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ABSTRACT: —Intact and dissociated dorsal root ganglia from 8-day chick embryos were examined for their ability to incorporate radio-precursors into RNA and protein in unsupplemented medium or in medium supplemented with Nerve Growth Factor, insulin, Concanavalin A, fetal calf serum, or several combinations of such agents. In the absence of any agent, incorporation into RNA and protein declined with time. All four agents maintained or improved the initial incorporation rates, and optimal doses were determined in each case. Different combinations of two agents led to potentiated, full or partially additive, or inhibited effects; in particular, NGF promoted incorporation even in conjunction with insulin (additive) or serum (potentiating). Several differences were noted between the responses of intact and of dissociated ganglia.
Journal of Neurochemistry 10/2006; 23(4):689 - 695. · 4.06 Impact Factor
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ABSTRACT: Previous studies have demonstrated that partial cortical devascularization results in increased levels of nerve growth factor protein within the tissue immediately surrounding the infarcted region. In the present study, we have used this lesion model to further characterize the nerve growth factor increase by investigating: (i) the time course for this phenomenon; (ii) the impact of the devascularizing lesion on cortical regions not directly impinged upon by the lesion; and (iii) the response of nerve growth factor-sensitive nucleus basalis neurons providing afferent cortical innervation to the increased availability of nerve growth factor within their target territory. Our results indicate that, within the infarcted cortex, nerve growth factor levels increase rapidly following the lesion (up 51% by one day post lesion), reach a maximum of 136% above controls by three days and undergo a slow decline back to baseline levels by 23 days. Within the frontal and cingulate cortices, which are not devascularized by the lesion and show no signs of pathological damage, nerve growth factor levels increase over a similar time course, and with a similar magnitude, to those in the lesioned cortex. Nerve growth factor-sensitive nucleus basalis neurons on the side ipsilateral to the lesion respond to increased cortical nerve growth factor levels with an increased accumulation of nerve growth factor within their cell bodies (revealed by nerve growth factor immunohistochemistry and quantitative enzyme-linked immunosorbent assay) which was apparent at three days following the lesion, but no longer discernible at seven or 14 days or later. The present study investigated a model of cortical devascularization for its ability to alter nerve growth factor levels within the cortex. Nerve growth factor levels were rapidly increased within the infarcted cortical tissue beneath the lesion but were also elevated to a similar extent, and with a similar time course, in cortical regions not directly impinged upon by the lesion. The retrograde impact of elevated cortical nerve growth factor levels was demonstrated by an increased accumulation of nerve growth factor within the cell bodies of nucleus basalis neurons providing innervation to the cortex. This lesion model should provide a potential avenue for investigating the functional role(s) of nerve growth factor in the intact and lesioned adult central nervous system, as well as the internal mechanisms for regulating its synthesis, release, uptake, and degradation.
Neuroscience 04/1998; 83(4):1003-11. · 3.38 Impact Factor
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ABSTRACT: Nerve growth factor (NGF) was recently found to be largely associated with sedimentable fractions of adult rat brain and treatments of the fractions by alkaline pH increased the measurable amount of their NGF antigen as well as its solubilization [M.C. Hoener, E. Hewitt, J.M. Conner, J.W. Costello and S. Varon, Nerve growth factor (NGF) content in adult rat brain tissues is several-fold higher than generally reported and is largely associated with sedimentable fractions, Brain Res., 728 (1996) 47-56; M.C. Hoener and S. Varon, Effects of sodium chloride, Triton X-100, and alkaline pH on the measurable contents and sedimentability of the nerve growth factor (NGF) antigen in adult rat hippocampal tissue extracts, J. Neurosci. Res., in press (1997); C. Zettler, D.C.McL. Bridges, X.-F. Zhou and R.A. Rush, Detection of increased tissue concentrations of nerve growth factor with improved extraction procedure, J. Neurosci. Res., 46 (1996) 581-594]. We have further investigated the reversibility of these pH effects. Reversal of the pH of an adult rat hippocampal tissue extract from 10.5 to 7.4 led to an almost complete transfer of NGF back from nonsedimentable to sedimentable fractions and to a remasking of the previously unmasked portion of NGF antigen. Thus, molecules causing masking and sedimentation of NGF at pH 7.4 were likely to be present in the alkaline extract. A gel filtration column in PBS, pH 10.5 was used to separate such putative binding molecules from the NGF. All of the NGF antigen from rat hippocampal alkaline extract was found to elute with 19 kDa fractions. The same apparent molecular weight was found for mouse submaxillary beta-NGF and recombinant human beta-NGF. Masking and sedimentation no longer occurred when newly generated 19 kDa rat brain NGF was returned to pH 7.4. When high molecular weight fractions derived from the same gel filtration (in PBS, pH 10.5) were added back to the 19 kDa NGF pool at pH 7.4 and the mixture incubated and centrifuged, the measurability of 19 kDa rat brain NGF antigen was markedly reduced and half of the antigen was recovered in sedimentable fractions. Similar but less dramatic results were obtained when mixing the same high molecular weight fractions with 19 kDa mouse or human beta-NGF. These findings provide new opportunities to identify molecules to which NGF may be bound within intact brain tissues.
Brain Research 11/1997; 772(1-2):1-8. · 2.73 Impact Factor
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ABSTRACT: Previous studies revealed that NGF-like immunoreactivity is present in cells from the adult rat anterior pituitary lobe, both in vivo and in vitro, and that in both situations NGF colocalizes with the thyroid-stimulating hormone (TSH). More recently, brain-derived neurotrophic factor (BDNF) was similarly found to occur in the anterior pituitary tissue, again with a general colocalization with TSH. In the present study, we have extended the use of adult rat anterior pituitary cultures to show their content of BDNF-immunoreactive cells and their main colocalization with TSH. We have also explored the question of whether neurotrophins nerve growth factor (NGF) and/or BDNF are actually produced within anterior pituitary cells. Use of the sensitive method reverse transcription-polymerase chain reaction (RT-PCR) has allowed us to confirm the presence of NGF and BDNF mRNAs in the cell suspension freshly derived from adult anterior pituitary. In situ hybridization techniques applied to the cell cultures from such a suspension, however, have revealed only a variable presence of NGF mRNA-positive cells but no recognizable BDNF mRNA. Thus, the question of whether the two neurotrophins are produced within the very cells whose immunoreactive content can be recognized remains an open one.
Journal of Neuroscience Research 09/1997; 49(3):355-63. · 2.74 Impact Factor
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ABSTRACT: Nerve growth factor (NGF) was found to be largely associated with sedimentable fractions of hippocampal and other neural tissues of the adult rat (Hoener et al.: Brain Res 728:47-56, 1996), verified by both bioassay and ELISA techniques. In the present study, the ELISA assay conditions were improved and simplified. Bovine serum albumin was needed in the phosphate buffered saline for maximal measurability of NGF antigen. Hippocampal tissue sonicates were separated into nonsedimentable supernatant and sedimentable pellet fractions. Individual or combined treatments with sodium chloride, Triton X-100, and pH were applied to the samples for possible effects on the i) measurable content of NGF antigen and ii) distribution of sedimentable and nonsedimentable forms. The amount of measurable NGF antigen was found to be increased in a dose dependent fashion by sodium chloride between 0.15 and 0.35 M, Triton X-100 between 0 and 0.5%, and pH between 8.5 and 10.5. The same treatment that led to maximal measurable NGF levels (0.7% Triton X-100 and pH 10.5) also caused the release of the NGF antigen from sedimentable to nonsedimentable fractions. Similar findings regarding maximal NGF antigen levels and release were seen for treatments applied to the sonicate before separation into a supernatant and pellet fraction.
Journal of Neuroscience Research 09/1997; 49(4):508-14. · 2.74 Impact Factor
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ABSTRACT: We have used enriched dissociated, low density cultures of neonatal rat corticospinal motor neurons to evaluate the survival-promoting effect of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and glial cell line-derived neurotrophic factor (GDNF) and the ciliary neurotrophic factor (CNTF). Our current findings demonstrated that CNTF promoted the survival of corticospinal motor neurons, in the same fashion and at an equivalent potency, as was previously described using a different assay system. Among the other factors tested, we also found that NT-4 and GDNF increased the number of surviving neurons in a dose-dependent manner, whereas NGF, BDNF and NT-3 showed no survival promoting effect on corticospinal motor neurons.
Brain Research 08/1997; 762(1-2):56-60. · 2.73 Impact Factor
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ABSTRACT: In the current investigation, we have examined the developmental profile of nerve growth factor immunoreactivity (NGF-ir) in the postnatal rat. During the first 3 weeks after birth, NGF-ir was observed within the hippocampal mossy fiber region, where it persists throughout adulthood and appeared transiently within three additional zones-the dentate gyrus supragranular zone, the tenia tecta/intermediate lateral septum, and the cingulate/retrosplenial cortex. In all cases, the appearance of NGF-ir progressed in a rostrocaudal pattern over time. A strong correlation was seen between the pattern of NGF-ir and cholinergic innervation in the dentate gyrus supragranular zone, both spatially and temporally, suggesting that NGF may direct the innervation of cholinergic afferents to this region. A spatial correlation was also observed between NGF-ir and cholinergic innervation within the retrosplenial cortex and tenia tecta. With our current techniques, however, we were unable to determine at what point during development the adult-like pattern of cholinergic terminal innervation in these regions occurred and, thus, were not able establish a temporal correlation in these regions. Within the cingulate cortex, there was no evidence suggesting that the developmental appearance of NGF-ir in this region was associated with a specific enhancement of cholinergic innervation. Thus, the results of the current investigation clearly identify the presence of transiently occurring zones of NGF-ir during postnatal CNS development, although defining their exact functional role will require additional investigation.
Developmental Brain Research 08/1997; 101(1-2):67-79. · 1.78 Impact Factor
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ABSTRACT: Cyclized peptides corresponding to beta-loop regions of NGF were purified by HPLC and assayed for neurotrophic activity using DRG neurons. Peptides with the highest activity corresponded to loop region 29-35, a domain likely to interact with the p75 receptor. Unexpectedly, activity was confined to late-eluting HPLC fractions containing peptide multimers and primarily promoted neuronal survival without neurite outgrowth. Directed synthesis of dimer and monomer cyclized peptides demonstrated that dimers acted as partial NGF agonists in that they had both survival-promoting and NGF-inhibiting activity while monomer and linear peptides were inactive. Dimer activity was not affected by the Trk inhibitor K252a but was blocked by p75 receptor antibody and absent using p75 null mutant neurons. These studies suggest that region 29-35 peptide derivatives inhibit neuronal death via a structure- and p75-dependent mechanism.
Journal of Neuroscience Research 05/1997; 48(1):1-17. · 2.74 Impact Factor
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ABSTRACT: A sensitive immunohistochemical technique was used, along with highly specific affinity-purified antibodies to brain-derived neurotrophic factor (BDNF), to generate a detailed mapping of BDNF immunoreactivity (BDNF-ir) throughout the adult rat CNS. A parallel analysis of sites of BDNF synthesis was performed with in situ hybridization techniques using a cRNA probe to the exon encoding mature rat BDNF protein. These combined data revealed (1) groups of cell bodies containing diffuse BDNF-ir throughout the CNS that were strongly correlated with fields of cells containing BDNF mRNA; (2) varying degrees of BDNF-ir outside of cell bodies, in what appeared to be fibers and/or terminals; and (3) many regions containing extremely heavy BDNF-immunoreactive fiber/terminal labeling that lacked BDNF mRNA (e.g., medial habenula, central nucleus of the amygdala, bed nucleus of stria terminalis, lateral septum, and spinal cord). The latter observation suggested that in these regions BDNF was derived from anterograde axonal transport by afferent systems. In the two cases in which this hypothesis was tested by the elimination of select afferents, BDNF immunostaining was completely eliminated. These data, along with the observation that BDNF-ir was rarely found within dendrites or fibers en passage, suggest that BDNF protein produced in adult CNS neurons is polarized primarily along axonal processes and is preferentially stored in terminals within the innervation target.
Journal of Neuroscience 05/1997; 17(7):2295-313. · 7.11 Impact Factor
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ABSTRACT: Previous studies in adult rats have demonstrated that the neurotrophin, brain-derived neurotrophic factor (BDNF), is present in virtually all cells of the pituitary intermediate lobe. In the present study, we demonstrate that cells cultured from adult intermediate lobe pituitary (ILP) rapidly lose their BDNF immunoreactivity (IR). Furthermore, a similar loss of immunostaining occurs in whole (undissociated) ILP within 30 min after removal from the rat. However, when the dopamine agonist apomorphine is present throughout the dissociation procedure and during cultivation, BDNF-IR is preserved. Supplying apomorphine only during either dissociation or cultivation did not prevent the loss of BDNF-IR in the 24 h cultures. These results suggest that a tonic dopaminergic stimulus is required to maintain BDNF-IR in ILP cells.
Neuroreport 04/1997; 8(5):1089-93. · 1.66 Impact Factor
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ABSTRACT: Nerve growth factor (NGF) has been postulated to play an important role in the process of sympathetic sprouting into the septally deafferented hippocampal formation. In the current investigation we have used transplants of NGF-dependent neonatal superior cervical ganglion (SCG) neurons to investigate the influence of NGF and septal denervation (either alone or in combination with one another) upon neuronal survival and intrahippocampal sprouting. In the current model, SCG transplants were placed onto the dorsal surface of the CA1 hippocampal subfield and a continuous infusion device was used to deliver either NGF or vehicle into the hippocampal parenchyma. Following 15 days of vehicle infusion, little or no sympathetic neuronal survival was observed and no hippocampal fiber outgrowth was detected. NGF infusions, however, promoted both neuronal survival and intrahippocampal fiber outgrowth directed mainly toward the location of the infusion cannula. Septal denervation, achieved by either a septal ablation or fimbria-fornix transection, had no discernible impact upon SCG neuronal survival or fiber outgrowth, with or without NGF infusions. Similar results were also obtained when SCG were transplanted directly within the cortex, with or without an intracortical infusion. It appears, therefore, that NGF may be a sufficient, as well as necessary, component for eliciting and guiding the invasion of a tissue by NGF-sensitive fibers.
Experimental Neurology 11/1996; 141(2):310-7. · 4.70 Impact Factor
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ABSTRACT: Immunohistochemical techniques were used to determine the distribution of brain-derived neurotrophic factor (BDNF) in the adult rat pituitary gland. In the posterior lobe, BDNF staining was found only within fibers. Within the intermediate lobe, nearly all cells were labeled intensely for BDNF. In the anterior lobe, varying degrees of BDNF immunoreactivity were observed exclusively in cells shown by double-labeling techniques to contain thyroid stimulating hormone (TSH), although not all TSH-positive cells contained detectable BDNF labeling. These results are consistent with and extend information from previous studies demonstrating BDNF expression in the pituitary gland and further support the idea that this neurotrophin plays a role in endocrine function.
Neuroreport 09/1996; 7(12):1937-40. · 1.66 Impact Factor
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ABSTRACT: Initial studies had revealed that the bioactivity of nerve growth factor (NGF) in sonicates of adult rat hippocampal formation (HF) is several-fold greater in their pellet than their supernatant fractions. Such observations have prompted an analysis of NGF antigen (NGF-Ag) contents in pellets and supernatants from a variety of adult rat CNS tissues, both in the absence and the presence of exogenous beta-NGF. With HF tissues, NGF-Ag in the supernatants was comparable to most literature values, but pellet NGF-Ag was 3 to 5 times that amount. All other CNS tissue sonicates also revealed 3-6 fold higher NGF-Ag in their pellets than their supernatants, hence overall NGF-Ag contents were greatly in excess of reported ones. Presentation of mouse beta-NGF to a tissue, its sonicate, or its standard pellet resulted in a transfer to the final pellet of 30-50% of the added soluble NGF-Ag (and 30% of the added bioactivity). This percentage is much lower than that present in native pellets (80%), suggesting that the association of endogenous NGF with particulate matter may involve at least two compartments. Treatments of pellets with salt, alkaline pH, and/or the detergent Triton X-100 have revealed a third subset, namely additional pellet NGF-Ag that was not initially recognized by the antibody in our ELISA assay. The treatments also caused substantial release of NGF from pellet to supernatant. Further studies should clarify the nature of the association between NGF and the three subsets of pellet NGF and allow the investigation of the pellet molecules responsible for it.
Brain Research 08/1996; 728(1):47-56. · 2.73 Impact Factor
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ABSTRACT: The sprouting of peripheral sympathetic fibers into the septally denervated hippocampal formation is a well-characterized model of lesion-induced plasticity. While various studies have demonstrated the importance of nerve growth factor for evoking sympathetic sprouting, little is known concerning whether nerve growth factor continues to be required for maintaining innervation once it has occurred. In the present study we have addressed this point by (i) investigating the consequences of withdrawing exogenous nerve growth factor support from rats in which sympathetic innervation was enhanced by a nerve growth factor infusion and (ii) using blocking antibodies to interfere with the actions of endogenous nerve growth factor. The results of this investigation clearly indicate that a continuous supply of nerve growth factor (either exogenous or endogenous) is required to maintain sympathetic innervation within the hippocampal formation. Evidence is also provided demonstrating that the nerve growth factor must be made available locally within a given region to evoke and maintain the sympathetic innervation within this location. Axonal rearrangement within the developing and adult brain is believed to be an important mechanism underlying learning and memory is crucial for lesion-related plasticity. In various experimental paradigms, nerve growth factor has been shown to be an important cue for initiating axonal remodeling. In the current study, we have demonstrated that once such rearrangements have taken place, nerve growth factor may also be required to maintain them.
Neuroscience 07/1996; 72(4):933-45. · 3.38 Impact Factor
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ABSTRACT: The neurotrophin family of growth factors consists of proteins sharing a sizable degree of amino acid sequence and structural homology. These similarities greatly increase the probability that antibodies directed against any single neurotrophin may cross-react with other family-members. Various investigators have documented such cross-reactivity can occur under experimental conditions, although the extent of cross-reactivity reported in different studies has varied greatly. Although the use of different antibody preparations may have contributed to the differing degrees of cross-reactivity observed, it is important to note that different assay conditions were also used to evaluate cross-reactivity in the various studies. Little information is currently known about how antibody-antigen interactions vary as a function of the assay conditions used for the evaluation. The present study addressed this question by evaluating the cross-reactivity occurring between various neurotrophins and a single preparation of antibodies directed against purified mouse nerve growth factor-beta (beta-NGF) in a wide variety of immunological assay systems. Our results indicate that cross-reactivity between NGF antibodies and related neurotrophins can vary greatly depending upon the assay system chosen for the evaluation. These data strongly argue against transferring cross-reactivity data across various assay systems.
Journal of Neuroscience Methods 04/1996; 65(1):93-9. · 1.98 Impact Factor
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ABSTRACT: Following septal denervation of the hippocampal formation, sympathetic fibers from a transplanted superior cervical ganglion will innervate hippocampal tissue in a topographically restricted manner. Previously, we have shown a strong correlation between the regions innervated by the sprouting sympathetic axons and the distribution of NGF immunoreactivity in the hippocampal formation, suggesting that a restricted availability of NGF trophic support may regulate the topography of innervation by the NGF-sensitive sympathetic fibers. It was possible, however, that other molecular cues were responsible for restricting neurite outgrowth to selected hippocampal regions. In the current investigation, this idea was explored by experimentally altering the distribution of hippocampal NGF using a continuous intraparenchymal infusion device. Our results indicate that some hippocampal regions, not innervated by sympathetic fibers in control animals, do become occupied when the necessary trophic factor is provided, suggesting that these regions already contained an appropriate substratum for sympathetic neurite outgrowth but lacked the necessary trophic stimulus. Other regions, however, did not become innervated even though infused NGF was verifiably present in them. Together, these findings propose that a spatial restriction of NGF may be a crucial molecular mechanism for controlling the distribution of sprouting NGF-sensitive sympathetic fibers but that other endogenous signals may regulate NGF's ability to stimulate local terminal sprouting. The data are also consistent with the idea that a limited availability of endogenous NGF is regulating both the density of sympathetic innervation into the hippocampal formation and the extent of neuronal survival within the transplanted ganglion.
Experimental Neurology 01/1996; 136(2):123-35. · 4.70 Impact Factor
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ABSTRACT: Little is known about the neurotrophic factors that may regulate maintenance, growth, and/or repair of corticospinal motor neurons (CSMN) in the developing or the adult mammal. We have developed an adult rat in vivo model of CSMN injury involving (i) bilateral prelabeling of CSMN with a cervical spinal cord injection of cholera toxin B subunit (CTB), (ii) unilateral axotomy close to the cell bodies by an intracortical lesion between cell layer V and the corpus callosum, and (iii) implantation of a continuous infusion device in the cortical parenchyma near the lesion. Two weeks later, coronal sections of the cortex are immunostained for CTB, and CTB-stained neurons are counted over defined section areas and compared to those on the contralateral (nonlesioned, noninfused) side. CTB-stainable neurons were 30-40% of the control side when the lesion was about 200 microns from the deeper face of the cell layer, and survival increased with increasing lesion depths. The model can be used to assess protective effects of potential CSMN trophic factors. The low survival achieved with the more superficial lesions (200 and 300 microns) was markedly improved by continuous infusion of ciliary neurotrophic factor at 0.1 to 1.0 microgram/day.
Experimental Neurology 10/1995; 135(1):67-73. · 4.70 Impact Factor
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ABSTRACT: Nerve growth factor (NGF) has been well-characterized with respect to its role as a trophic agent for various peripheral nervous system (PNS) and central nervous system (CNS) neuronal populations. Recent evidence indicates that NGF may also play a functional role in endocrine systems, although investigations in this field are only beginning to define sites of action and molecular mechanisms involved in NGF-endocrine interactions. A potential site for such an interaction to occur is within the pituitary. Previous investigations have demonstrated the presence of NGF and NGF receptors in the pituitary and our group has recently reported the presence of NGF-like immunoreactivity exclusively within the thyrotrophic cells of the anterior pituitary of the adult rat. Since many questions regarding how NGF interacts in the anterior pituitary will be more efficiently addressed using an in vitro system, it was necessary to first determine if cultured adult anterior pituitary cells retain the NGF-like staining and unique association of NGF with thyroid-stimulating hormone-producing cells seen in vivo. Results of the present investigation confirm that cultured anterior pituitary cells retain the characteristics previously observed in vivo and further demonstrate the stability of these cells and their specific NGF and pituitary hormone contents in culture for as long as 6 days.
Journal of Neuroscience Research 06/1995; 41(1):73-8. · 2.74 Impact Factor
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ABSTRACT: In the present study, the authors reevaluated the temporal course and properties of neurotrophic activities present in the fluid accumulating in the silicone-chamber model for nerve regeneration. The fluid collected from silicone chambers was tested in four different dissociated neuronal cell cultures. Furthermore, the activity of the chamber fluid was examined, using a cell blot technique. There was one major peak of neurotrophic activity and this activity peaked early, about 3 to 6 hr after nerve injury. Results also indicate that the chamber fluid contains at least two types of neurotrophic activities, namely nerve growth factor and ciliary neurotrophic factor.
Journal of Reconstructive Microsurgery 06/1995; 11(3):231-5. · 1.43 Impact Factor
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ABSTRACT: Following cholinergic denervation of the hippocampal formation, peripheral sympathetic fibers from the superior cervical ganglion (SCG) sprout into hippocampal tissue. The molecular mechanism controlling this process is unknown, although a role by trophic factors seems likely. In the present study, neonatal SCG were used as biological probes to investigate the association between NGF-immunoreactive regions in the hippocampal formation and areas innervated by regrowing sympathetic fibers. Cholinergic deafferentation of the hippocampal formation was achieved by a fimbria-fornix transection and neonatal SCG were placed into the lesion cavity, abutting the rostral pole of the hippocampus. At 16 days following ganglia transplantation, NGF immunoreactivity within the hippocampal formation appeared indistinguishable from unlesioned controls and was localized within the mossy fiber region of the dentate gyrus and CA3 and CA2 hippocampal subfields. Sympathetic innervation, revealed in adjacent sections by dopamine beta-hydroxylase or p75LNGFR immunoreactivity, was also restricted primarily to the mossy fiber region. Ablation of the entorhinal cortex at the time of transplantation resulted in the appearance of an additional discrete band of NGF immunoreactivity within the outer molecular layer of the dentate gyrus. In animals receiving an entorhinal lesion concurrent with the SCG transplant, sympathetic fibers were observed not only within the mossy fiber region but also within the outer molecular layer of the dentate gyrus where the lesion-induced NGF immunoreactivity appeared. These results support the hypothesis that topographic distributions of NGF may be used in the hippocampal formation to define terminal fields for sprouting NGF-sensitive neuronal populations.
Experimental Neurology 12/1994; 130(1):15-23. · 4.70 Impact Factor
