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PubMed2002

Spatial and temporal patterns of distribution of the gap junctional protein connexin43 during retinal regeneration of adult newt.

Newts possess the ability to regenerate a functional retina after complete removal of the original retina. We performed immunoblot and immunohistochemical analyses of newt retinas at different stages of regeneration by using an antibody against a gap junction channel protein, connexin43 (Cx43). The specificity of the antibody was shown on immunoblots as well as immunohistochemical staining pattern in the normal retina. Punctate Cx43 immunolabeling was detected intensely between proliferating cell nuclear antigen-immunoreactive progenitor cells in the regenerating retinas, and the amount of this labeling tended to be prominent along both scleral and vitreal sides. The amount of Cx43 became less abundant as regeneration proceeded. This temporal loss of Cx43 during regeneration was also shown on the immunoblot analysis. Furthermore, the loss of Cx43 was observed in a spatial manner in the peripheral retina, where progenitor cells clustered at the ciliary marginal zone (CMZ) are adding new cells of all types in order toward the central retina. Immunolabeling often extended longitudinally throughout the retina when regenerating retinas became thick. Double immunolabeling with Cx43 and glial fibrillary acidic protein indicated the overlapping between the Cx43 and Müller cell processes. At the beginning of the synaptic formation, immunolabeling almost disappeared in the entire retina. However, in the completely regenerated retina, Cx43 reappeared in the distal end of Müller cells and pigment epithelial cells in the same pattern as in the normal retina. The above observations lead us to speculate that Cx43-mediated gap junctions may play an important role in regenerating events. Possible roles of Cx43 during regeneration are discussed.

Animals↗
PubMed2003

Increased expression of multiple neurofilament mRNAs during regeneration of vertebrate central nervous system axons.

Characteristic changes in the expression of neuronal intermediate filaments (nIFs), an abundant cytoskeletal component of vertebrate axons, accompany successful axon regeneration. In mammalian regenerating PNS, expression of nIFs that are characteristic of mature neurons becomes suppressed throughout regeneration, whereas that of peripherin, which is abundant in developing axons, increases. Comparable changes are absent from mammalian injured CNS; but in goldfish and lamprey CNS, expression of several nIFs increases during axon regrowth. To obtain a broader view of the nIF response of successfully regenerating vertebrate CNS, in situ hybridization and video densitometry were used to track multiple nIF mRNAs during optic axon regeneration in Xenopus laevis. As in other successfully regenerating systems, peripherin expression increased rapidly after injury and expression of those nIFs characteristic of mature retinal ganglion cells decreased. Unlike the decrease in nIF mRNAs of regenerating PNS, that of Xenopus retinal ganglion cells was transient, with most nIF mRNAs increasing above normal during axon regrowth. At the peak of regeneration, increases in each nIF mRNA resulted in a doubling of the total amount of nIF mRNA, as well as a shift in the relative proportions contributed by each nIF. The relative proportions of peripherin and NF-M increased above normal, whereas proportions of xefiltin and NF-L decreased and that of XNIF remained the same. The increases in peripherin and NF-M mRNAs were accompanied by increases in protein. These results are consistent with the hypothesis that successful axon regeneration involves changes in nIF subunit composition conducive to growth and argue that a successful injury response differs between CNS and PNS.

Animals↗
PubMed1986

Regeneration of the cerebellofugal projection after transection of the superior cerebellar peduncle in kittens: morphological and electrophysiological studies.

In contrast to the current concept of abortive regeneration of mammalian central axons, occurrence of marked, functionally active regeneration of the cerebellofugal projection was proved in kittens after complete transection of the decussation of the brachium conjunctivum (BCX). By means of the anterograde axonal transport of horseradish peroxidase that was injected into the cerebellar lateral and interpositus nuclei, the origin, course, and destination of the regenerated fibers were identified unambiguously and the time-course of axonal regeneration was clarified. Functional connectivity of the regenerated cerebellothalamic projection was tested electrophysiologically. In eight out 82 animals, marked regeneration of the cerebellofugal projection occurred; in the majority of the rest of the animals, trace amounts of regenerated fibers were observed. In the former but not in the latter animals, marked cerebellocerebral responses, as in intact animals, were evoked in the frontal motor and parietal association cortices. Most of the regenerated axons took a course similar to that of the normal projection and terminated in the normal projection areas, whereas a small proportion of fibers showed an aberrant course and termination. The cut ends of axons began to swell as early as 15 minutes after transection, and the regenerated axons produced dense terminals in the thalamus by 19 days.

Aging↗
PubMed1988

Normal and regenerating optic fibers in goldfish tectum: HRP-EM evidence for rapid synaptogenesis and optic fiber-fiber affinity.

The distribution of normal and regenerating retinal fibers and synapses was studied on tectum in goldfish by light (LM) and electron microscopy (EM). Since labeling of the early regenerating fibers was previously reported to be difficult, a new 'cold-fill' HRP labeling protocol was developed, which labeled regenerating optic fibers and terminals on tectum as early as 14 days after nerve crush when they first arrive on tectum. In order to characterize the laminar distribution of optic afferents in normal fish and in fish regenerating for 14-240 days, EM photomontages of areas 14 microns wide by 160 microns deep through the HRP-labeled primary optic innervation layer (S-SO-SFGS) were constructed. The time points in regeneration that were examined spanned the period in which others have shown that an initially diffuse retinotopic map becomes spatially restricted. At the LM level regenerating optic fibers were restricted to the optic lamina. They reinnervated tectum in an anterior to posterior sequence as previously seen with autoradiography. In addition, at 14 days, some "pioneer" optic fascicles were found to have already grown to posterior tectum where they gave rise to branches with boutonlike terminations and growth-cone-like processes. Form the ultrastructural analysis it was clear that optic fibers and terminals observed strict laminar boundaries as they partitioned themselves in the optic laminae (S, SO and SFGS) in both normal and regenerating fish. The behavior of optic fibers was lamina specific with respect to synapse formation and the orientation of fiber outgrowth. As early as 14 days regeneration, optic fibers made synapses onto the four types of postsynaptic profiles observed in normal fish. Numerous optic terminals were labeled at 14 days, and there appeared to be no waiting period between fiber ingrowth to the SO and synapse formation in the S and SFGS. At 14-60 days, atypical synaptic contacts which appear to be nascent synapses were made by labeled optic fibers in fascicles and by growth-cone-like processes. By 21-30 days, the density of optic terminals was high and there were many more fasciculated optic fibers in the SFGS than normal as late as 350 days. These findings suggest that optic fiber lamination is highly constrained by tectal cues, that fibers rapidly regenerate many synaptic terminals before retinotopic map refinement is complete, and that fibers have a strong affinity for each other.

Animals↗
PubMedDate not supplied

Influence of epidermal growth factor on liver regeneration after partial hepatectomy in rats.

The role of epidermal growth factor on liver regeneration after partial hepatectomy in rats was investigated. After a 70% hepatectomy in rats, the concentration of epidermal growth factor in portal venous blood was unchanged compared with unoperated controls. However, small amounts of epidermal growth factor could be identified in portal venous blood after intestinal instillation of epidermal growth factor. Brunner's glands and the submandibular glands secrete epidermal growth factor. Extirpation of Brunner's glands decreased liver regeneration, whereas removal of the submandibular glands had no effect on liver regeneration. Epidermal growth factor antiserum reduced liver regeneration significantly. Oral or s.c. administration of epidermal growth factor had no effect on liver regeneration, whereas epidermal growth factor enhanced the effect of insulin and glucagon on liver regeneration. The results suggest that endogenous epidermal growth factor participates in stimulation of liver regeneration after partial hepatectomy in rats. Epidermal growth factor given together with insulin and glucagon had a synergistic effect on liver regeneration which suggests that liver regeneration in the rat is controlled by multiple regulatory peptides.

Animals↗
PubMed2001

Heparan sulfate mimetics modulate calpain activity during rat Soleus muscle regeneration.

Skeletal muscle regenerates after injury. Tissue remodelling, which takes place during muscle regeneration, is a complex process involving proteolytic enzymes. It is inferred that micro and milli calpains are involved in the protein turnover and structural adaptation associated with muscle myolysis and reconstruction. Using a whole-crush injured skeletal muscle, we previously have shown that in vivo muscle treatment with synthetic heparan sulfate mimetics, called RGTAs (for ReGeneraTing Agents), greatly accelerates and improves muscle regeneration after crushing. This effect was particularly striking in the case of the slow muscle Soleus that otherwise would be atrophied. Therefore, we used this regeneration model to study milli and micro calpain expressions in the regenerating Soleus muscle and to address the question of a possible effect of RGTAs treatment on calpain levels. Micro and milli calpain contents increased by about five times to culminate at days 7 and 14 after crushing respectively, thus during the phases of fibre reconstruction and reinnervation. After 64 days of regeneration, muscles still displayed higher levels of both calpains than an intact uninjured muscle. Milli calpain detected by immunocytochemistry was shown in the cytoplasm whereas micro calpain was in both nuclei and cytoplasm in small myofibres but appeared almost exclusively in nuclei of more mature fibres. Interestingly, the treatment of muscles with RGTA highly reduced the increase of both milli and micro calpain contents in Soleus regenerating muscles. These results suggest that the improvement of muscle regeneration induced by RGTA may be partly mediated by minimising the consequences of calpain activity.

Animals↗
PubMed2004

Resistance to TGF-beta-induced apoptosis in regenerating hepatocytes.

Treatment with transforming growth factor beta (TGF-beta) of hepatocytes from two different proliferative conditions, such as fetal development and adult liver regeneration, shows that regenerating cells respond to this cytokine in terms of growth inhibition, but are less sensitive than the fetal ones to the apoptosis induced by this factor. Regenerating TGF-beta treated cells show higher cell viability and lower percentage of apoptotic cells than the fetal treated ones. Furthermore, TGF-beta treated regenerating hepatocytes maintain a well-preserved parenchyma-like organization. Treatment with TGF-beta induces the loss of mitochondrial transmembrane potential in fetal but not in regenerating hepatocytes and activation of caspase-3 is lower in regenerating than in fetal cells. Regenerating hepatocytes show higher intracellular levels of some antiapoptotic proteins, such as Bcl-x(L) and c-IAP-1 and, interestingly, they present higher intracellular glutathione levels, which might provide of mechanisms to avoid potential dangerous effects of the oxidative stress-mediated apoptosis induced by TGF-beta. In fact, treatment with BSO (a glutathione synthesis inhibitor) restores the response of regenerating hepatocytes to TGF-beta in terms of cell death. In conclusion, increased levels of Bcl-x(L) and cIAP-1 and higher intracellular glutathione levels could confer resistance to the apoptosis induced by TGF-beta during liver regeneration.

Animals↗
PubMed2003

Capsaicin-sensitive nerve fibers: a potential extra-ACTH mechanism participating in adrenal regeneration in rats.

Pituitary-derived factors, including ACTH, have been widely implicated in initiating adrenal regeneration. However, recent work has demonstrated that adrenal regeneration is also modulated by adrenal nerves that extensively reinnervate the regenerating adrenal. Moreover, transection of the splanchnic nerve removes sensory calcitonin gene-related peptide (CGRP) and preganglionic sympathetic vesicular acetylcholine transporter (VAChT)-positive fibers from the regenerating gland and delays regeneration. However, it is not known whether the splanchnic nerve effects on adrenal regeneration are mediated by the CGRP-positive or VAChT-positive innervation. The present studies use the drug capsaicin, a neurotoxin selective for a subset of primary afferent neurons, to specifically remove CGRP-positive fibers from the adrenal gland and assess subsequent effects on the recovery of adrenal mass and function after surgical enucleation. Male, Sprague-Dawley rats were anesthetized and treated with capsaicin (vs. vehicle) periaxonally to the thoracic splanchnic nerve (33 mM, 15 minutes) or systemically (30-100 mg/kg for 4 days, s.c.). After 7-12 days of recovery, rats received right adrenalectomy and left adrenal enucleation. At 14 and 21 days postenucleation, prestress and poststress plasma and adrenals glands were collected; adrenals were weighed and fixed for immunolabeling of CGRP-positive nerve fibers. Periaxonal capsaicin treatment decreased adrenal CGRP content prior to surgical enucleation; however, reinnervation by CGRP-positive fibers was not prevented and regeneration was not affected. Systemic capsaicin treatment attenuated the reinnervation by CGRP-positive fibers and increased the rate, but not extent, of adrenal regeneration. These results support the hypothesis that adrenal innervation represents an extra-ACTH mechanism to modulate the rate of adrenal regeneration.

Adrenal Glands↗
PubMed1976

Regeneration from different levels along the tail of the newt, Notophthalmus viridescens.

Some aspects of the influence of position on regeneration have been examined by comparing regeneration from different levels along the newt tail. Tails amputated such that either three-fourths one-half or one-fourth of the tail was removed pass through the same morphological and histological stages at the same times after amputation. In tails amputated at these three different levels, the rate of elongation of regenerates from more proximal levels is greater than that of regenerates from more distal levels. The total lengths of regenerates from different levels are proportional to the lengths of tail removed by amputation. Furthermore, the number of vertebrae formed in a tail regenerate is directly proportional to the number of vertebrae removed by amputation. When a tail blastema is transplanted to a more proximal level tail stump, intercalary regeneration between the stump and transplant occurs and the resulting regenerate has a complement of vertabrae appropriate to its new level along the tail. The results indicate that position along the appendage does not influence the developmental sequence of events of regeneration, but that it does influence the rate of growth and the structures to be replaced.

Amputation, Surgical↗
PubMed1984

Limb regeneration in anuran tadpoles following repeated amputations.

Limbs were amputated through the thigh in stages from V onward in Rana pipiens, R. sylvatica, and Pseudacris nigrita tadpoles to establish regenerative capacity. Normal regenerates were produced through stages XII, XI, and XIII, respectively, for the three species. However, hypomorphic forms with reduced toe numbers or a single spikelike spur, or nonregeneration, could appear as early as stages VII or VIII, and increased in frequency thereafter. Pseudacris produced the largest fraction of hypomorphs and R. sylvatica the smallest. Regenerated limbs of various stages were reamputated just distad of the initial transection level and produced regenerates with almost the same frequency as did the initial amputees. In R. pipiens reamputation and regeneration was followed for up to six sequences, with but little change in frequency or quality of regeneration, even when the contralateral control limbs were in stages XIV-XVII, well beyond the possibility of regeneration after transection through the thigh. Clearly, the hormonal milieu did not limit regeneration, though rate of regeneration accelerated as metamorphic climax was approached. Foot sizes were measured in R. pipiens, and were seen in control animals to be correlated to both stage and to tadpole length. Regenerated feet tended to be slightly larger than control feet of the same stage, showed comparable relationships between length and width, but correlated more poorly with tadpole length.

Amputation, Surgical↗
PubMed2007

Antler regeneration: a dependent process of stem tissue primed via interaction with its enveloping skin.

Deer antlers are unique mammalian appendages in that each year they are cast and fully regenerate from permanent bony protuberances, called pedicles. In a previous study, we found that there is a difference in the degree of association between pedicle bone and its enveloping skin: tight at the distal third and loose at the proximal two thirds of a pedicle stump. The distal part has been termed the "potentiated" region, and the proximal part the "dormant" region. In the present study, pedicle stumps were artificially created in yearling sika deer by cutting off the tissue distal to either the potentiated or the dormant region. A piece of impermeable membrane was then inserted into the space between the bone and the skin of each treated pedicle stump, while the control pedicles had the same surgery without membrane insertion. The results showed that the inserted membrane blocked pedicle skin participation in the process of antler regeneration. All three potentiated bony pedicle stumps regenerated skin-less antlers; whereas, one of the three dormant bony pedicle stumps failed to regenerate any antler tissue. The other two dormant stumps eventually regenerated normal antlers; however, this only occurred after loss of the inserted membrane. No antler tissue regenerated from the dormant stumps while the inserted membrane remained in place (up to 55 days). All control pedicle stumps regenerated normal antlers. Therefore, we conclude that it is the pedicle bone, but not pedicle skin, that gives rise to regenerating antlers, and that pedicle bone can acquire the potential to regenerate an antler only when it is primed via interaction with its enveloping skin.

Animals↗
PubMed1982

Age-related impeded regeneration of mouse minced anterior tibial muscle.

The effect of increasing age on the completeness of anterior tibial muscle regeneration from autotransplants of minced muscle has been studied in Swiss Webster and C57/B6J mice aged 18 to 120 days. A progressively declining capability to regenerate new myofibers was associated with a decreasing phagocytic clearance of implanted myofiber debris. Concurrently, there was decreased presumptive myoblast proliferation and new myofiber formation. The importance of age-related host factors, including nonspecific macrophage activity, in muscle mince regeneration was demonstrated by: (1) the successful regeneration of muscle in heterotransplanted muscle minces from older mice implanted in younger animals and (2) the failure of muscle regeneration when the reverse experiment was performed in syngeneic animals. Heterologous striated muscle from the diaphragm regenerated in the bed of the excised anterior tibial muscle, whereas heterologous cardiac muscle failed to regenerate as expected because of the absence of satellite cells. The failure of phagocytic clearance of implanted myofiber mince and concurrent retardation of regeneration suggests a major age-related nonimmune role of phagocytic macrophages in the early stages of regeneration of anterior tibial muscle from isotopic minced muscle implants.

Aging↗
PubMed1985

Regeneration of frog twitch and slow muscle fibers after mincing.

Iliofibularis muscles of Rana temporaria were minced and allowed to regenerate in the iliofibularis or the sartorius bed of the same frog. Regenerated muscles were examined for the presence of slow muscle fibers using electrophysiologic, histochemical, and contractile parameters. Muscle regeneration from sartorius mince was also studied. Regeneration was more successful from iliofibularis than from sartorius mince, and the iliofibularis bed was more favorable for regeneration than the sartorius bed for both types of muscle. Twitch fibers regenerated within a few months, but slow fibers could not be identified earlier than 14 months after muscle destruction. Slow muscle fibers regenerated only from iliofibularis mince, both orthotopically and heterotopically. All regenerates capable of maintaining a K-contracture contained histochemically identified slow fibers; the membrane properties of electrophysiologically identified slow fibers were normal. It is concluded that slow muscle fibers regenerate only from the remnants of a muscle that contains slow fibers. The results are discussed with respect to the role of innervating nerve fibers.

Animals↗
PubMed1988

Neural attrition following limb loss and regeneration in juvenile lobsters.

Lobsters have considerable regenerative capacity, being able to regrow an entire, albeit smaller, limb in one intermolt. Whether there is a corresponding downscaling in the hemiganglion and its nerves to the regenerate side compared with its contralateral intact side was examined in juvenile lobsters which had undergone single or multiple (2, 4, and 6) cycles of limb loss and regeneration on the one side. The limbs studied were the enlarged thoracic chelipeds or claws which appeared as paired symmetrical cutter-type claws. The size of the regenerate limb, as indicated by its propus length, was approximately 30% smaller than its intact counterpart. Correspondingly, the total number of axons in the nerves to the regenerate side was smaller than on the intact, contralateral side. Such attrition was also by about 30% in lobsters experiencing a single cycle of limb loss and regeneration, but was considerably greater with multiple cycles. Tissue degeneration was occasionally seen in the nerves to the regenerate side but not in the ganglion. The paired hemiganglia were equivalent in all respects except in the size of the neuropil, which was smaller on the regenerate side compared with the contralateral intact side. Neuropil attrition was most marked with multiple cycles of limb loss and regeneration. Such attrition in nerve and neuropil are most likely due to the reduced number of sensory elements in the newly regenerated, but smaller, limb.

Animals↗
PubMed1997

Absence of neural crest cell regeneration from the postotic neural tube.

The preotic neural tube has a variable ability for regeneration of neural crest depending on the neuraxial level. There is robust regeneration of neural crest in the caudal midbrain/rostral hindbrain. In contrast, removal of the cardiac neural crest results in cardiovascular abnormalities suggesting the lack of regeneration in this area, although the regenerative capacity of the cardiac crest region has never been tested directly. Premigratory cardiac neural crest was ablated bilaterally using laser irradiation or extirpation by tungsten needle, and the remaining ventral neural tube was labeled with DiI to examine any neural crest regeneration from the neural tube. The results indicate that there is very little regeneration of crest cells from the cardiac region of the neural tube if the ablation is done prior to the 5-somite stage and no regeneration after the 6-somite stage with either ablation procedure. Furthermore no compensatory response occurs from the adjacent regions of the neural crest. By contrast, we were able to confirm that regeneration of neural crest occurs in the preotic rhombencephalic neural tube even after laser irradiation. An analysis in the trunk region suggests that the trunk neural tube is similar to the cardiac region in that it does not regenerate crest cells in the ventral migratory pathway after ablation. However, melanocytes generated cranial and caudal to the ablated region migrate radially and fill in the ablated region so that there is no interruption of the normal pigment pattern. This study indicates that even though there is a variable capacity for crest regeneration in the preotic neural tube, the postotic neural tube does not have such regenerative ability.

Animals↗
PubMed2002

Extracellular matrix remodeling and metalloproteinase involvement during intestine regeneration in the sea cucumber Holothuria glaberrima.

The sea cucumber, Holothuria glaberrima, has the capacity to regenerate its internal organs. Intestinal regeneration is accomplished by the thickening of the mesenteric border and the invasion of this thickening by mucosal epithelium from the esophagus and the cloaca. Extracellular matrix (ECM) remodeling has been associated with morphogenetic events during embryonic development and regeneration. We have used immunohistochemical techniques against ECM components to show that differential changes occur in the ECM during early regeneration. Labeling of fibrous collagenous components and muscle-related laminin disappear from the regenerating intestine and mesentery, while fibronectin labeling and 4G7 (an echinoderm ECM component) are continuously present. Western blots confirm a decrease in fibrous collagen content during the first 2 weeks of regeneration. We have also identified five 1,10-phenanthroline-sensitive bands in collagen gelatin zymographs. The gelatinolytic activities of these bands are enhanced during early stages of regeneration, suggesting that the metalloprotease activity is associated with ECM remodeling. Inhibition of MMPs in vivo with 1,10-phenanthroline, p-aminobenzoyl-Gly-Pro-D-Leu-D-Ala hydroxamate or N-CBZ-Pro-Leu-Gly hydroxamate produces a reversible inhibition of intestinal regeneration and ECM remodeling. Our results show that significant changes in ECM content occur during intestine regeneration in the sea cucumber and that the onset of these changes is correlated to the proteolytic activities of MMPs.

Animals↗
PubMed1993

Spinal cord transplants support the regeneration of axotomized neurons after spinal cord lesions at birth: a quantitative double-labeling study.

After spinal cord lesions in newborn rats, transplants of fetal spinal cord tissue rescue immature axotomized neurons, support the growth of axons into and through the site of injury and prolong the critical period for developmental plasticity. Both late-developing (uninjured) and regenerating axons contribute to this transplant-induced anatomical plasticity. After lesions in the mature CNS, transplant-induced axonal elongation is spatially restricted. The current study was designed (1) to determine the magnitude of transplant-induced regeneration, (2) to test the hypothesis that the long distance growth beyond the site of injury is mediated by late-developing axonal pathways, whereas axonal elongation by regenerating pathways is spatially restricted as it is in the adult, and (3) to determine if particular nuclei have a greater inherent capacity for regeneration than others. We used temporally spaced retrograde tracing with the fluorescent dyes fast blue and diamidino yellow to address this issue. Fast blue was placed into the site of a spinal cord overhemisection in rat pups < 48 h old to label those neurons which were axotomized by a neonatal lesion. The tracer was removed and a transplant of Embryonic Day 14 fetal spinal cord tissue was placed into the lesion site. Three to six weeks later a second tracer (diamidino yellow) was injected bilaterally into the host spinal cord caudal to the transplant. We counted the number of double-labeled (regenerated), single diamidino yellow-labeled (late-growing), and single fast blue-labeled (nonbridging) neurons in the cortex, red nucleus, raphe nuclei, and locus coeruleus. By systematically varying the distance of the diamidino yellow injection site caudal to the transplant, we were able to compare the distance which injured axons regenerate with the distance that late-growing axons extend. When the diamidino yellow injection was placed within 5 mm caudal to the transplant 28% of the axotomized neurons in the red nucleus, 32% of the axotomized neurons in the locus coeruleus, and 37% of the axotomized neurons in the raphe nuclei were double-labeled (regenerating). Although the percentage of double-labeled neurons decreased as the distance beyond the transplant increased, a substantial population of regenerating neurons was identified in each of the brain stem nuclei examined following diamidino yellow injections up to 15 mm caudal to the transplant. Thus, after spinal cord lesions and transplants at birth, both regenerating neurons and late-developing neurons extended axons long distances (up to 15 m) caudal to the lesion site. The capacity for regenerative growth was similar in each of the nuclei examined.

Amidines↗
PubMed1993

Time course of dorsal root axon regeneration into transplants of fetal spinal cord: an electron microscopic study.

Intraspinal transplants of fetal CNS tissue permit or enhance the regeneration of cut central axons of adult dorsal root ganglion (DRG) neurons. Some of these regenerated axons establish synapses with transplant neurons. The aims of the present study were to determine when regenerated DRG axons begin to form synapses with transplanted embryonic spinal cord neurons and whether these synapses are permanent. We also examined the development of transplant neuropil in areas innervated by the regenerated axons. Whole pieces of Embryonic Day 14 spinal cord were introduced into hemisection cavities made at the level of the lumbar enlargement, and the cut L4 or L5 dorsal root was juxtaposed to the transplant. Regenerated DRG axons immunoreactive for calcitonin gene-related peptide (CGRP) were labeled by immunohistochemical methods and examined by electron microscopy from 1 week to 1 year after surgery. CGRP-immunoreactive axon terminals made synaptic contacts with dendrites and perikarya of transplant neurons by 1 week after axotomy. The morphology of the synapses was immature. Large growth cone-like structures were also present at 1 week but not at 2 weeks or later. At 2 weeks, regenerated unmyelinated axons formed terminals similar to those found in animals surviving for 48 weeks. Axoaxonic synapses in which the pre- and postsynaptic elements were immunolabeled for CGRP and regenerated CGRP-labeled myelinated axons were observed at 4 weeks and later. The area of distribution of CGRP staining increased until 12 weeks and the synaptic density of regenerated CGRP-labeled terminals increased for 24 weeks. The results indicate that the synaptic terminals of regenerated primary afferent axons are permanently retained within fetal spinal cord transplants. Transplants may therefore contribute to the permanent restoration of interrupted neural circuits.

Animals↗