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At least 1,009 records · Page 56Linked to original sources
PubMed2005

The lateral ventromedial thalamic nucleus spreads nociceptive signals from the whole body surface to layer I of the frontal cortex.

Neurons within the lateral ventromedial thalamic nucleus (VMl) convey selectively nociceptive information from all parts of the body. The present experiments were performed in rats and were designed to determine the organization of cortical projections from VMl neurons. In a first series of experiments, these cells were characterized electrophysiologically and individually labelled in a Golgi-like manner following juxtacellular electrophoresis of biotin-dextran. In a second experimental series, topical applications of the tracers fluorogold and tetramethylrhodamine-labelled dextran were placed into both the rostral-most and caudal areas of layer I of the dorsolateral frontal cortex, respectively. All VMl nociceptive neurons were fusiform and their full dendritic arborizations were bipolar, extending in the lateromedial axis. VMl cells are thus particularly well located to receive widespread nociceptive inputs via a brainstem link, viz. the medullary subnucleus reticularis dorsalis. VMl neurons driven by 'whole body' nociceptive receptive fields project to the rostral part of the layer I of the dorsolateral frontal cortex. These projections are widespread because double-labelling data showed a great number of VMl neurons labelled from both rostral and caudal dorsolateral cortices. The VMl comprises a homogeneous, organized subset of thalamic neurons that allow any signals of pain to modify cortical activity in a widespread manner, by interacting with the entire layer I of the dorsolateral neocortex.

Action Potentials↗
PubMed2005

Opposite impacts of tenascin-C and tenascin-R deficiency in mice on the functional outcome of facial nerve repair.

The glycoproteins tenascin-C (TNC) and tenascin-R (TNR) are extracellular matrix proteins involved in the development, plasticity and repair of the nervous system. Altered expression patterns after nerve lesions in adult animals have suggested that these molecules influence axonal regeneration. To test this hypothesis, we investigated adult mice constitutively deficient in the expression of TNC, TNR or both, using the facial nerve injury paradigm. Quantitative analysis of vibrissal movements prior to nerve transection and repair (facial-facial anastomosis) did not reveal genotype-specific differences, and thus impacts of the mutations on motor function in intact animals. Two months after nerve repair, recovery of vibrissal whisking was poor in wild-type mice, a typical finding after facial-facial anastomosis in rodents. Differential effects of the mutations on whisking were found: recovery of function was worse in TNC-deficient and better in TNR null mice compared with wild-type littermates. In double-knockout animals, vibrissal performance was insufficient, but to a lesser extent compared with TNC null mutant mice. Retrograde labelling of motoneurons in the same animals showed that similar numbers of motoneurons had reinnervated the whisker pads in all experimental groups precluding varying extents of motoneuron death and/or axon regeneration failures as causes for the different outcomes of nerve repair. Our results provide strong evidence that TNC promotes and TNR impedes recovery after nerve lesion. These findings are of particular interest with regard to the scanty knowledge about factors determining success of regeneration in the peripheral nervous system of mammals.

Anastomosis, Surgical↗
PubMed2005

Suppression of fibrous scarring in spinal cord injury of rat promotes long-distance regeneration of corticospinal tract axons, rescue of primary motoneurons in somatosensory cortex and significant functional recovery.

Traumatic injury of the central nervous system results in formation of a collagenous basement membrane-rich fibrous scar in the lesion centre. Due to accumulation of numerous axon-growth inhibitory molecules the lesion scar is considered a major impediment for axon regeneration. Following transection of the dorsal corticospinal tract (CST) at thoracic level 8 in adult rats, transient suppression of collagenous scarring in the lesion zone by local application of a potent iron chelator and cyclic adenosine monophosphate resulted in the delay of fibrous scarring. Treated animals displayed long-distance growth of CST axons through the lesion area extending for up to 1.5-2 cm into the distal cord. In addition, the treatment showed a strong neuroprotective effect, rescuing cortical motoneurons projecting into the CST that normally die (30%) after thoracic axotomy. Further, anterogradely traced CST axons regenerated through both grey and white matter and developed terminal arborizations in grey matter regions. In contrast to controls, injured animals receiving treatment showed significant functional recovery in the open field, in the horizontal ladder and in CatWalk locomotor tasks. We conclude that the fibrous lesion scar plays a pivotal role as a growth barrier for regenerating axons in adult spinal cord and that a delay in fibrotic scarring by local inhibition of collagen biosynthesis and basement membrane deposition is a promising and unique therapeutic strategy for treating human spinal trauma.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2006

Re-growth of catecholaminergic fibers and protection of cholinergic spinal cord neurons in spinal repaired rats.

The extent of re-growth of catecholaminergic fibers, the survival of cholinergic neurons and the degree of autonomic dysreflexia were assessed in complete spinal cord-transected adult rats that received a repair treatment of peripheral nerve grafts and acidic fibroblast growth factor (aFGF). The rats were randomly divided into three groups: (1) sham control group (laminectomy only); (2) spinal cord transection at T8 (transected group); and (3) spinal cord transection at T8, followed by aFGF treatment and peripheral nerve graft (repaired group). The spinal cords and brains of all rats were collected at 6 months post-surgery. Immunohistochemistry for tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH), and fluoro-gold (FG) retrograde tracing were used to evaluate axon growth across the damage site, and immunocytochemistry for choline acetyl transferase (ChAT) was used to evaluate cholinergic neuronal cell survival following the injury and treatment. When comparing with the transected group, the repaired group showed: (1) lower elevation of mean arterial pressure during colorectal distension; (2) retrogradely labeled neurons in the hypothalamus, zona incerta, subcoeruleus nuclei and rostral ventrolateral medulla following application of FG below the repair site; (3) the presence of TH- and DBH-labeled axons below the lesion site; (4) higher numbers of ChAT-positive neurons in ventral horn and intermediolateral column near the lesion site. We conclude that peripheral nerve graft and aFGF treatments facilitate the re-growth of catecholaminergic fibers, also protect sympathetic preganglionic neurons and spinal motor neurons, and reduce autonomic dysfunction in a T-8 spinal cord-transected rat model.

Acetylcholine↗
PubMed2006

Mice lacking L1 cell adhesion molecule have deficits in locomotion and exhibit enhanced corticospinal tract sprouting following mild contusion injury to the spinal cord.

L1 is a member of the immunoglobulin superfamily of cell adhesion molecules that is associated with axonal growth, including formation of the corticospinal tract (CST). The present study describes the effects of L1 deletion on hindlimb function in locomotion, and examines the role of L1 in recovery and remodeling after contusive spinal cord injury (SCI) in mice. Uninjured adult L1 knockout (Y/-) mice had impaired performance on locomotor tests compared with their wild-type littermates (Y/+). Anterograde tracing demonstrated that CST axons project to thoracic, but not lumbar, levels of the spinal cord of Y/- mice, and revealed a diversion of these fibers from their position in the base of the dorsal columns. Retrograde tracing also revealed reduced numbers of descending projections from paraventricular hypothalamus and red nuclei to the lumbar spinal cord in Y/- mice. SCI at the mid-thoracic level produced a lesion encompassing the center of the spinal cord, including the site of the dorsal CST and surrounding gray matter (GM). The injury caused lasting deficits in fine aspects of locomotion. There was no effect of genotype on final lesion size or the growth of axons into the lesion area. However, injured Y/- mice demonstrated a robust expansion of CST projections throughout the GM of the cervical and thoracic spinal cord rostral to the lesion compared with Y/+ littermates. Thus, L1 is important for the development of multiple spinal projections and also contributes to the restriction of CST sprouting rostral to the site of a SCI in adults.

Animals↗
PubMed2006

Consequences of unilateral nigrostriatal denervation on the thalamostriatal pathway in rats.

The position of the caudal intralaminar nuclei within basal ganglia circuitry has largely been neglected in most studies dealing with basal ganglia function. During the past few years, there has been a growing body of evidence suggesting that the thalamic parafascicular nucleus in rodents (PF) exerts a multifaceted modulation of basal ganglia nuclei, at different levels. Our aim was to study the activity of the thalamostriatal pathway in rats with unilateral dopaminergic depletion. The experimental approach comprised first unilateral delivery of 6-OHDA in the medial forebrain bundle. Thirty days post-lesioning, animals showing a clear asymmetry were then subjected to bilateral injection of Fluoro-Gold (FG) within the striatum. Subsequently, expression of the mRNA encoding the vesicular glutamate transporter 2 (vGLUT2) was detected within thalamostriatal-projecting neurons (FG-labeled) by in situ hybridization and the results were confirmed by laser-guided capture microdissection microscopy followed by real-time PCR. The data showed that there was a marked neuronal loss restricted to PF neurons projecting to the dopamine-depleted striatum. Moreover, PF neurons innervating the dopamine-depleted striatum were intensely hyperactive. These neurons showed a marked increase on the expression of vGLUT2 mRNA as well as for the mRNA encoding the subunit I of cytochrome oxidase as compared with those neurons projecting to the striatum with normal dopamine content. Thus, the selective neurodegeneration of PF neurons innervating the striatum together with the increased activity of the thalamostriatal pathway coexist after nigrostriatal denervation.

Animals↗
PubMed2006

Injury-induced axonal sprouting in the hippocampus is initiated by activation of trkB receptors.

Penetrating head injuries are often accompanied by the delayed development of post-traumatic epilepsy. Schaffer collateral transection leads to axonal sprouting and hyperexcitability in area CA3 of hippocampal slice cultures. We used this model to test the hypothesis that the injury-induced axonal sprouting results from increased neurotrophin signaling via trkB receptors near the lesion. Using rats and mice, we established that sprouting CA3 pyramidal cell axons are labeled with an antibody to the growth-associated protein GAP-43. We observed two- to threefold increases in the level of brain-derived neurotrophic factor and trkB protein in area CA3 by 24-48 h after Schaffer collateral transection, preceding the onset of axonal sprouting. Finally, we demonstrated that injury-induced axonal sprouting of GAP-43-immunoreactive axons is impaired in hippocampal slice cultures from mice expressing low levels of trkB receptors. We conclude that injury-induced axonal sprouting is initiated by brain-derived neurotrophic factor-trkB signaling and suggest that this process may be critical for the genesis of post-traumatic epilepsy.

Animals↗
PubMed2005

Extracellular signal-regulated kinase 1/2 mediates survival, but not axon regeneration, of adult injured central nervous system neurons in vivo.

Neurotrophins play important roles in the response of adult neurons to injury. The intracellular signaling mechanisms used by neurotrophins to regulate survival and axon growth in the mature CNS in vivo are not well understood. The goal of this study was to define the role of the extracellular signal-regulated kinases 1/2 (Erk1/2) pathway in the survival and axon regeneration of adult rat retinal ganglion cells (RGCs), a prototypical central neuron population. We used recombinant adeno-associated virus (AAV) to selectively transduce RGCs with genes encoding constitutively active or wild-type mitogen-activated protein kinase kinase 1 (MEK1), the upstream activator of Erk1/2. In combination with anterograde and retrograde tracing techniques, we monitored neuronal survival and axon regeneration in vivo. MEK1 gene delivery led to robust and selective transgene expression in multiple RGC compartments including cell bodies, dendrites, axons and targets in the brain. Furthermore, MEK1 activation induced in vivo phosphorylation of Erk1/2 in RGC bodies and axons. Quantitative analysis of cell survival demonstrated that Erk1/2 activation promoted robust RGC neuroprotection after optic nerve injury. In contrast, stimulation of the Erk1/2 pathway was not sufficient to induce RGC axon growth beyond the lesion site. We conclude that the Erk1/2 pathway plays a key role in the survival of axotomized mammalian RGCs in vivo, and that activation of other signaling components is required for axon regeneration in the growth inhibitory CNS environment.

Animals↗
PubMed2006

Blockade of PARP activity attenuates poly(ADP-ribosyl)ation but offers only partial neuroprotection against NMDA-induced cell death in the rat retina.

Recent reports have linked neuronal cell death by necrosis to poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation. It is believed that under stress, the activity of this enzyme is up-regulated, resulting in extensive poly(ADP-ribosyl)ation of nuclear proteins, using NAD(+) as its substrate, which, in turn, leads to the depletion of NAD(+). In efforts to restore the level of NAD(+), depletion of ATP occurs, resulting in the shutdown of ATP-dependent ionic pumps. This results in cell swelling and eventual loss of membrane selectivity, hallmarks of necrosis. Reports from in vitro and in vivo studies in the brain have shown that NMDA receptor activation stimulates PARP activity and that blockade of the enzyme provides substantial neuroprotection. The present study was undertaken to determine whether PARP activity is regulated by NMDA in the rat retina, and whether blockade of PARP activity provides protection against toxic effects of NMDA. Rat retinas exposed to intravitreal injections containing NMDA, with or without the PARP inhibitor N-(6-oxo-5, 6-dihydrophenanthridin-2-yl)-(N,-dimethylamino) acetamide hydrochloride (PJ-34), were assessed for changes in PARP-1 activity as evidenced by poly(ADP-ribosyl)ation (PAR), loss of membrane integrity, morphological indicators of apoptosis and necrosis, and ganglion cell loss. Results showed that: NMDA increased PAR formation in a concentration-dependent manner and caused a decline in retinal ATP levels; PJ-34 blockade attenuated the NMDA-induced formation of PAR and decline in ATP; NMDA induced the loss of membrane selectivity to ethidium bromide (EtBr) in inner retinal neurons, but loss of membrane selectivity was not prevented by blocking PARP activity; cells stained with EtBr, or reacted for TUNEL-labeling, displayed features characteristic of both apoptosis and necrosis. In the presence of PJ-34, greater numbers of cells exhibited apoptotic features; PJ-34 provided partial neuroprotection against NMDA-induced ganglion cell loss. These findings suggest that although blockade of PARP activity fully attenuates NMDA-induced PAR formation and loss of retinal ATP content, and improves the survival of select populations of ganglion cells, this approach does not provide full neuroprotection. In contrast, blockade of PARP activity promotes apoptotic-like cell death in the majority of cells undergoing cell death. Furthermore, these studies show that the loss of membrane selectivity is not dependent upon PAR formation or the resulting decline of ATP, and suggests that an alternative pathway, other than PARP activation, exists to mediate this event.

Adenosine Triphosphate↗
PubMedDate not supplied

Role of brainstem structures in seizures initiated from the deep prepiriform cortex of rats.

Previous studies showed that brainstem seizures can still be evoked after transections that separate forebrain from brainstem. We sought to determine whether forebrain-evoked electrographic seizures require brainstem connections for initiation and generalization. Male Sprague-Dawley rats weighing 295-320 g implanted with epidural electrodes had brain transections placed at the pre-, mid-, or postcollicular level. In experiment 1, the transections were limited to severing the brainstem, sparing the telencephalon laterally; these are referred to as "core" transections. In experiment 2, the transections severed the brainstem and also cut through the lateral telencephalon. These "extended" transections were either (a) bilateral, (b) unilateral (i.e., a hemitransection confined to one hemisphere), or (c) partial (sparing pathways ventral to the pretectal nuclei). All transections were performed under ether anesthesia, and seizures were initiated 3 h later by focal infusion of bicuculline (BIC) into the area tempestas (AT) through a previously implanted guide cannula. In experiment 1, bilateral forebrain electrographic seizures occurred in the complete absence of connections between forebrain and brainstem, showing that the brainstem is not required for forebrain-evoked seizures. In experiment 2, forebrain seizures evoked by BIC in AT were suppressed by bilateral extended transections which interrupted connections between AT and the caudal lateral telencephalon. Under these circumstances, application of carbachol with BIC reinstated the forebrain seizure response. These results indicate that carbachol application served to compensate for loss of an excitatory influence on AT resulting from the severing of connections with the caudal telencephalon. The demonstration of direct projections from entorhinal cortex to AT using Fluoro-Gold tracing together with the finding that extended brain transections caudal to the telencephalon do not suppress focally evoked forebrain seizures provided further support for the notion that AT afferents from the caudal telencephalon regulate the sensitivity of AT to BIC. The present findings provide further evidence that seizure substrates in the forebrain and brainstem are separable and independent.

Afferent Pathways↗
PubMed2003

Endogenous ciliary neurotrophic factor protects GABAergic, but not cholinergic, septohippocampal neurons following fimbria-fornix transection.

Application of neurotrophic proteins including ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), members of the family of gp130-associated cytokines, can rescue CNS neurons from injury-induced degeneration. However, it is not clear so far if these effects reflect a physiological function of the endogenous cytokines. Using fimbria-fornix transection as a model, we examined whether responses of GABAergic and cholinergic septohippocampal neurons to axotomy are altered in mice lacking CNTF. In addition, we studied the cellular expression of CNTF, LIF and related cytokine receptor components in the septal complex following lesion. Degeneration of septohippocampal GABAergic neurons in the medial septum as indicated by the loss of parvalbumin-immunoreactive neurons was accelerated and permanently enhanced in CNTF(-/-) mice as compared to wild-type animals. Unexpectedly, the number of axotomized cholinergic MS neurons was significantly higher in CNTF-deficient mice during the first 2 weeks postlesion. Both in wild-type and in CNTF(-/-) mutants, expression of mRNA for the CNTF-specific alpha-subunit of the cytokine receptor complex was specifically upregulated in axotomized GABAergic septal neurons, whereas enhanced expression of the LIF-binding beta-subunit was specifically observed in axotomized cholinergic neurons. Following lesion, CNTF expression in wild-type mice was induced in activated astrocytes surrounding the axotomized neurons and at the lesion site. Expression of LIF mRNA was localized in the GABAergic and cholinergic septohippocampal neurons. These results strongly indicate that endogenous CNTF, supplied by reactive glia cells, acts as a neuroprotective factor for axotomized CNS neurons. In the septum, endogenous CNTF specifically supports lesioned GABAergic projection neurons, whereas LIF may play a similar role for the cholinergic counterparts.

Acetylcholinesterase↗
PubMed2004

Ciliary neurotrophic factor protects retinal ganglion cells from secondary cell death during acute autoimmune optic neuritis in rats.

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS which leads to demyelination, axonal destruction and neuronal loss in the early stages. Available therapies mainly target the inflammatory component of the disease but fail to prevent neurodegeneration. To investigate the effect of ciliary neurotrophic factor (CNTF) on the survival of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve, we used a rat model of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. Optic neuritis in this model was diagnosed by recording visual evoked potentials, and RGC function was monitored by measuring electroretinograms. This study demonstrates that CNTF has a neuroprotective effect on affected RGCs during acute optic neuritis. Furthermore, we demonstrate that CNTF exerts its neuroprotective effect through activation of the Janus kinase/signal transducer and activator of transcription pathway, mitogen activated protein kinases and a shift in the Bcl-2 family of proteins towards the anti-apoptotic side. In summary, our results demonstrate that CNTF can serve as an effective neuroprotective treatment in a rat model of MS that especially reflects the neurodegenerative aspects of this disease.

Analysis of Variance↗