevant anatomical references along the entire GPN pathway, which will be divided into the brain stem, cisternal, cranial base (to which we will add the parasympathetic pathway leaving the main trunk of the GPN at the cranial base) and cervical segments. For that purpose, we will take advantage of cadaveric slices and dissections, our own developed drawings and schemes, and computed tomography (CT) and magnetic resonance imaging (MRI) cross-sectional images from our hospital's radiological information system and picture and archiving communication system. TEACHING POINTS: • The glossopharyngeal nerve is one of the most hidden cranial nerves. • It conveys sensory, visceral, taste, parasympathetic and motor information. • Radiologists' knowledge must go beyond the limitations of conventional imaging techniques. • The nerve's pathway involves the brain stem, cisternal, skull base and cervical segments. • Systematising anatomical references will help with nerve pathway tracking.

Influenza-related hospitalizations in children younger than three years of age.

BACKGROUND: To determine the rates of influenza-related hospitalization and to know the clinical manifestations and underlying diseases in children younger than 3 years who are hospitalized with influenza. METHODS: Retrospective, descriptive study (1996-2003), performed in a tertiary teaching hospital in Madrid. Data of hospitalized children, younger than 3 years, with influenza virus isolation from nasal aspirates were collected. Rates of hospitalization for every year were calculated. RESULTS: Overall, 146 children hospitalized with influenza were identified: 117 had community-acquired influenza as the only disease, 18 had community-acquired influenza and were coinfected with other pathogens, and 11 had nosocomial infection. Rates of influenza hospitalization for years 1996, 1997, 1998, 1999, 2000, 2001, 2002, and 2003 were 0.42, 0.11, 1.46, 1.54, 0.53, 0.25, 0.19, and 0.82, respectively, per 1000 children younger than 3 years of age. Children

Amyloid-ß plaques disrupt axon initial segments.

UNLABELLED: Amyloid-ß (Aß) plaques are one of the central pathologies of Alzheimer's disease (AD). Plaque formation in animal models of AD coincides with the appearance of synaptic abnormalities, aberrant neuronal excitability, and cognitive decline. Aß plaques may disrupt neuronal excitability since they have been proposed to be synaptotoxic, to induce axonal varicosities and neurite breakage, and to significantly decrease spine density. Axon initial segments (AIS) also regulate neuronal excitability and help maintain neuronal polarity. Despite these essential functions, the effects of plaques on AIS structure have not been fully determined. Using a mouse AD model, we measured a significant decrease in the density of AIS up to 75µm away from the center of fibrillar, thioflavin-labeled plaques. The reduction was observed in animals with both moderate and severe plaque loads, and was associated with increased densities of microglia near the plaques. Furthermore, animals with severe plaque loads had significantly reduced AIS lengths adjacent to Aß plaques. These results suggest the local environment surrounding Aß plaques may be harmful to the AIS. We propose that AIS loss is a previously unappreciated consequence of AD that could significantly impact brain function. SIGNIFICANCE STATEMENT: This paper demonstrates that neurons near Aß plaques have disrupted axon initial segments. Loss or disruption of AIS is predicted to have detrimental consequences for brain function.

Aspectos epidemiológicos, sociais e sanitários em áreas do médio Solimöes: I - Estudo das localidades de Säo Francisco do Laranjal, Aranaí e Säo Lázaro do Surubim, município de Coari, Amazonas / Epidemiological, social and sanitary aspects in area of Médio Solimöes: I - Study of localities of Säo Francisco do Laranjal, Aranaí and Säo Lázaro do Surubim, municipality of Coari, State of Amazonas

Um estudo seccional foi realizado em 1991 nas localidades de Säo Francisco do Laranjal, Aranaí e Säo Lázaro, no município de Coari, localizado no Médio Solimöes, no Estado do Amazonas, envolvendo 406 pessoas residentes, visando determinar as condiçöes sociais e sanitárias e indicaçöes epidemiológicos e laboratoriais específicos sobre a prevalência de anemia, parasitoses intestinais, malária, toxoplasmose, hepatite B e hanseníase. No inquérito foram aplicadas duas fichas padronizadas, uma domiciliar para avaliaçäo das condiçöes econômicas e sanitárias e outra individual para anamnese e exame físico. De cada pessoa foi solicitado amostra de fezes para exames pelos métodos de Lutz (sedimentaçäo) e de Baerman, e colhido sangue para dosagem de hemoglobina e micro-hematócrito, gota, gota expessa e esfregaço para a malária, sorologia para toxoplasmose e para hepatite por vírus B (HBsAg e Anti-HBs). A principal atividade econômica da populaçäo é a agricultura de subsistência e a pesca. Nas três localidades existe escola de 1§ grau mas em nenhuma existe posto de saúde. O índice de aglomeraçäo foi em média 5,3 pessoas por domicílio dos quais 84,2 por cento säo construídos de madeira e 77,5 por cento têm apenas um dormitório para toda a família. O abastecimento de água é feito diretamente do rio; em 89,4 por cento das casas näo existem instalaçöes sanitárias e em sua totalidade o lixo é abandonado ou jogado no próprio rio. A anemia esteve presente em 56,4 por cento dos examinados, 16,2 por cento com menos de 10g/Hg por cento. O exame de fezes revelou 81,9 por cento com um ou mais parasitos (72,6 por cento com mais de um parasito), com predomínio do Ascaris lumbricoides. Chama a atençäo a E. histolytica com 15,6 por cento, diagnósticada com métodos näo específicos. Surpeendentemente todas as lâminas foram negativas para malária; 65,8 por cento dos soros foram reagentes para toxoplasmose, 10,6 por cento com títulos iguais ou superiores a 1: 1024. No exame físico foram diagnósticados três casos de hanseníase (7,38 por 1.000). Apenas 1,9 por cento dos soros foram HBSAg positivos porém 34,3 por cento tinham anticorpos Anti-HBs