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PubMed1987

Axonal trajectories between mouse somatosensory thalamus and cortex.

An in vitro brain slice preparation has been used to label fibers connecting the somatosensory thalamus and cortex of the mouse. In 400-800-micron brain slices, the pathway between the ventrobasal complex and somatosensory cortex was labeled under direct vision with horseradish peroxidase crystals (HRP), HRP-Nonidet P-40 (NP40) detergent chips, or a solution of HRP/dimethylsulfoxide. Thalamocortical and corticofugal fibers are organized into a plexiform system of bundles that appears to be fairly constant from animal to animal. Bundles of fibers projecting from the ventrobasal complex course between regularly spaced groups of thalamic neurons. Thalamocortical axons do not invariably leave the thalamus via the fiber bundle closest to the perikarya. Thus, nearest-neighbor relationships are abolished before these axons have even left the thalamus. The axon bundles traverse the thalamic reticular nucleus lateral to the complex. The axons then rotate about one another, analogous to the coiling of strands in rope about a central axis. This accounts for the well known 180 degrees rotation in the mediolateral direction between thalamic and cortical maps. Laterally, fiber bundles converge and diverge within the internal capsule so that nearest-neighbor relationships are lost. Individual thalamocortical axons do not bifurcate proximal to the subcortical white matter. After single bundles of fibers reach a point just below the subcortical white matter, their individual fibers diverge widely. Within the subcortical white matter most afferent fibers make a small dorsally concave loop prior to taking one of two possible courses: some of the fibers ascend directly into the overlying cortex usually angled towards the dorsal surface of the brain; other fibers run in the subcortical white matter for variable distances prior to ascending into cortex. Within somatosensory cortex, smooth axons branch near their terminals in layers IV and VI. Axonal terminal and branching patterns of these axons within somatosensory cortex are similar to those found in in vivo preparations. Most axons are smooth, but other axons are beaded. Some beaded axons project to layer I. Corticofugal fibers are labeled. Fibers leaving somatosensory cortex have an angle of descent opposite to the angle of ascent for afferent fibers, and are often fasciculated in the cortex and subcortical white matter. Within the subcortical white matter efferent fibers often loop in a direction opposite to that of afferent fibers. Corticofugal fibers occasionally give off a collateral corticostriatal branch within the internal capsule.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗
PubMed1989

Regrowth of retinal ganglion cell axons into a peripheral nerve graft in the adult hamster is enhanced by a concurrent optic nerve crush.

Transplantation of a segment of peripheral nerve to the retina of the adult hamster resulted in regrowth of damaged ganglion cell axons into the graft, with the fastest regenerating axons extending at 2 mm/day after an initial delay of 4.5 days (Cho and So 1987b). In this study, the effect of making 2 lesions on the same axon (the conditioning lesion effect) on the regrowth of ganglion cell axons into the peripheral nerve graft was examined. When a conditioning lesion (first lesion) was made by crushing the optic nerve 7 or 14 days before the peripheral nerve grafting (the second lesion) to the retina, the distance of regrowth achieved by the fastest regenerating axons in the graft, measured at the 7th post-grafting day, was lower than in animals with a peripheral nerve grafted to a normal eye. This indicated that in contrast to the situation in peripheral nerve axons (Forman et al. 1980) and goldfish optic axons (Edwards et al. 1981), the conditioning lesion was unable to enhance the regrowth of mammalian retinal ganglion cell axons. However, when crushing of the optic nerve was followed immediately by peripheral nerve grafting, an enhancement in axonal regrowth could be observed. The initial delay time before the axons extended into the peripheral nerve graft was reduced by 1 day while the rate of elongation of the fastest regrowing axons in the graft apparently remained unchanged. Moreover, the shortening of the initial delay could still be observed even when the sequence of performing the 2 lesions was reversed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Axonal regeneration after crush injury of rat central nervous system fibres innervating peripheral nerve grafts.

Recent experimental studies in adult rodents indicate that neurons in many regions of the brain and spinal cord are capable of extensive axonal growth along peripheral nerve grafts inserted into the C.N.S. To explore further the capacity of damaged intrinsic C.N.S. neurons to initiate and sustain fibre growth we have studied the regenerative response of brain stem and spinal neurons to the crushing of their axons after such axons had already grown across peripheral nerve 'bridges' linking both these levels of the neuraxis. In adult rats, an autologous segment of sciatic nerve approximately 4 cm long was used to connect the medulla oblongata and the lower cervical spinal cord. After 6-42 weeks, when C.N.S. axons are known to have regenerated across these 'bridges', the nerve grafts were crushed near both their rostral and caudal insertions into the C.N.S. Axonal regeneration beyond the sites of injury was investigated 4-11 weeks after crush by retrogradely labelling C.N.S. neurons with horseradish peroxidase (HRP) applied 1 cm away from the injured site, along the assumed course of the C.N.S. fibres regrowing across the graft. The number and distribution of HRP-labelled neurons was found to be similar to that in rats with uncrushed grafts. To prove that such axonal regrowth from spinal and brain stem nerve cells did originate from injury of central nerve fibres innervating the graft and not by sprouting from undamaged C.N.S. neurons at both ends of the 'bridge', we first labelled with the fluorescent dye Fast Blue (FB) the cells whose axons were interrupted by the crush and, after two weeks, applied a second dye, Nuclear Yellow (NY) 1 cm beyond the site of injury. The presence of FB and NY double-labelled C.N.S. neurons in these animals, together with the results of the HRP-labelling experiments, suggest that central neurons whose axons innervate peripheral nerve grafts are capable of renewed growth after axonal injury. Under such experimental conditions these intrinsic C.N.S. neurons respond to axonal interruption in a manner that resembles the responses of cells that normally project along peripheral nerves. We believe this to be an additional indication of the powerful role in regeneration of interactions between neurons and the axonal environment.

Animals↗
PubMed1986

Collateral sprouting of sensory axons in the glabrous skin of the hindpaw after chronic sciatic nerve lesion in adult and neonatal rats: a morphological study.

The anterograde transport of wheat germ agglutinin-horseradish peroxidase conjugate was used to study the normal distribution of sensory nerve axons in the plantar skin of the rat hindlimb and at various times after chronic sciatic nerve injury in adult and neonatal rats. In adults, thin saphenous nerve axons were found in a small area laterally to the normal saphenous nerve territory 2-24 weeks after sciatic nerve lesion. In neonatal rats, at 6 and 10 weeks after sciatic nerve injury thin saphenous nerve axons were found almost or all over the sole of the foot, respectively, and in all 5 toes. At longer survival times, the area innervated by saphenous nerve axons became smaller. However, this area was now occupied by thin, as well as coarse axons. When adult animals were subjected to saphenous nerve crush simultaneously with the sciatic nerve lesion, thin, as well as coarse, nerve axons were found laterally to the normal saphenous nerve territory. The findings indicate that thin cutaneous sensory axons of adult mammals can extend collateral sprouts in glabrous skin for a short distance. This capacity appears to be greater in neonatally lesioned animals, where it is present for coarse cutaneous sensory axons as well. However, after neonatal nerve injury collateral sprouts seem to disappear from the initially most distally reinnervated area. Regenerating sensory axons in adult rats seem to have a greater capacity for collateral sprouting than intact axons. Coarse and thin cutaneous sensory axons could be found in this instance. In all instances a great part of the plantar skin remained denervated, suggesting that there is an upper limit for the territory which can be maintained by cutaneous sensory neurons reinnervating glabrous skin.

Age Factors↗
PubMed1996

Differential compartmentalization of vasopressin messenger RNA and neuropeptide within the rat hypothalamo-neurohypophysial axonal tracts: light and electron microscopic evidence.

Arginine vasopressin messenger RNA is axonally transported in the rat hypothalamo-neurohypophysial system [for review see Mohr et al. (1993) In Vasopressin (eds Gross P., Richter D. and Robertson C. L.), pp. 119-129, John Libbey Eurotext]. Upon chronic dehydration (2% saline-feeding for seven days), vasopressin messenger RNA within this axonal compartment is dramatically increased and appears aggregated in a selected subset of axonal swellings confined to the median eminence and posterior pituitary. In this study, we analysed the axonal distribution of the vasopressin messenger RNA within the hypothalamo-neurohypophysial tracts of control and saline-fed animals, and compared this distribution to that of the vasopressin peptide. Our data further support a selective aggregation of the vasopressin messenger RNA in a subset of distal axonal swellings and/or terminals of the median eminence and posterior pituitary. The selective aggregation is observed not only in saline-fed animals, but also in control animals. Although the osmotic stimulus dramatically enhances the axonal transport of vasopressin messenger RNA, the consequent general distribution pattern of the messenger RNA in the hypothalamo-neurohypophysial system is not changed. However, the physiological perturbation does increase the number of vasopressin messenger RNA-containing swellings within the median eminence and the posterior pituitary. In both saline-fed and control animals, the level of messenger RNA label within individual swellings appeared roughly similar to that found in the perikaryal cytoplasm of extra-hypothalamic vasopressinergic neurons. A detailed comparison of the axonal compartmentalization of vasopressin messenger RNA and vasopressin peptide demonstrates that the axonal distribution of vasopressin messenger RNA does not precisely overlap that of vasopressin peptide along the hypothalamo-neurohypophysial tract. In seven-day saline-fed animals, the majority of the messenger RNA-containing swellings of the median eminence also contain detectable vasopressin peptide; however in the same animals, nearly all the messenger RNA-containing swellings of the posterior pituitary appear devoid of vasopressin peptide. Therefore, our work strongly suggests that at least in the posterior pituitary, the vasopressin messenger RNA might be selectively targeted and aggregated in a selected subset of axonal swellings containing little if any vasopressin, and hence very few neurosecretory granules. Given this evidence that vasopressin messenger RNA and neuropeptide are differentially compartmentalized in axons of magnocellular neurons, we propose that vasopressin messenger RNA and peptide probably rely on different intracellular transport systems with respect to packaging, transport and/or aggregation within these selected axonal locations.

Animals↗
PubMed2005

Myelinated and unmyelinated axons of the corpus callosum differ in vulnerability and functional recovery following traumatic brain injury.

Traumatic axonal injury (TAI), a common feature of traumatic brain injury, is associated with postinjury morbidity and mortality. However, TAI is not uniformly expressed in all axonal populations, with fiber caliber and anatomical location influencing specific TAI pathology. To study differential axonal vulnerability to brain injury, axonal excitability and integrity were assessed in the corpus callosum following fluid percussion injury in the rat. In brain slice electrophysiological recordings, compound action potentials (CAPs) were evoked in the corpus callosum, and injury effects were quantified separately for CAP waveform components generated by myelinated axons (N1 wave) and by unmyelinated axons (N2 wave). Ultrastructural analyses were also conducted of TAI-induced morphological changes in these axonal populations. The two populations of axons differed in response to brain injury, and in their functional recovery, during the first week postinjury. Amplitudes of N1 and N2 were significantly depressed at 3 h, 1 day, and 3 days survival. N1 amplitudes exhibited a recovery to control levels by 7 days postinjury. In contrast, N2 amplitudes were persistently suppressed through 7 days postinjury. Strength-duration properties of evoked CAPs further differentiated the effects of injury in these axonal populations, with N2 exhibiting an elevated strength-duration time constant postinjury. Ultrastructural observations revealed degeneration of myelinated axons consistent with diffuse injury sequelae, as well as previously undocumented pathology within the unmyelinated fiber population. Collectively, these findings demonstrate differential vulnerabilities of axons to brain injury and suggest that damage to unmyelinated fibers may play a significant role in morbidity associated with brain injury.

Action Potentials↗
PubMed1997

Electron microscopic evidence for coexistence of leucine5-enkephalin and gamma-aminobutyric acid in a subpopulation of axon terminals in the rat locus coeruleus region.

We recently described ultrastructural evidence for morphologically heterogeneous axon terminals containing the endogenous opioid peptide, methionine5-enkephalin (ENK), that formed synapses with neurons containing the catecholamine synthesizing enzyme, tyrosine hydroxylase, in the locus coeruleus (LC) of the rat brain. The morphological characteristics of these terminals suggested that ENK may be co-localized with either an excitatory or inhibitory amino acid. To further test this hypothesis, we combined immunogold-silver localization of gamma-aminobutyric acid (GABA) and immunoperoxidase labeling for ENK in single sections through the LC, in the present study, to determine whether ENK and GABA were contained within single axon terminals. Light microscopic analysis of ENK and GABA immunoreactivities in the LC indicated that both transmitters were enriched in the dorsal pons. Although electron microscopy revealed that ENK and GABA were located primarily in axon terminals, some dendrites also contained immunolabeling for GABA. The dense core vesicles were consistently the most immunoreactive in ENK containing axon terminals and were identified toward the periphery of the axon terminal distal to the synaptic specialization. Axon terminals containing either ENK or GABA immunoreactivities contained pleomorphic vesicles as well as large dense core vesicles, varied in size and formed heterogeneous types of synaptic specializations (i.e. asymmetric vs. symmetric). Approximately 38% (n = 76) of the axon terminals containing ENK immunoreactivity (n = 200) also contained GABA. Some axon terminals containing peroxidase labeling for ENK (22%; n = 44) converged on common targets with GABA-labeled axon terminals. Finally, a few ENK-labeled axon terminals (14%; n = 28) formed asymmetric (excitatory-type) synapses with dendrites containing gold-silver labeling for GABA. The results, therefore, indicate that the opioid peptide, ENK, and the inhibitory amino acid, GABA, may influence LC neurons by concerted actions via (1) release from a common axon terminal, and (2) via separate sets of afferents converging on similar portions of the plasmalemma of target neurons. Furthermore, these studies also suggest a cellular substrate for opioid inhibition of LC neurons via activation (i.e. asymmetric synapses) of inhibitory GABAergic neurons. Future studies are required to determine whether the receptive sites for ENK and GABA are located at similar sites on the plasma membranes of LC neurons pre- or postsynaptically and whether there is differential release of either transmitter from single terminals in the LC.

Animals↗
PubMed1999

Axons from anteroventral cochlear nucleus that terminate in medial superior olive of cat: observations related to delay lines.

The differences in path length of axons from the anteroventral cochlear nuclei (AVCN) to the medial superior olive (MSO) are thought to provide the anatomical substrate for the computation of interaural time differences (ITD). We made small injections of biotinylated dextran into the AVCN that produced intracellular-like filling of axons. This permitted three-dimensional reconstructions of individual axons and measurements of axonal length to individual terminals in MSO. Some axons that innervated the contralateral MSO had collaterals with lengths that were graded in the rostrocaudal direction with shorter collaterals innervating more rostral parts of MSO and longer collaterals innervating more caudal parts of MSO. These could innervate all or part of the length of the MSO. Other axons had restricted terminal fields comparable to the size of a single dendritic tree in the MSO. In the ipsilateral MSO, some axons had a reverse, but less steep, gradient in axonal length with greater axonal length associated with more rostral locations; others had restricted terminal fields. Thus, the computation of ITDs is based on gradients of axonal length in both the contralateral and ipsilateral MSO, and these gradients may account for a large part of the range of ITDs encoded by the MSO. Other factors may be involved in the computation of ITDs to compensate for differences between axons.

Animals↗
PubMed1996

Node-paranode regions as local degradative centres in alpha-motor axons.

Lysosomes play an important role for the maintenance of a normal internal milieu in the cell. In neurons lysosomes are abundant in the perikaryon and dendrites, but have been observed to a much lesser degree in the axon. A general opinion has therefore formed among biologists interested in the nervous system that axonal material destined for degradation has to be transported to the neuronal perikaryon. The lysosomal occurrence and distribution at the level of the axon have, however, not been investigated systematically. This review summarizes recent morphological data based on light, fluorescence, and electron microscopic observations in peripheral nerve fibres of cats and rats providing evidence that node-paranode regions mainly along the peripheral parts of alpha motor axons, where the axon cross-section area decreases to 10-25% of internodal values, can control the passage and participate in a lysosome-mediated degradation of axonally transported materials directed towards the neuronal perikaryon. An important role is played by the paranodal axon-Schwann cell networks, which are lysosome-rich entities whereby the Schwann cells can sequester material from the axoplasm of large myelinated peripheral nerve fibres. The networks also seem to serve as depots for axonal waste products. The degradative ability of node-paranode regions in alpha-motor axons could be of some significance for the protection of the motor neuron perikarya from being flooded with and perhaps injured by indigestible materials as well as potentially deleterious, exogenous substances imbibed by the axon terminals in the muscle. A similar degradative capacity may not be needed in nerve fibres with synaptic terminals in the CNS where the local environment is regulated by the blood-brain barrier.

Animals↗
PubMed1990

Specificity of initial axonal projections to embryonic chick wing.

Anterograde transport of HRP was used to map initial segmental projection patterns of motor and sensory axons to the chick embryo wing. At the earliest stages of innervation, before the peripheral nerves had formed, motor axons were distributed as two loosely organized sheets, one directed towards the dorsal muscle mass and the other to the ventral. Labeled axons emerging from a given spinal cord segment were distributed within the sheets in a pattern that reflected the origin of the axons along the rostro-caudal axis of the lateral motor column. The segmental specificity of the motor projections was analyzed again after the axonal sheets had formed recognizable nerve trunks and muscle nerves. As was observed at the younger stages, axons were distributed in a pattern that was correlated with both the relative antero-posterior (A/P) and proximo-distal (P/D) position of the forming nerve, with cranial spinal nerves projecting to anterior and proximal limb regions. Whereas most axons emerging from a given ventral root projected in accord with what would be expected from the known adult motor pool maps, segmentally unexpected projections were frequently observed. The proportion of aberrantly projecting axons appears to be quite small, and in most embryos, it was impossible to determine whether the erroneous projections originated from unbranched axons or were collateral branches of others. The findings indicate that the initial projections of motor axons to the developing wing are patterned along the A/P axis of the wing and are largely accurate; however, the guidance processes are not sufficiently precise to exclude fibers entirely from inappropriate nerves. It is likely that later developmental processes act to fine-tune the initial projection pattern.

Animals↗
PubMed1993

On the guidance of regenerating axons from a half-retina in the adult goldfish.

We have examined the guidance of regenerating optic axons from half-retinal fragments in the goldfish. Axons regenerating from a dorsal, ventral, or nasal half-retina showed no bias to grow through the retinotopically appropriate parts of the optic tract. By contrast, axons from a temporal half-retina did show a bias, albeit a small one, to grow through the correct part of the tract. In addition, we found evidence that axons from the temporal quadrant of dorsal or ventral half-retinas showed a similar bias. In the optic tectum, axons regenerating from a dorsal, ventral, or temporal half-retina showed strong biases to invade the retinotopically appropriate portion of the synaptic field. Of these three, temporal axons showed the sharpest restriction in their field of innervation. Nasal fibers were unique in that they invaded the entire tectum with little evidence of a preference for their appropriate field. Our results indicate that there is minimal guidance offered to regenerating optic axons in the optic tract. However, once dorsal, ventral, or temporal axons reach the tectum they appear to encounter strong organizing forces which constrain them to preferentially invade their retinotopically appropriate areas. Nasal axons appear to be exempt from these forces. In both the optic tract and tectum, axons from a temporal half-retina are the most effectively guided and constrained.

Animals↗
PubMed1999

The effects of FK506 on dorsal column axons following spinal cord injury in adult rats: neuroprotection and local regeneration.

There is considerable evidence that immunophilin ligands can promote the regeneration of axons in peripheral nerves and act as neuroprotective agents in the CNS. We have examined the effects of FK506 and GPI 1046 on the responses to partial transection of ascending spinal dorsal column axons at T9, in some cases combined with crush of one sciatic nerve. FK506 (0.5 or 2.0 mg/kg) and GPI 1046 (10 or 40 mg/kg) was administered subcutaneously immediately after surgery and five times a week thereafter. Some animals received methylprednisolone (MP) (two subcutaneous doses of 30 mg/kg) in addition to, or instead of, FK506. After survival times of 1-12 weeks, dorsal column axons were labeled transganglionically with cholera toxin B-HRP. There was massive axonal sprouting at the lesion sites in animals with sciatic nerve injury and immunophilin ligand treatment. In FK506-treated animals a few severed sensory axons regenerated for up to 10 mm rostral to the lesion. Of greater significance, 30% of 71 FK506-treated animals had spared axons in the dorsal column, extending to the nucleus gracilis, versus 8% of 50 control animals (P < 0.05), showing that FK506 reduces the likelihood of axonal destruction due to secondary injury. A combination of FK506 and MP afforded greater protection than MP alone (P < 0.05), but axonal survival was not affected by sciatic nerve crush, dose of FK506, or survival time after injury. GPI 1046 (n = 11) did not promote axonal survival. Thus FK506 protects axons from secondary injury following spinal cord trauma, and in this experimental model, its neuroprotective effect is greater than that of MP.

Animals↗
PubMed1985

Ultrastructural observations on the cytoarchitecture of axons processed by rapid-freezing and freeze-substitution.

The structure and organization of axons in the cervical connective of wild-type Drosophila fruit flies were examined in anticipation of studies of various neurological mutants. Dissected flies were rapid-frozen from the living state against a copper block cooled with liquid helium, freeze-substituted, and prepared for electron microscopic examination of thin sections. These cryotechniques showed new details of the structure of cell organelles and cytoplasm in Drosophila axons. The cytoplasmic matrix of axons and glia consists of a material with a fine granular texture enmeshed in a three-dimensional meshwork of short, fine filaments which vary in shape, size and electron density. No neurofilaments are present, but bundles of microtubules are interwoven into the filamentous matrix of the axoplasm. The round wall of microtubules (27 nm overall diameter) is composed of twelve cylindrical protofilaments with a typical substructural periodicity. Mitochondria frequently make contact with microtubules in both axons and glial processes. A thin layer of electron-dense filamentous matrix, which appears to be an axonal basal lamina, contacts most of the axonal exoplasmic surface, especially that of axons where they are surrounded by processes of glial cells, but is scant wherever single axons are contiguous. Thus, an axonal basal lamina occupies the constricted spaces around axons, where extracellular K+ accumulates during neural activity.

Animals↗
PubMed1975

Distribution along the axon and into various subcellular fractions of molecules labeled with (3H)leucine and rapidly transported in the garfish olfactory nerve.

The distribution of molecules labeled with [3H]leucine by fast axoplasmic transport in vivo has been studied in the garfish olfactory nerve after incorporation of the amino acid by the olfactory mucosa. Owing to the size of the nerve, it has been possible to follow the fate of the labeled molecules in 10 different subcellular fractions of 6 consecutive nerve segments. Each segment represents a different part of the profile developed by the transported radioactive molecules. In order to determine the influence of the perikaryon (rate of protein synthesis and rate of protein release into the axon) transport was studied under 3 different conditions: (1) intact nerves (simply labeled with [3H]leucine); (2) nerves cut from the cell bodies 6 h after application of [3H]leucine; and (3) nerves pulse-chase labeled for 1 h. Several conclusions can be drawn. (1) The bulk of the rapidly transported molecules are membranous axonal proteins, as determined by enzyme markers. Most are found in subcellular fractions representing 17% of the total axonal protein. They are synthesized very rapidly in the cell bodies (less than 1 h after isotope deposition) and exhibit the highest specific activities measured. These high specific activities were found in the same axonal membrane fractions in both plateau and crest, suggesting that the membrane precursors are transported as particles rather than as subunits. (2) The majority of these proteins are released into the axon immediately after synthesis; however, at least 30% of the labeled axonal membranous proteins are not released with the fast wave itself but progressively over a long period of time. (3) The majority of the moving material, particularly in membranous fractions, is left behind the fast wave and is deposited in the axon. When the front base of the fast wve has covered 70% of the total nerve length, only 19% of the labeled material of the main axonal membranous fraction appears still to be moving. (4) Proteins with high specific activities are found near the cell bodies and may be the result of early axonal transport of amino acids, diffusing later into the surrounding cells and being incorporated into proteins. Some free amino acids are also transported along the axon.

Acetylcholinesterase↗
PubMed1982

Tropism in nerve regeneration in vivo. Attraction of regenerating axons by diffusible factors derived from cells in distal nerve stumps of transected peripheral nerves.

We re-examined the hypothesis of Cajal3, later refuted by Weiss and Taylor20, that cells in distal stumps of transected peripheral nerves exert an attractive (tropic) effect on regenerating axons. This question was re-assessed in vivo using surgical materials and assay procedures not available to those workers. Proximal stumps of transected rat sciatic or cat peroneal nerves were inserted into the single inlet end of a hollow, Y-shaped Silastic implant. Regenerating axons were provided with alternative targets consisting of a vacant arm vs one occupied by a sciatic nerve graft (rat), or a tibial (Tout) vs peroneal (Pout) distal nerve stump (cat). In some cases Pout was rendered metabolically compromised relative to Tout by exposing the former to dry ice and inhibitors of DNA and RNA synthesis. At 4.5 or 6 weeks postoperatively, the number of regenerating axons in each fork of the implant was assessed by morphometric analysis (total number of non-myelinated and myelinated axons greater than 1 micron in diameter at 4.5 weeks, and total number of myelinated axons at 6 weeks postoperatively), or by quantification of an axonally transported label. Rat sciatic nerve fibers exclusively regenerated toward the nerve graft, suggesting the existence of a neurotropic lure. In cats, morphometric analysis revealed a 10-(4.5 week) and 6-fold (6 week) greater number of axons growing towards untreated Tout vs treated Pout. When both distal stumps were untreated, more axons were seen in forks leading to Pout. Analysis of transported label confirmed the preferential growth of axons towards untreated Tout vs treated Pout for both motor and sensory axons. In separate experiments, Nuclepore filters (0.2 microns, pore size) were inserted between distal nerve stumps and outlet ends of Silastic implants. Preferential regeneration toward untreated stumps was observed if the distance between proximal and distal nerve stumps was equal to but not greater than 4-5 mm. These results suggest that peripheral nerve fiber regeneration in vivo can be directed by cells in distal stumps of transected nerves, and that this effect can be mediated over distances of several millimeters via diffusible factors.

Animals↗
PubMed1990

Limited topographic specificity in the targeting and branching of mammalian retinal axons.

We have studied in rats the topographic targeting of retinocollicular axons anterogradely labeled by focal retinal injections of the axon tracer DiI. We find that developing retinal axons widely mistarget along both the medial-lateral and the rostral-caudal axes of the superior colliculus (SC). In neonatal rats, labeled axons originating from injection sites in the temporal periphery covering less than 1% of the retina grow over most of the contralateral SC, suggesting that the growth cones of many axons initially fail to recognize their appropriate target region at the rostral SC border. Some of these axons correct their targeting errors and are retained; most do not and are eliminated. In neonates, peripheral nasal axons transiently develop branches throughout the SC. Branches formed by nasal axons are later restricted to a discrete terminal zone at the topographically appropriate, caudal SC border. At the neonatal stage, injections in temporal or nasal retina do result in a zone of increased labeling in the topographically correct region of the SC, but this zone is considerably larger than that labeled by a similar injection at a later stage. Thus, although the early projection is very diffuse, there is some bias for the correct region of the SC. Our findings indicate that in rats, developing retinal axons show only a limited specificity in their topographic targeting and branching. We conclude that mechanisms in addition to directed axon growth are required to establish the order characteristic of mature mammalian retinal projections.

Aging↗
PubMed2006

Traumatic axonal injury in the perisomatic domain triggers ultrarapid secondary axotomy and Wallerian degeneration.

Traumatic axonal injury (TAI) arising from diffuse brain injury (DBI) results in focally impaired axonal transport with progressive swelling and delayed disconnection over several hours within brainstem axons. Neocortical DBI-mediated perisomatic axotomy does not result in neuronal death, suggesting that a comparably delayed axotomy progression was responsible for this unanticipated response. To evaluate delayed perisomatic axotomy, the current study was initiated. Rats received intracerebroventricular 10-kDa dextran followed by moderate midline/central fluid percussion injury (FPI) or FPI alone. At 15, 30, 60, and 180 min post-injury, light and transmission electron microscopy identified impaired axonal transport via antibodies targeting amyloid precursor protein (APP), while double-label fluorescent microscopy explored concomitant focal axolemmal alterations via dextran-APP co-localization. At 15 min post-injury, perisomatic TAI was identified with LM within dorsolateral and ventral posterior thalamic nuclei. Using TEM, many sustaining somata and related proximal/distal axonal segments revealed normal ultrastructural detail that was continuous with focal axonal swellings characterized by cytoskeletal and organelle pathology. In other cases, axotomy was confirmed by loss of axonal continuity distal to the swelling. By 30 min post-injury, perisomatic axotomy predominated. By 60-180 min, somatic, proximal axonal segment, and swelling ultrastructure were comparable to earlier time points although swelling diameter increased. Distal axonal segment ultrastructure now revealed the initial stages of Wallerian degeneration. The site of perisomatic axotomy did not internalize dextran, suggesting that its pathogenesis occurred independent of altered axolemmal permeability. Collectively, this DBI-mediated ultrarapid perisomatic axotomy and its sequelae further illustrate the varied axonal responses to trauma.

Amyloid beta-Protein Precursor↗
PubMed2004

Neurofilament subunits undergo more rapid translocation within retinas than in optic axons.

Axonal transport of neurofilaments (NFs) has long been considered to be regulated by phosphorylation, although recent studies have challenged this hypothesis. Our prior analyses of axonal transport in optic axons demonstrated two distinct NF transport rates that spatially and temporally correlated with changes in NF phosphorylation. In our prior studies, we focused on subunits already within axons. Re-examination of these data using additional approaches and examining additional earlier time points have allowed us to calculate rates at which subunits transport out of retinas and into optic axons. NF subunits were radiolabeled by intravitreal injection of 35S-methionine. NF axonal transport was monitored by following the location of the front of radiolabeled subunits immunoprecipitated from retinas and segments of optic axons, which demonstrated four distinct transport rates. Subunits within retinas exhibited the fastest rate, and underwent a 50% slowing upon exiting the retina and entering optic axons. While this slowing could be due to a regional caliber increase and/or regional increase in NF phosphorylation within the first segment, prior studies indicated that inhibition of phosphatase activities increased NF phosphorylation within retinas and slowed NF subunit exit from retinas to a degree similar to that normally observed within the first segment of axons, suggesting that regional phosphorylation played a major role in slowing of NF transport following their exit from the retina. These findings provide additional support for the notion that phosphorylation regulates NF axonal transport.

Animals↗