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Journal of Neurotrauma Feb 2015Deficits in bladder function are complications following spinal cord injury (SCI), severely affecting quality of life. Normal voiding function requires coordinated...
Deficits in bladder function are complications following spinal cord injury (SCI), severely affecting quality of life. Normal voiding function requires coordinated contraction of bladder and urethral sphincter muscles dependent upon intact lumbosacral reflex arcs and integration of descending and ascending spinal pathways. We previously reported, in electrophysiological recordings, that segmental reflex circuit neurons in anesthetized male rats were modulated by a bilateral spino-bulbo-spinal pathway in the mid-thoracic lateral funiculus. In the present study, behavioral measures of bladder voiding reflexes and hematuria (hemorrhagic cystitis) were obtained to assess the correlation of plasticity-dependent recovery to the degree of lateral funiculus sparing and mid-thoracic lesion level. Adult rats received mid-thoracic-level lesions at one of the following severities: complete spinal transection; bilateral dorsal column lesion; unilateral hemisection; bilateral dorsal hemisection; a bilateral lesion of the lateral funiculi and dorsal columns; or a severe contusion. Voiding function and hematuria were evaluated by determining whether the bladder was areflexic (requiring manual expression, i.e., "crede maneuver"), reflexive (voiding initiated by perineal stroking), or "automatic" (spontaneous voiding without caretaker assistance). Rats with one or both lateral funiculi spared (i.e., bilateral dorsal column lesion or unilateral hemisection) recovered significantly faster than animals with bilateral lateral funiculus lesions, severe contusion, or complete transection. Bladder reflex recovery time was significantly slower the closer a transection lesion was to T10, suggesting that proximity to the segmental sensory and sympathetic innervation of the upper urinary tract (kidney, ureter) should be avoided in the choice of lesion level for SCI studies of micturition pathways. In addition, hematuria duration was significantly longer in males, compared to females, despite similar bladder reflex onset times. We conclude that the sparing of the mid-thoracic lateral funiculus on one side is required for early recovery of bladder reflex voiding function and resolution of hematuria.
Topics: Animals; Disease Models, Animal; Female; Hematuria; Male; Rats; Rats, Wistar; Recovery of Function; Reflex; Spinal Cord Injuries; Urinary Bladder; Urination
PubMed: 25137571
DOI: 10.1089/neu.2013.3247 -
The International Journal of... 2014Much biological experimental data are represented as curves, including measurements of growth, hormone, or enzyme levels, and physical structures. Here we consider the...
Much biological experimental data are represented as curves, including measurements of growth, hormone, or enzyme levels, and physical structures. Here we consider the multiple testing problem of comparing two or more nonlinear curves. We model smooth curves of unknown form nonparametrically using penalized splines. We use random effects to model subject-specific deviations from the group-level curve. We present an approach that allows examination of overall differences between the curves of multiple groups and detection of sections in which the curves differ. Adjusted p-values for each single comparison can be obtained by exploiting the connection between semiparametric mixed models and linear mixed models and employing an approach for multiple testing in general parametric models. In simulations, we show that the probability of false-positive findings of differences between any two curves in at least one position can be controlled by a pre-specified error level. We apply our method to compare curves describing the form of the mouse dorsal funiculus - a morphological curved structure in the spinal cord - in mice wild-type for the gene encoding EphA4 or heterozygous with one of two mutations in the gene.
Topics: Animals; Bayes Theorem; Computer Simulation; Genotype; Male; Mice; Models, Statistical; Mutation; Nonlinear Dynamics; Sensitivity and Specificity; Spinal Cord Diseases
PubMed: 24902010
DOI: 10.1515/ijb-2013-0003 -
Stem Cells and Development Jul 2014Spinal cord injury triggers a cascade of degenerative changes leading to cell death and cavitation. Severed axons fail to regenerate across the scar tissue and are only...
Spinal cord injury triggers a cascade of degenerative changes leading to cell death and cavitation. Severed axons fail to regenerate across the scar tissue and are only capable of limited sprouting. In this study, we investigated the effects of adult human adipose-derived stem cells (ASC) on axonal regeneration following transplantation into the injured rat cervical spinal cord. ASC did not induce activation of astrocytes in culture and supported neurite outgrowth from adult rat sensory dorsal root ganglia neurons. After transplantation into the lateral funiculus 1 mm rostral and caudal to the cervical C3-C4 hemisection, ASC continued to express brain-derived neurotrophic factor, vascular endothelial growth factor, and fibroblast growth factor-2 for 3 weeks but only in animals treated with cyclosporine A. Transplanted ASC stimulated extensive ingrowth of 5HT-positive raphaespinal axons into the trauma zone with some terminal arborizations reaching the caudal spinal cord. In addition, ASC induced sprouting of raphaespinal terminals in C2 contralateral ventral horn and C6 ventral horn on both sides. Transplanted cells also changed the structure of the lesion scar with numerous astrocytic processes extended into the middle of the trauma zone in a chain-like pattern and in close association with regenerating axons. The density of the astrocytic network was also significantly decreased. Although the transplanted cells had no effect on the density of capillaries around the lesion site, the activity of OX42-positive microglial cells was markedly reduced. However, ASC did not support recovery of forelimb function. The results suggest that transplanted ASC can modify the structure of the glial scar and stimulate axonal sprouting.
Topics: Adipocytes; Adipose Tissue; Animals; Axons; Cervical Cord; Humans; Nerve Regeneration; Rats; Spinal Cord Injuries; Stem Cell Transplantation; Stem Cells
PubMed: 24803143
DOI: 10.1089/scd.2013.0416 -
Development (Cambridge, England) May 2014During vertebrate development, centrally projecting sensory axons of the dorsal root ganglia neurons first reach the embryonic spinal cord at the dorsolateral margin....
During vertebrate development, centrally projecting sensory axons of the dorsal root ganglia neurons first reach the embryonic spinal cord at the dorsolateral margin. Instead of immediately projecting into the grey matter, they bifurcate and extend rostrally and caudally to establish the longitudinal dorsal funiculus during a stereotyped waiting period of approximately 48 h. Collateral fibres then extend concurrently across multiple spinal segments and project to their appropriate targets within the grey matter. This rostrocaudal extension of sensory afferents is crucial for the intersegmental processing of information throughout the spinal cord. However, the precise cues that prevent premature entry during the waiting period remain to be identified. Here, we show that semaphorin 5B (Sema5B), a member of the semaphorin family of guidance molecules, is expressed in the chick spinal cord during this waiting period and dorsal funiculus formation. Sema5B expression is dynamic, with a reduction of expression apparent in the spinal cord concomitant with collateral extension. We show that Sema5B inhibits the growth of NGF-dependent sensory axons and that this effect is mediated in part through the cell adhesion molecule TAG-1. Knockdown of Sema5B in the spinal cord using RNA interference leads to the premature extension of cutaneous nociceptive axons into the dorsal horn grey matter. These premature projections predominantly occur at the site of dorsal root entry. Our results suggest that Sema5B contributes to a repulsive barrier for centrally projecting primary sensory axons, forcing them to turn and establish the dorsal funiculus.
Topics: Animals; Avian Proteins; Axons; Body Patterning; Chick Embryo; Gene Expression Regulation, Developmental; Gene Knockdown Techniques; Neurons, Afferent; Nociception; Proprioception; RNA, Messenger; RNA, Small Interfering; Semaphorins; Sensory Receptor Cells; Spinal Cord
PubMed: 24718987
DOI: 10.1242/dev.103630 -
Journal of Neuropathology and... Apr 2014We provide evidence of cortical neuronopathy in myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis, an established model of...
We provide evidence of cortical neuronopathy in myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis, an established model of chronic multiple sclerosis. To investigate phenotypic perturbations in neurons in this model, we used apoptotic markers and immunohistochemistry with antibodies to NeuN and other surrogate markers known to be expressed by adult pyramidal Layer V somas, including annexin V, encephalopsin, and Emx1. We found no consistent evidence of chronic loss of Layer V neurons but detected both reversible and chronic decreases in the expression of these markers in conjunction with evidence of cortical demyelination and presynaptic loss. These phenotypic perturbations were present in, but not restricted to, the neocortical Layer V. We also investigated inflammatory responses in the cortex and subcortical white matter of the corpus callosum and spinal dorsal funiculus and found that those in the cortex and corpus callosum were delayed compared with those in the spinal cord. Inflammatory infiltrates initially included T cells, neutrophils, and Iba1-positive microglia/macrophages in the corpus callosum, whereas only Iba1-positive cells were present in the cortex. These data indicate that we have identified a new temporal pattern of subtle phenotypic perturbations in neocortical neurons in this chronic multiple sclerosis model.
Topics: Animals; Caspase 3; Cell Death; Disease Models, Animal; Encephalitis; Freund's Adjuvant; Humans; In Situ Nick-End Labeling; Male; Mice; Mice, Inbred C57BL; Motor Neurons; Multiple Sclerosis; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Neocortex; Peptide Fragments; Phosphopyruvate Hydratase; Synaptophysin; Time Factors
PubMed: 24607968
DOI: 10.1097/NEN.0000000000000058 -
Neuroscience Letters Feb 2014Central projections originated from a single dorsal root ganglion (DRG) were studied in the chicken focusing on the rostrocaudal extension of primary afferents in each...
Central projections originated from a single dorsal root ganglion (DRG) were studied in the chicken focusing on the rostrocaudal extension of primary afferents in each lamina by using anterograde labeling by lectin-HRP injection into either the 15th or the 24th DRG. In the injection into the 15th DRG, labeled fibers (LFs) were found in a wide rostrocaudal range of laminas IV (the spinal segment (SS) 1-20) and V (SS 4-18) and in a narrow range of other laminas. In the injection into the 24th DRG, LFs were distributed in a similar rostrocaudal range in all laminas except for laminas VIII and IX. LFs in laminas VIII and IX were restricted in the tracer injected segment. LFs in the lateral funiculus derived from both the enlargements projected into the rostral lamina III in addition to the lower medulla oblongata. There was little overlap in the extent of the primary terminal areas from both the enlargements.
Topics: Afferent Pathways; Animals; Chickens; Ganglia, Spinal; Lumbosacral Region; Medulla Oblongata; Neck
PubMed: 24394912
DOI: 10.1016/j.neulet.2013.12.052 -
Neuron Dec 2013The spinal cord contains many descending and ascending longitudinal tracts whose development appears to be controlled by distinct guidance systems. We identified a...
The spinal cord contains many descending and ascending longitudinal tracts whose development appears to be controlled by distinct guidance systems. We identified a population of dorsal spinal neurons marked by coexpression of the transcription factor Zic2 and the guidance receptor EphA4. Zic2+;EphA4+ neurons are surrounded by mechanosensory terminals, suggesting innervation by mechanoreceptor afferents. Their axons form an ipsilateral ascending pathway that develops during embryogenesis and projects within the ventral aspect of the dorsal funiculus, the same location as the descending corticospinal tract (CST), which develops postnatally. Interestingly, the same guidance mechanism, namely, ephrinB3-induced EphA4 forward signaling, is required for the guidance of both ascending and descending axon tracts. Our analysis of conditional EphA4 mutant mice also revealed that the development of the dorsal funiculus occurs independently of EphA4 expression in descending CST axons and is linked to the distribution of Zic2+;EphA4+ spinal neurons and the formation of the ascending pathway.
Topics: Animals; Axons; Cell Tracking; Cells, Cultured; Central Nervous System; Embryonic Development; Ephrin-B3; Gene Expression Regulation, Developmental; Interneurons; Mice; Mice, Knockout; Mice, Transgenic; Neural Pathways; Posterior Horn Cells; Receptor, EphA4; Spinal Cord; Transcription Factors
PubMed: 24360544
DOI: 10.1016/j.neuron.2013.10.006 -
Clinical & Developmental Immunology 2013The glial scar formed by reactive astrocytes and axon growth inhibitors associated with myelin play important roles in the failure of axonal regeneration following...
The glial scar formed by reactive astrocytes and axon growth inhibitors associated with myelin play important roles in the failure of axonal regeneration following central nervous system (CNS) injury. Our laboratory has previously demonstrated that immunological demyelination of the CNS facilitates regeneration of severed axons following spinal cord injury. In the present study, we evaluate whether immunological demyelination is accompanied with astrogliosis. We compared the astrogliosis and macrophage/microglial cell responses 7 days after either immunological demyelination or a stab injury to the dorsal funiculus. Both lesions induced a strong activated macrophage/microglial cells response which was significantly higher within regions of immunological demyelination. However, immunological demyelination regions were not accompanied by astrogliosis compared to stab injury that induced astrogliosis which extended several millimeters above and below the lesions, evidenced by astroglial hypertrophy, formation of a glial scar, and upregulation of intermediate filaments glial fibrillary acidic protein (GFAP). Moreover, a stab or a hemisection lesion directly within immunological demyelination regions did not induced astrogliosis within the immunological demyelination region. These results suggest that immunological demyelination creates a unique environment in which astrocytes do not form a glial scar and provides a unique model to understand the putative interaction between astrocytes and activated macrophage/microglial cells.
Topics: Animals; Astrocytes; Cell Survival; Demyelinating Diseases; Female; Gliosis; Macrophage Activation; Macrophages; Microglia; Nerve Tissue Proteins; Rats; Spinal Cord Injuries
PubMed: 24319469
DOI: 10.1155/2013/812456 -
Toxicology Letters Jan 2014Developmental exposure to glycidol induces aberrations of late-stage neurogenesis in the hippocampal dentate gyrus of rat offspring, whereas maternal animals develop...
Developmental exposure to glycidol induces aberrations of late-stage neurogenesis in the hippocampal dentate gyrus of rat offspring, whereas maternal animals develop axonopathy. To investigate the possibility whether similar effects on adult neurogenesis could be induced by exposure in a framework of 28-day toxicity study, glycidol was orally administered to 5-week-old male Sprague-Dawley rats by gavage at 0, 30 or 200 mg/kg for 28 days. At 200 mg/kg, animals revealed progressively worsening gait abnormalities as well as histopathological and immunohistochemical changes suggestive of axonal injury as evidenced by generation of neurofilament-L(+) spheroids in the cerebellar granule layer and dorsal funiculus of the medulla oblongata, central chromatolysis in the trigeminal nerve ganglion cells and axonal degeneration in the sciatic nerves. At the same dose, animals revealed aberrations in neurogenesis at late-stage differentiation as evidenced by decreases of both doublecortin(+) and dihydropyrimidinase-like 3(+) cells in the subgranular zone (SGZ) and increased reelin(+) or calbindin-2(+) γ-aminobutyric acid-ergic interneurons and neuron-specific nuclear protein(+) mature neurons in the dentate hilus. These effects were essentially similar to that observed in offspring after maternal exposure to glycidol. These results suggest that glycidol causes aberrations in adult neurogenesis in the SGZ at the late stage involving the process of neurite extension similar to the developmental exposure study in a standard 28-day toxicity study.
Topics: Animals; Antigens, Nuclear; Apoptosis; Axons; Carcinogens; Cell Count; Cell Differentiation; Dentate Gyrus; Doublecortin Protein; Epoxy Compounds; Female; Gait Disorders, Neurologic; Hippocampus; Hormones; Immunohistochemistry; Interneurons; Nerve Tissue Proteins; Neurogenesis; Pregnancy; Prenatal Exposure Delayed Effects; Propanols; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Reelin Protein; Stem Cells; Thyroid Hormones
PubMed: 24185127
DOI: 10.1016/j.toxlet.2013.10.026 -
Neuroscience Dec 2013In this review we discuss recent advances in the understanding of the development of forebrain projections attending to their origin, fate determination, and axon... (Review)
Review
In this review we discuss recent advances in the understanding of the development of forebrain projections attending to their origin, fate determination, and axon guidance. Major forebrain connections include callosal, corticospinal, corticothalamic and thalamocortical projections. Although distinct transcriptional programs specify these subpopulations of projecting neurons, the mechanisms involved in their axonal development are similar. Guidance by short- and long-range molecular cues, interaction with intermediate target populations and activity-dependent mechanisms contribute to their development. Moreover, some of these connections interact with each other showing that the development of these axonal tracts is a well-orchestrated event. Finally, we will recapitulate recent discoveries that challenge the field of neural wiring that show that these forebrain connections can be changed once formed. The field of reprogramming has arrived to postmitotic cortical neurons and has showed us that forebrain connectivity is not immutable and might be changed by manipulations in the transcriptional program of matured cells.
Topics: Animals; Axons; Cerebral Cortex; Humans; Nerve Net; Prosencephalon
PubMed: 24042037
DOI: 10.1016/j.neuroscience.2013.08.070