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J M Conner

Publications and source records attributed to J M Conner.

31 records · Page 2Linked to original sources
PubMed1995

Effects of exogenous nerve growth factor upon sympathetic sprouting into the hippocampal formation.

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.

Animals↗
PubMed1995

NGF modulates sympathetic innervation of lymphoid tissues.

Immune tissues are known to be innervated by the sympathetic nervous system, but little is known of what directs the innervation to specific tissue compartments. This report examines the sympathetic innervation of immune tissues in transgenic mice that overexpress nerve growth factor (NGF) in skin and other epithelial structures. NGF transgenic mice exhibited dramatic hyperinnervation in the splenic marginal zone, and the medulla and capsule of peripheral lymph nodes. In contrast, the transgenic mesenteric lymph nodes showed no hyperinnervation. This difference correlated with the location of these nodes; peripheral lymph nodes drain skin where the transgene was expressed while mesenteric lymph nodes drain non-transgene-expressing structures. In addition, the level of innervation correlated with the level of NGF peptide content as assayed by ELISA (3- and 13-fold increase in transgenic spleen and axillary lymph nodes, respectively; no increase in mesenteric nodes) and immunocytochemistry. RT-PCR showed that the NGF transgene was not being expressed in the immune tissues, suggesting that immune tissues can concentrate transgene-produced NGF. It was also demonstrated that the change in innervation had functional consequences. The mitogen response to concanavalin A (ConA) by spleen cells was decreased in the transgenics suggesting that elevated catecholamines or NGF can modulate the proliferative response of these cells. These mice demonstrate that NGF can modulate the sympathetic innervation and function of the immune system.

Animals↗
PubMed1994

Changes in nerve growth factor immunoreactivity following entorhinal cortex lesions: possible molecular mechanism regulating cholinergic sprouting.

To assess the possible role of trophic factors in lesion-induced plasticity, we have used a sensitive immunohistochemical technique to evaluate changes in nerve growth factor (NGF) staining in the hippocampal formation 3, 8, 16, and 30 days following entorhinal cortex lesions. Our results indicate that a band of NGF immunoreactivity appears in the outer molecular layer of the ipsilateral dentate gyrus following entorhinal ablation. The distribution of the NGF-immunoreactive band exactly coincides with the distribution of sprouting cholinergic terminals revealed by acetylcholinesterase histochemistry or NGF-receptor immunostaining. Increased NGF-immunoreactivity is detectable at 3 days postlesion, is most intense at 8 days, and decreases to near control levels by 30 days. Lesion-induced increases in NGF immunostaining also occur in animals in which septohippocampal fibers had been removed by prior destruction of the fimbria-fornix. Increases in NGF-immunoreactivity, however, are substantially reduced in animals receiving intraventricular injections of colchicine, which presumably blocks NGF release. These results indicate that 1) increases in NGF immunostaining, which occur following entorhinal lesions, precede any changes in cholinergic sprouting parameters and are greatest during the period of maximal cholinergic sprouting; 2) increased NGF-immunoreactivity is not due to NGF binding by septohippocampal fibers; and 3) increased NGF-immunoreactivity appears to depend on the release of NGF by neurons that produce it. We hypothesize that, following entorhinal lesions, NGF immunostaining within the hippocampal formation may represent NGF "anchored" within the tissue and that NGF accumulation by such a mechanism may direct the sprouting response of NGF-sensitive cholinergic neurons.

Acetylcholinesterase↗
PubMed1994

Nerve growth factor-like immunoreactive profiles in the primate basal forebrain and hippocampal formation.

The distribution of nerve growth factor (NGF), the prototypic neurotropin, within the basal forebrain and hippocampal formation of young adult monkeys and aged humans was characterized with an affinity purified polyclonal beta-NGF antibody raised against mouse beta-NGF. In the basal forebrain of both primates, a granular NGF-like immunoreactive (ir) reaction product was observed within neurons of the medial septum, nucleus of the diagonal band, and nucleus basalis of Meynert. NGF-like immunoreactivity exclusively colocalized within p75 NGF receptor (NGFR) containing basal forebrain neurons. The intensity of NGF immunolabeling varied between cell bodies. Many NGF-ir perikarya were highly immunoreactive. In other basal forebrain neurons, NGF-like immunoreactivity was either undetectable or minimally expressed. In the hippocampus of both species, NGF-like immunoreactivity was mainly localized within the hilus of the dentate gyrus and within CA3 and CA2 hippocampal subfields. A marked diminution in NGF-like staining was seen in CA1. Within the hippocampal formation, NGF-like immunoreactivity was heaviest within the neuropil of stratum radiatum, intermediate in stratum oriens, and lightest in stratum pyramidal. NGF-like immunoreactivity was not found within the granule or pyramidal cells of the dentate gyrus and hippocampal formation, respectively. These findings demonstrate the presence of an NGF-like antigen in association with monkey and human magnocellular basal forebrain neurons and within their hippocampal target sites. This lends support to the hypothesis that NGF is internalized from sources located within target regions of the primate cholinergic basal forebrain neurons and is retrogradely transported to these cell bodies where the NGF trophic effect likely occurs.

Animals↗
PubMed1994

Nerve growth factor influences the distribution of sympathetic sprouting into the hippocampal formation by implanted superior cervical ganglia.

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.

Animals↗
PubMed1994

Nerve growth factor in CNS repair.

The hypothesis that neurotrophic factors play important roles in the adult central nervous system (CNS) has been successfully investigated in the past decade with regard to experimental and pathologic situations. Trophic roles in adult CNS axonal regeneration, on the other hand, have received much less attention. We review three groups of recent studies that demonstrate the relevance of nerve growth factor (NGF) for the regeneration of selected axons into adult central nervous tissue. The first group concerns a septohippocampal model where transected septal cholinergic axons are allowed to regrow into the hippocampal formation through a peripheral nerve bridge implanted into the transection lesion gap. NGF is required in the bridge, enhances penetration of the hippocampal tissue when infused there, and both attracts and promotes sprouting within the septum when infused in the lateral ventricle or the septal tissue itself. The second group of studies concerns the development of a spinal cord sensory regeneration model, where dorsal root ganglionic axons regrow into a nerve bridge placed within the dorsal spinal cord. Preliminary data indicate that NGF infusion rostral to the bridge once again promotes substantial penetration of the adult cord tissue by the regenerating NGF-sensitive fibers. In the third group of studies, attention has been shifted to the location of endogenous NGF in the adult rat hippocampal formation and the normal or lesion-induced occurrence of extrasomal NGF immunoreactivity. These regions of anchored NGF have the ability to attract NGF-sensitive growing axons and may provide opportunities to investigate local cues for final definition of terminal fields.

Animals↗
PubMed1993

Nerve growth factor immunoreactivity in the anterior pituitary of the rat.

Nerve growth factor (NGF) has long been recognized for its neurotrophic actions upon sensory and sympathetic neurons of the PNS and upon cholinergic neurons of the CNS basal forebrain. Much evidence, however, suggests that potential reciprocal interactions between NGF and various endocrine systems may also occur. In the present investigation we used immunohistochemical techniques to investigate whether NGF is found within the adult rat pituitary, thereby suggesting a possible interaction within this critical neuroendocrine gland. Our results indicate that NGF immunoreactivity is present only within the anterior lobe of the male and female rat pituitary and is exclusively localized within cells immunoreactive for thyroid stimulating hormone (TSH).

Animals↗
PubMed1992

Distribution of nerve growth factor-like immunoreactive neurons in the adult rat brain following colchicine treatment.

Using immunohistochemical techniques, we have previously localized nerve growth factor (NGF)-like immunoreactivity in the normal adult rat central nervous system (CNS) exclusively in the hippocampal mossy fiber region and within basal forebrain cholinergic neurons--a cell population believed to be primary NGF consumers within the CNS. In the present investigation, we have attempted to identify potential producers of NGF by pretreating animals with colchicine. Such a treatment would be expected to block microtubule-assisted neuritic transport mechanisms, thus preventing the accumulation of antigens normally obtained by retrograde transport and forcing the accumulation of cell products normally exported anterogradely. Forty-eight hours after colchicine administration within their innervation territories, basal forebrain cholinergic neurons showed a marked loss of NGF-like immunoreactivity. Conversely, following colchicine treatment, many new populations of NGF-like immunoreactive cells were detected, several of which have been previously observed with in situ hybridization techniques for NGF mRNA. Many NGF-like immunoreactive populations, however, were not previously recognized by in situ hybridization methods, including cells of the striatum, reticular thalamic nucleus, paraventricular hypothalamic nucleus, supraoptic nucleus, lateral and medial septum, substantia innominata, and nucleus basalis. Furthermore, evidence is provided that colchicine-blocked, NGF-like immunoreactive neurons within the basal forebrain are not cholinergic, thus reinforcing the hypothesis that trophic support for these NGF-dependent neurons may be derived from distant and local sources. The distinctive distribution of NGF-like immunoreactive cells observed in this study strongly correlates with the reported distribution of NGF mRNA in CNS neurons, thus suggesting that our antibodies are uniquely recognizing NGF and not other related neurotrophins.

Animals↗
PubMed1992

The localization of nerve growth factor-like immunoreactivity in the adult rat basal forebrain and hippocampal formation.

The role of nerve growth factor (NGF) as a target derived neurotrophic agent for specific cell populations in the peripheral nervous system has been well documented and much evidence suggests that NGF may serve a similar neurotrophic role in the CNS supporting the cholinergic neurons of the basal forebrain. Previous attempts to localize NGF by immunocytochemical methods, however, have not yielded evidence confirming the regional distribution expected based upon reported levels of extractable NGF. In the present study, affinity purified polyclonal antibodies to beta-NGF and a modified immunohistochemical protocol were used to demonstrate specific NGF-like immunoreactivity in the adult rat hippocampal formation and basal forebrain. In the hippocampal formation, NGF-like immunoreactivity was localized primarily within the hilus of the dentate gyrus and within stratum lucidum of the CA3 and CA2 hippocampal subfields. Staining appeared to be associated with cell processes and was similar to the reported distribution of mossy fibers suggesting that granule cells may either serve as a primary source of hippocampal NGF or that mossy fibers selectively accumulate NGF produced by other cell populations. In the basal forebrain, NGF-like immunoreactivity was localized within neuronal cell bodies of the medial septum, diagonal band, and nucleus basalis of Meynert and was further demonstrated to colocalize exclusively with LNGF-R positive neurons. These findings demonstrate the presence of an NGF-like antigen in association with cholinergic neurons of the basal forebrain and strongly support the hypothesis that NGF may serve as an endogenous trophic factor for this adult neuronal population.

Animals↗
PubMed1991

Dose-dependent responses to nerve growth factor by adult rat cholinergic medial septum and neostriatum neurons.

This study describes the relationship between the concentration of intraventricularly infused nerve growth factor (NGF) and several responses by axotomized cholinergic medial septum neurons and normal cholinergic neostriatal neurons of the adult rat. NGF infused for 14 days starting either immediately after a unilateral fimbria-fornix transection or after a 2-week delay period elicited similar dose-response relationships for the maintenance or restoration of ChAT and NGF receptor positivity and cell body size and for intraseptal 'sprouting' of the axotomized medial septum neurons. Thus, in the medial septum it appears that the expression of 'marker' molecules, cell body size and the induction of 'sprouting' are regulated by virtually the same concentrations of NGF in the two treatment strategies. This suggests that NGF has a general regulatory role and injured but untreated neurons remain fully susceptible to NGF at least up to 2 weeks after the lesion. A 14-day infusion with NGF also induced an above-normal cell body size (hypertrophy) both in axotomized medial septum and in intact striatal cholinergic neurons. The hypertrophic response of normal striatal neurons required less NGF than did that of medial septum neurons. Since the striatal response began to be detectable at a similar concentration as that required for the full maintenance or restoration of ChAT and NGF receptor positivity it could be seen as an unwanted side-effect. The definition of a sub-optimal dose with which a significant, but not maximal response can be elicited will allow future evaluations of potentially additive or synergistic actions by other agents.

Animals↗
PubMed1989

Nerve growth factor (NGF) reverses axotomy-induced decreases in choline acetyltransferase, NGF receptor and size of medial septum cholinergic neurons.

Intraventricular nerve growth factor (NGF) infusion in the adult rat can prevent and also, if delayed, reverse the disappearance of most of the axotomized medial septum cholinergic neurons immunostained for choline acetyltransferase (ChAT). We have utilized the delayed NGF treatment protocol to (i) extend to 3 months the delay time between axotomy and NGF treatment, (ii) define the time course of their recovery, (iii) determine that immunostaining for the (lower affinity) NGF receptor (NGFR) parallels loss and reversal of the ChAT marker, and (iv) evaluate changes in cholinergic somal size following axotomy and subsequent NGF treatment. While NGF treatments starting only 7 days after the fimbria-fornix transection (axotomy) almost entirely restored the number of both ChAT- and NGFR-positive medial septum neurons, longer delayed (2-3 weeks) treatment brought about recovery from the baseline of 20-25% to only about 70% of the control numbers. This limited recoverability, however, persisted even after a 95 day delay period. In all cases examined maximal recoveries were achieved within 3-7 days of NGF treatment. Neuronal size analyses provided evidence for an axotomy-induced atrophy. NGF treatments, started with 1 or 2 week delays, not only reversed fully the average somal size loss but also induced an actual hypertrophy of several of those neurons. These results provide additional evidence that at least half of the apparent loss of cholinergic medial septum neurons upon axotomy is due to a loss of markers such as the transmitter-related enzyme ChAT and NGFR rather than to actual neuronal cell death. These results also show that NGF exerts a genuine trophic influence by regulating the size of its target neurons as well as their content of several proteins.

Animals↗
PubMedDate not supplied

Artifact formation during smoke trapping: an improved method for determination of N-nitrosamines in cigarette smoke.

Studies in our laboratory revealed artifactual formation of N-nitrosamines during trapping of mainstream and sidestream tobacco smoke by the method of Hoffmann and coworkers (2, 4). Both volatile and tobacco-specific N-nitrosamines were produced. This artifact formation took place on the Cambridge filter, which is part of the collection train used in the previously published procedure. When the filter was treated with ascorbic acid before smoke collection, artifact formation was inhibited. The improved method resulting from these studies was applied to a comparative analysis of N-nitrosamines in smoke from cigarettes that heat, but do not burn, tobacco (the test cigarette) and several reference cigarettes. Concentrations of volatile and tobacco-specific N-nitrosamines in both mainstream and sidestream smoke from the test cigarette were substantially lower than in the reference cigarettes.

Antioxidants↗