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PubMed1995

Complementary distribution of receptors for neurotensin and NPY in small neurons in rat lumbar DRGs and regulation of the receptors and peptides after peripheral axotomy.

Neurotensin (NT) has been reported to have antinociceptive effects at the spinal level. In situ hybridization, electrophysiology, immunohistochemistry, and electronmicroscopy were used to investigate the distribution of NT receptors, possible effects of NT on primary sensory neurons, and the effect of nerve injury on the expression of NT receptors and NT. NT receptor (R) mRNA was observed in more than 25% of the small dorsal root ganglion (DRG) neurons, which lacked neuropeptide Y NPY-R mRNA and essentially other neuropeptide mRNAs. Intracellular recording using voltage-clamp mode showed that NT evokes an outward current in NPY-insensitive small neurons, and NPY an outward current in NT-insensitive small neurons. Both peptides lacked effect on several small DRG neurons. In the superficial dorsal horn NT immunoreactive (IR) terminals directly contacted primary afferent terminals without synaptic specializations. This new category (> 25%) of the small DRG neurons expressing NT-R mRNA was complementary to the around 60% of small neurons expressing NPY-R mRNA (and also substance P and calcitonin gene-related peptide mRNAs) and to the rest exhibiting somatostatin mRNA expression. The electrophysiological results support this classification, showing that NT and NPY have inhibitory effects on separate subpopulations of small DRG neurons. After sciatic nerve transection, a marked decrease was observed in (1) the number of NT-R mRNA-positive neurons in DRGs, (2) NT mRNA-positive neurons in the dorsal horn, and (3) NT-IR cell bodies and fibers in laminae I-II. Thus, axotomy causes downregulation of several NT systems at the spinal level, suggesting that the possible effects of NT on primary sensory neurons is attenuated after peripheral axotomy.

Afferent Pathways↗
PubMed1994

BDNF and NT-3 rescue sensory but not motoneurones following axotomy in the neonate.

Following axotomy of the sciatic nerve in the neonatal rat, there is loss of almost half of the sensory neurones of the lumbar dorsal root ganglia (DRG) and a similar number of spinal motoneurones. Consistent with effects in vitro, the neurotrophins BDNF and NT-3 have previously been shown to afford partial rescue of motoneurones at 1 week following axotomy. Using stereological quantitative methods we show here that at the longer time point of 3 weeks, local application of BDNF or NT-3 to the proximal stump of a lesioned sciatic nerve failed to rescue motoneurones (44% and 51% loss, respectively), but provided almost complete rescue of the loss of 41% of DRG neurones seen in L4 and L5 of vehicle-treated control animals.

Animals↗
PubMed1994

Axotomy results in delayed death and apoptosis of retinal ganglion cells in adult rats.

Using quantitative anatomical techniques, we show that after intraorbital optic nerve transection in adult rats, virtually all retinal ganglion cells (RGCs) survive for 5 d and then die abruptly in large numbers, reducing the RGC population to approximately 50% of normal by day 7 and to less than 10% on day 14. During this period of rapid cell loss, some RGCs show cytochemical alterations indicative of apoptosis ("programmed cell death"), a change not previously categorized after axotomy in adult mammals. With intracranial lesions 8-9 mm from the eye, the onset of cell death is delayed until day 8 and is greater with cut than crush. The demonstration that axotomy results in apoptosis, the long interval between axonal injury and RGC death, and the different time of onset of the massive RGC loss with optic nerve lesions near or far from the eye suggest that axonal interruption triggers a cascade of molecular events whose outcome may be critically dependent on the availability of neuronal trophic support from endogenous or exogenous sources. The role of such molecules in RGC survival and the reversible nature of these injury-induced changes is underscored by the temporary rescue of most RGCs by a single intravitreal injection of brain-derived neurotrophic factor during the first 5 d after intraorbital optic nerve injury (Mansour-Robaey et al., 1994). The delayed pattern of RGC loss observed in the present experiments likely explains such a critical period for effective neurotrophin administration.

Animals↗
PubMed1994

GAP-43 expression in primary sensory neurons following central axotomy.

Primary sensory neurons are capable of successful regenerative growth in response to peripheral nerve but not dorsal root injury. The present study is concerned with the differential expression of the mRNA for GAP-43, a growth-associated protein, in these sensory neurons, in response to injury of their central or peripheral axonal branches. Peripheral axotomy resulted in an elevation in message detectable within 24 hr, using Northern blot and in situ hybridization, which was maintained for 30 d, whereas dorsal root section produced no change except a transient and small increase if the axotomy was immediately adjacent to the dorsal root ganglia (DRG). Dorsal root section had no effect on GAP-43 mRNA levels in the dorsal horn or in neighboring intact DRG. It also failed to alter the laminar boundaries of the GAP-43 central terminal labeling produced by peripheral nerve section, even though vacant synaptic sites were produced in unstained laminae by this procedure. This indicates that the location of GAP-43 immunolabeling in the central terminals of primed sensory cells may not depend only on the location of vacant synaptic sites. We conclude that distinct control mechanisms regulate the response of DRG neurons to peripheral nerve and dorsal root injury, and these may be related both to the glial environment and the particular target influences exerted on the central and peripheral branches of the primary sensory neuron. Central denervation alone is insufficient to upregulate GAP-43 levels, and this may explain the relative absence of collateral sprouting after the production of central vacant synaptic sites. The failure of dorsal root section to increase GAP-43 expression may contribute to the poor regenerative response initiated by such lesions.

Animals↗
PubMed1996

Protection of retinal ganglion cells from natural and axotomy-induced cell death in neonatal transgenic mice overexpressing bcl-2.

Approximately half of the retinal ganglion cells (RGCs) present in the rodent retina at birth normally die during early development. Overexpression of the photo-oncogene bcl-2 recently has been shown to rescue some neuronal populations from natural cell death and from degeneration induced by axotomy of nerves within the peripheral nervous system. Here we study in vivo the role of the overexpression of bcl-2 in the natural cell death of RGCs and in the degenerative process induced in these cells by transection of the optic nerve. We find that in newborn bcl-2 transgenic mice, the number of RGCs undergoing natural cell death is considerably lower than in wild-type pups. Consistently, a vast majority (90%) of the ganglion cells found in the retina of neonatal transgenics are maintained in adulthood, whereas only 40% survive in wild-type mice. After transection of the optic nerve, the number of degenerating ganglion cells, determined by counting pyknotic nuclei or nuclei with fragmented DNA, is substantially reduced in transgenic mice. In wild-type animals, almost 50% of ganglion cells degenerate in the 24 hr after the lesion, whereas almost the entire ganglion cell population survives axotomy in transgenic mice. Therefore, overexpression of bcl-2 is effective in preventing degeneration of this neuronal population, raising the possibility that ganglion cells are dependent on the endogenous expression of bcl-2 for survival. The remarkable rescue capacity of bcl-2 overexpression in these neurons makes it an interesting model for studying natural cell death and responses to injury in the CNS.

Animals↗
PubMed1997

Adult mammalian sensory and motor neurons: roles of endogenous neurotrophins and rescue by exogenous neurotrophins after axotomy.

We have tested the ability of neurotrophins to reverse axotomy-induced changes in adult motor and sensory neurons, using the physiological measure of conduction velocity. Five weeks after axotomy, sensory and motor conduction velocities were greatly reduced. NT-3 at 60 microg/d, pumped directly onto the cut nerve stump, largely prevented the change in sensory fibers. Lower doses were less effective, and NT-4/5 was without effect. In contrast, both NT-3 and NT-4/5 were effective at rescuing motoneurons, with similar dose dependencies. This amelioration of physiological deficits in adult mammalian neurons suggests possible therapeutic application of neurotrophins. We have also studied the physiological effects of neurotrophin deprivation on intact peripheral neurons. After 2 weeks of sequestration of trkB ligands (BDNF and NT-4/5), motor, but not sensory, neuron conduction was significantly slowed. Sequestration of NT-3 was found to affect both motor and sensory fiber velocities but more modestly and only with higher doses of sequestering agent. These data therefore suggest that peripherally produced neurotrophins are necessary for the maintenance of normal functional properties of peripheral neurons.

Animals↗
PubMed1997

Lectin histochemistry of the metathoracic ganglion of the locust Schistocerca gregaria before and after axotomy of the tympanal nerve.

The thoracic ganglia of insects exhibit a highly ordered organization. It seems possible that the information underlying the emergence of this order during development and its maintenance throughout insect life is given via a distinct pattern of molecules distributed within the ganglion. The question we asked was whether the adult insect ganglion is subdivided by the distribution of specific carbohydrates and furthermore whether or not this distribution changes during degeneration and regeneration of neurons. In order to determine the normal carbohydrate distribution, we stained sections of the intact metathoracic ganglion of the locust Schistocerca gregaria with fluorescence-coupled lectins. We succeeded in labeling three sensory neuropil areas with either peanut agglutinin (PNA): Phaseolus vulgaris erythrolectin (PVE), soybean agglutinin, wheat germ agglutinin (WGA), or Vicia villosa agglutinin. Apart from this, PNA, WGA, and succinylated WGA also selectively labeled some neuronal cell bodies, including dorsal unpaired median neurons. Datura stramonium lectin (DSL), Griffonia simplicifolia lectin II, and Solanum tuberosum lectin (STL) bound to glial cells or glia surrounding extracellular matrix. A few lectins stained all structures within the ganglion; some showed no binding at all. In the second part of our study, we tested whether carbohydrates were differentially regulated during transient deafferentation after the axotomy of the tympanal nerve. Binding of PNA and PVE within the auditory neuropil did not change. However, binding of the two glia-associated markers, DSL and STL, clearly differed from that found in intact animals; they bound transiently (day 3-4 until day 10-20 post-surgery) to axonal tracts and neuropils of the axotomized sensory afferents.

Afferent Pathways↗
PubMed1998

Axotomy-induced neuronal death and reactive astrogliosis in the lateral geniculate nucleus following a lesion of the visual cortex in the rat.

Following a unilateral lesion of the visual cortex (cortical areas 17, 18, and 18a) in adult rats, neurons in the ipsilateral dorsal lateral geniculate nucleus (LGN) are axotomized, which leads to their atrophy and death. The time course of this neuronal degeneration was studied quantitatively, and the astroglial response was examined with glial fibrillary acidic protein immunohistochemistry. More than 95% of the neurons in the ipsilateral LGN survive during the first 3 days following a lesion of the visual cortex. However, in the next 4 days, massive neuronal death ensues, reducing the number of surviving neurons to approximately 33% of normal by the end of the first postoperative week. Between 2 weeks and 24 weeks postoperatively, the number of neurons present in the LGN declines very gradually from 34% to 17% of normal. Three days after a lesion of the visual cortex, the mean cross-sectional areas of ipsilateral LGN neurons are 13% smaller than normal (87%). By 1 week after the operation, surviving LGN neurons have atrophied to 66% of their normal area. Subsequently, the size of surviving neurons declines slowly to approximately 50% of normal at 24 weeks after the cortical lesion. Astrocytes in the ipsilateral LGN also react to cortical damage. At 1 day after a lesion of the visual cortex, glial fibrillary acidic protein immunoreactivity in the LGN is almost undetectable, but a distinct increase in immunoreactivity is seen at 3 days. Immunoreactivity peaks between 1 week and 2 weeks postoperatively and, thereafter, remains intense for at least 24 weeks. Thus, following a lesion of the visual cortex, the somata of neurons in the LGN remain essentially normal morphologically for about 3 days before the onset of rapid atrophy and death. Moreover, most of the neural cell death that occurs in the LGN after axotomy takes place in the last half of the first postoperative week.

Animals↗
PubMed2000

Galectin-3 is upregulated in microglial cells in response to ischemic brain lesions, but not to facial nerve axotomy.

We have recently demonstrated that the beta-galactoside-specific lectin galectin-3 is expressed by microglial cells in vitro, but not by normal resting microglia in vivo. In the present study, we have analyzed the expression of galectin-3 by microglia under traumatic conditions in vivo using two experimental rat models which substantially differ in the severity of lesion related to a breakdown of the blood-brain barrier (BBB) and the occurrence of inflammatory processes. These two features are absent after peripheral nerve lesion and present after cerebral ischemia. Here we show that, following facial nerve axotomy under conditions allowing (nerve anastomosis) or not subsequent regeneration (nerve resection), galectin-3 is not expressed by microglia in the corresponding facial nucleus 1-112 days after lesion. Galectin-3 is also absent in microglia at sites of a defective BBB in the normal brain, such as the circumventricular organs. Following experimental ischemia (i.e., permanent occlusion of the middle cerebral artery), in contrast, galectin-3 becomes strongly expressed by activated microglia as early as 48 hours after trauma, as determined by immunohistochemistry and Western blot analysis. Our findings suggest that the expression of galectin-3 by microglia in vivo correlates with the state of microglial activation.

Animals↗
PubMed2002

Medial forebrain bundle axotomy during development induces apoptosis in dopamine neurons of the substantia nigra and activation of caspases in their degenerating axons.

There is growing evidence that programmed cell death may play a role in degenerative neurologic disease. The caspases are a family of cell death proteins that mediate proteolytic cascades in the death process. Although there is clear evidence that caspases play a role in the destruction of the components of the neuronal soma, it has been controversial whether they play a role in the degeneration of axons that accompanies the death of the cell body. It is important to define the molecular mechanisms of axonal degeneration, because terminal degeneration may occur early in neurodegenerative disease. We have therefore investigated whether caspases play a role in axonal degeneration in the dopaminergic nigrostriatal system following axotomy of the median forebrain bundle during development. We find that this lesion induces apoptosis in midbrain dopaminergic neurons at the level of the cell soma. Concomitantly with this induction of apoptosis, degeneration of dopaminergic axons occurs and is characterized by the formation of axonal swellings and spheroids. Immunohistochemical analysis reveals that the activated form of caspase-3 and a caspase cleavage product of beta-actin are abundantly expressed in these degenerating fibers. We conclude that caspases are activated in degenerating dopaminergic axons as the somata undergo programmed cell death in this model. These results raise the possibility that caspase activation may occur in other programmed cell death contexts for these neurons, and, if this is so, then their inhibition may be a useful therapeutic target.

Animals↗
PubMed2004

Failure to restore vision after optic nerve regeneration in reptiles: interspecies variation in response to axotomy.

Optic nerve regeneration within the reptiles is variable. In a snake, Viper aspis, and the lizard Gallotia galloti, regeneration is slow, although some retinal ganglion cell (RGC) axons eventually reach the visual centers (Rio et al. [1989] Brain Res 479:151-156; Lang et al. [1998] Glia 23:61-74). By contrast, in a lizard, Ctenophorus ornatus, numerous RGC axons regenerate rapidly to the visual centers, but unless animals are stimulated visually, the regenerated projection lacks topography and animals remain blind via the experimental eye (Beazley et al. [2003] J. Neurotrauma 20:1263-1269). V. aspis, G. galloti, and C. ornatus belong respectively to the Serpentes, Lacertidae, and Agamidae within the Eureptilia, the major modern group of living reptiles comprising the Squamata (snakes, lizards, and geckos) and the Crocodyllia. Here we have extended the findings on Eureptilia to include two geckos (Gekkonidae), Cehyra variegata and Nephrurus stellatus. We also examined a turtle, Chelodina oblonga, the Testudines being the sole surviving representatives of the Parareptilia, the more ancient reptilian group. In all three species, visually elicited behavioral responses were absent throughout regeneration, a result supported electrophysiologically; axonal tracing revealed that only a small proportion of RGC axons crossed the lesion and none entered the contralateral optic tract. RGC axons failed to reach the chiasm in C. oblonga, and in G. variegata, and N. stellatus RGC axons entered the opposite optic nerve; a limited ipsilateral projection was seen in G. variegata. Our results support a heterogeneous response to axotomy within the reptiles, each of which is nevertheless dysfunctional.

Animals↗
PubMed2002

APP knockout attenuates microglial activation and enhances neuron survival in substantia nigra compacta after axotomy.

Focal microglial activation and progressive dopaminergic neurodegeneration in substantia nigra compacta (SNc) have characterized Parkinson's disease (PD). We have hypothesized that the microglial response may be provoked by molecular signals from chronically stressed SNc neurons. To test whether amyloid precursor protein (APP) could serve as such a signal, we evaluated microglial activation in SN after unilateral transection of the medial forebrain bundle (MFB) in mice either wild-type (WT) or null (KO) for APP. WT and KO mice displayed comparable microglial response at the MFB transection site. In WT mice microglial activation was first apparent in the ipsilateral SN at 3 days postlesion (dpl), marked by morphological change and increased isolectin immunoreactivity. The microglial response intensified at 7 dpl and persisted in the medial nigra through 14 dpl. In contrast, in KO mice activated microglia appeared predominantly at 7 dpl, with little activation at 3 dpl and none at 14 dpl. Neuron number in affected WT SNc at 14 dpl was significantly reduced compared with loss in affected KO SNc. The delayed and limited local microglial activation and increased neuron survival in response to distal axotomy of SNc neurons in APP KO mice are consistent with the important role APP in neuronal stress responses in vivo.

Amyloid beta-Protein Precursor↗
PubMed2002

Promoting axonal regeneration in the central nervous system by enhancing the cell body response to axotomy.

Neurons projecting into the peripheral nervous system (PNS) regenerate their axons after injury, in contrast to those confined to the central nervous system (CNS). Both neuronal and nonneuronal factors contribute to the lack of CNS regeneration. In this review we concentrate on the differential gene expression response to axotomy in PNS vs. CNS neurons. In general CNS neurons fail to up-regulate or sustain the expression of regeneration-associated proteins (RAGs), including trophic factors and their receptors. The presumed lack of trophic support of axotomized CNS neurons provided the rationale for the exogenous application of trophic factors, either to the lesion site or to the cell bodies. Here, we review our data on the application of trophic factors to rubrospinal and corticospinal neurons. Cell body treatment of axotomized rubrospinal neurons with brain-derived neurotrophic factor (BDNF) reversed atrophy, increased GAP-43 and Talpha-1 tubulin mRNA expression, and promoted axonal regeneration into peripheral nerve grafts. Importantly, BDNF cell body treatment was still effective in the chronic setting, i.e., when initiated 1 year after injury, but BDNF had no effect when applied to the chronic spinal cord injury site. The ability to promote regeneration in chronically injured neurons will hopefully contribute to the development of treatment strategies for chronic spinal injuries.

Animals↗
PubMed2005

Effects of axotomy on telomere length, telomerase activity, and protein in activated microglia.

The adult central nervous system (CNS) is generally thought of as a postmitotic organ. However, DNA labeling studies have shown that one major population of nonneuronal cells, called microglia, retain significant mitotic potential. Microglial cell division is prominent during acute CNS injury involving neuronal damage or death. Prior work from this laboratory has shown that purified microglia maintained in vitro with continual mitogenic stimulation exhibit telomere shortening before entering senescence. In the current study, we sought to investigate whether telomere shortening occurs in dividing microglia in vivo. For this purpose, we used a nerve injury model that is known to trigger localized microglial proliferation in a well-defined CNS region, the facial motor nucleus. Adult Sprague-Dawley rats underwent facial nerve axotomy, and facial motor nuclei were microdissected after 1, 4, 7, and 10 days. Whole tissue samples were subjected to measurements of telomere length, telomerase activity, and telomerase protein. Results revealed a tendency for all of these parameters to be increased in lesioned samples. In addition, microglial cells isolated directly from axotomized facial nuclei with fluorescence-activated cell sorting (FACS) showed increased telomerase activity relative to unoperated controls, suggesting that microglia are the primary cell type responsible for the increases observed in whole tissue samples. Overall, the results show that microglia activated by injury are capable of maintaining telomere length via telomerase during periods of high proliferation in vivo. We conclude that molecular mechanisms pertaining to telomere maintenance are active in the injured CNS.

Animals↗
PubMed2002

Patterned gene programs and target remodeling following axotomy at a major site for sensory innervation.

The genetic mechanisms that a target uses to reestablish the connections of regenerating axons were explored using oligonucleotide microarrays and real-time PCR. In normal and denervated mouse vibrissa follicles, patterns of genetic regulation were assessed in adjacent targets that normally receive different types of sensory and autonomic innervation. We show that a target remodeling occurs following axotomy involving reduced hair growth, altered hair follicle integrity and remodeling of the extracellular matrix. Also, we found two orphan receptors putatively involved in hair growth. Our data further demonstrate region-specific regulation of genes putatively involved in target-axon interactions. Thus, this study shows for the first time that major target remodeling occurs following denervation and suggests putative functions for several novel genes.

Animals↗
PubMed2004

Novel changes in gene expression following axotomy of a sympathetic ganglion: a microarray analysis.

Neurons of the peripheral nervous system are capable of extensive regeneration following axonal injury. This regenerative response is accompanied by changes in gene expression in axotomized neurons and associated nonneuronal cells. In the sympathetic nervous system, a few of the genes affected by axonal injury have been identified; however, a broad sampling of genes that could reveal additional and unexpected changes in expression has been lacking. We have used DNA microarray technology to study changes in gene expression within 48 h of transecting the postganglionic trunks of the adult rat superior cervical ganglion (SCG). The expression of more than 200 known genes changed in the ganglion, most of these being genes not previously associated with the response to injury. In contrast, only 10 genes changed following transection of the preganglionic cervical sympathetic trunk. Real-time RT-PCR analysis verified the upregulation of a number of the axotomy-induced genes, including activating transcription factor-3 (ATF-3), arginase I (arg I), cardiac ankyrin repeat protein, galanin, osteopontin, pituitary adenylate cyclase-activating polypeptide (PACAP), parathyroid hormone-related peptide, and UDP-glucoronosyltransferase. Arg I mRNA and protein were shown to increase within neurons of the axotomized SCG. Furthermore, increases in the levels of putrescine and spermidine, a diamine and polyamine produced downstream of arg I activity, were also detected in the axotomized SCG. Our results identified many candidate genes to be studied in the context of peripheral nerve regeneration. In addition, the data suggest a potential role for putrescine and spermidine, acting downstream of arg I, in the regenerative process.

Animals↗
PubMed2005

Ciliary neurotrophic factor protects retinal ganglion cells from axotomy-induced apoptosis via modulation of retinal glia in vivo.

Adenoviral-mediated transfer of ciliary neurotrophic factor (CNTF) to the retina rescued retinal ganglion cells (RGCs) from axotomy-induced apoptosis, presumably via activation of the high affinity CNTF receptor alpha (CNTFRalpha) expressed on RGCs. CNTF can also activate astrocytes, via its low affinity leukemia inhibitory receptor beta expressed on mature astrocytes, suggesting that CNTF may also protect injured neurons indirectly by modulating glia. Adenoviral-mediated overexpression of CNTF in normal and axotomized rat retinas was examined to determine if it could increase the expression of several glial markers previously demonstrated to have a neuroprotective function in the injured brain and retina. Using Western blotting, the expression of glial fibrillary acid protein (GFAP), glutamate/aspartate transporter-1 (GLAST-1), glutamine synthetase (GS), and connexin 43 (Cx43) was examined 7 days after intravitreal injections of Ad.CNTF or control Ad.LacZ. Compared to controls, intravitreal injection of Ad.CNTF led to significant changes in the expression of CNTFRalpha, pSTAT(3), GFAP, GLAST, GS, and Cx43 in normal and axotomized retinas. Taken together, these results suggest that the neuroprotective effects of CNTF may result from a shift of retinal glia cells to a more neuroprotective phenotype. Moreover, the modulation of astrocytes may buffer high concentrations of glutamate that have been shown to contribute to the death of RGCs after optic nerve transection.

Animals↗
PubMed1998

Expression of MHC class I and beta2-microglobulin in rat spinal motoneurons: regulatory influences by IFN-gamma and axotomy.

The low expression of MHC antigens is believed to be one factor of importance contributing to the immune-privileged status of CNS neurons. We here describe that motoneurons, in contrast to other nerve cells in the lumbar spinal cord of the adult rat, express both MHC class I and beta2-microglobulin mRNA. The motoneurons also display in situ hybridization signal for IFN-gamma receptor mRNA. After a peripheral axotomy, the motoneurons show a clear upregulation of beta2-microglobulin mRNA. IFN-gamma treatment of cultured rat embryonic spinal motoneurons causes a similar upregulation of especially beta2-microglobulin. Based on these facts, we propose that spinal motoneurons can be influenced by IFN-gamma and recognized by cytotoxic CD8+ T-cells. These findings could be of relevance in the search for pathogenetic mechanisms in motoneuron-specific diseases, such as ALS.

Animals↗