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PubMed1998

Forebrain expression of c-fos due to active maternal behaviour in lactating rats.

To reveal brain sites simultaneously active during the expression of maternal behaviour in lactating rats, we used immunocytochemical visualization of the nuclear protein product Fos of the immediate-early gene c-fos as a marker of neuronal activity. After a 48 h separation from their litter, day 7 postpartum dams received a 1 h period of physical interaction with pups either capable or incapable of suckling, inaccessible pups in a wire-mesh box, an empty box, or no stimulation. Physical interaction with pups elicited high levels of pronurturant maternal behaviour (retrieval, licking, mouthing), and suckling elicited nursing behaviour as well. Exposure to the box, with or without pups, elicited high levels of investigatory sniffing, self-grooming, and general activity. Distal stimulation from pups did not differentially activate Fos in any of 20 sites, including olfactory-processing structures such as the piriform cortex and medial amygdala. Physical interaction with pups, with or without suckling, elicited higher levels of Fos-immunoreactive nuclei than that of other conditions in numerous sites, including many previously implicated in maternal behaviour (medial preoptic nucleus, nucleus accumbens, lateral septum, lateral habenula, and the bed nucleus of the stria terminalis). Similar group patterns of Fos expression also occurred in sites not previously implicated in maternal behaviour (somatosensory cortex and paraventricular thalamic nucleus). Interaction with nonsuckling pups elicited the highest levels of Fos in the cortical amygdala, whereas suckling did not activate higher Fos than nonsuckling interaction in any site included in this report, including hypothalamic nuclei involved in lactation (paraventricular, supraoptic, and arcuate). There was little or no Fos in cingulate cortex, olfactory tubercle, medial septum, medial habenula, or ventromedial hypothalamus. These data suggest that trigeminal stimuli received by lactating rats during the performance of pronurturant maternal behaviour promote cellular activity resulting in neuronal expression of c-fos in many forebrain sites including the medial preoptic nucleus, several sites connected with it that are part of the mesotelencephalic dopamine system, and in the somatosensory cortex. In contrast, in these forebrain sites suckling does not elicit greater levels of Fos than that seen in nonsuckled rats and distal stimuli from pups are ineffective in increasing Fos levels compared with non-stimulated controls.

Animals↗
PubMed1999

Differential increase in Fos immunoreactivity in hypothalamic and septal nuclei by arginine8-vasopressin and desglycinamide9-arginine8-vasopressin.

Subcutaneous or intracerebroventricular injection of either arginine8-vasopressin or desglycinamide9-arginine8-vasopressin has been shown to facilitate memory, reduce or reverse the effects of amnesic drugs, and maintain tolerance to some effects of ethanol. These actions of vasopressin (and, by inference, of desglycinamide9-arginine8-vasopressin) are mediated by vasopressin V1 receptors in brain, via a c-fos-dependent mechanism, but the receptors at which the desglycinamide analog acts have not been identified. The precise central sites are also not known, but evidence of several types suggested the anterior hypothalamus and septum as probable loci of vasopressin action. In the present work, this question was studied by immunocytochemistry, using antibodies against Fos and Fos-like proteins. The numbers of Fos-immunoreactive nuclei were counted in several related brain regions and structures, after administration of arginine8-vasopressin, des-Gly9-[Arg8]-vasopressin or saline. A subcutaneous injection of vasopressin, but not of saline, enhanced Fos expression in the paraventricular, supraoptic and suprachiasmatic nuclei of the hypothalamus, but the desglycinamide analog stimulated Fos expression only in the suprachiasmatic nucleus. Vasopressin injection significantly increased the number of Fos-immunoreactive cells in the intermediate lateral septum, medial septum, and dorsal and ventral divisions of the lateral septum. In contrast, the desglycinamide analog increased the numbers of Fos-immunoreactive cells in the dorsal and intermediate portions of the lateral septum, but caused no change in the medial septum, and a decrease in the ventral portion of the lateral septum. Increased Fos expression was also found in the subfornical organ after subcutaneous injection of either vasopressin or the desglycinamide analog. Double labeling with antibodies against Fos protein and against vasopressin revealed that most of the vasopressin-induced Fos-immunoreactive cells in the supraoptic, paraventricular and suprachiasmatic hypothalamic nuclei are also vasopressin immunoreactive, i.e. they are vasopressin-producing neurons. These findings suggest that a circuit involving V1 receptors in the subfornical organ, connecting fibres to the suprachiasmatic nucleus, and vasopressinergic projections from the suprachiasmatic nucleus to the lateral septum, may play a central role in mediating the actions of both vasopressin and its desglycinamide analog in the maintenance of ethanol tolerance.

Animals↗
PubMed1998

4-Hydroxynonenal modifies the effects of serum growth factors on the expression of the c-fos proto-oncogene and the proliferation of HeLa carcinoma cells.

In this study, the effect of 4-hydroxynonenal (HNE), a peroxidation product of omega-6-poly-unsaturated fatty acids, on the expression of the c-fos proto-oncogene and growth factor-induced proliferation of HeLa carcinoma cells in vitro was investigated. The Fos protein forms the heterodimer AP-1 with the Jun protein and regulates the cell cycle by inducing cyclin D1. Agents that are able to induce c-fos include serum, platelet-derived growth factor (PDGF), and epidermal growth factor (EGF), all of which were used in this study. The proliferation rate was determined by cell counting (viable and dead cells according to trypan blue exclusion) and the BrdU assay. The c-fos mRNA level was monitored by the reverse transcriptase/polymerase chain reaction. In the absence of HNE, serum-deprived cells responded to serum stimulation with a more than 10-fold increase of the c-fos mRNA level as well as with an increased rate of DNA synthesis and cell multiplication. Both EGF and PDGF (applied in combination with insulin) were able to substitute for FCS and induced rapid growth of the tumor cells preincubated in serum-deprived medium. In the absence of growth factors a negative correlation between the HNE concentration (range: 1-250 microM) and the c-fos mRNA level was observed. We suppose that HNE interferes in this case with the basal activity of the c-fos promoter. EGF, when applied after the HNE treatment, induced rapid growth of the tumor cells preincubated in serum-free medium, if HNE was used in a physiological concentration (1 microM). No difference was observed compared to the HNE-free control. c-fos mRNA level was nearly unchanged. In contrast, a cytotoxic concentration of the aldehyde (100 microM) caused a complete inhibition of proliferation, although a twofold increase of the c-fos mRNA level immediately after the aldehyde treatment was observed. A similar effect of HNE in cytotoxic concentration on c-fos expression was observed when cells were grown in presence of PDGF instead of EGF. Hence, in both cases HNE possibly interferes with the signal transduction pathway, which is initiated by external growth factors. The increased c-fos expression might be part of an abortive attempt to overcome the stressful condition raised by a cytotoxic concentration of HNE.

Aldehydes↗
PubMed2003

Induction of c-fos expression by nicotine in human periodontal ligament fibroblasts is related to cellular thiol levels.

Cigarette smoking is associated with increased incidence of periodontal disease and poor response to periodontal therapy. Several studies have shown the detrimental effects of nicotine on periodontal tissue. To investigate the molecular toxicological implications of cigarette smoking on periodontal tissue, expression of c-fos early stress response gene was examined in human periodontal ligament fibroblasts (PDLFs) after exposure to nicotine. The exposure of quiescent human PDLFs to nicotine resulted in the induction of c-fos mRNA expression. The levels of the c-fos mRNAs increased about 2.5 and 4.8-fold after exposure to 2.5 mm and 10 mm nicotine for 2 h, respectively. Moreover, the peak of c-fos mRNA levels induced by nicotine was 5 mm at 2-h incubation period. Kinetic investigations of c-fos mRNA expression in nicotine-treated cells revealed a rapid accumulation of the transcript, a significant signal first detectable after 30 min of exposure. This increase was transient and the level of c-fos mRNAs returned rapidly to that of control cells by 8 h. To determine whether thiol levels were important in induction of c-fos by nicotine, we pretreated cells with the glutathione (GSH) precursor, 2-oxothiazolidine-4-carboxylic acid (OTZ), to boost thiol levels, or buthionine sulfoximine (BSO) to deplete GSH. Our results demonstrate that OTZ pretreatment decreased in c-fos mRNA level and BSO pretreatment enhanced in c-fos mRNA level after exposure to nicotine. In addition, nicotine significantly depleted intracellular GSH in a dose-dependent manner (P < 0.05). At a concentration of 5 mm and 20 mm, nicotine depleted about 22.2% and 56% of GSH, respectively. Taken together, c-fos gene expression might be one signal transduction pathway linked to the induction of early response genes by cigarette smoking. These results suggest that the nicotine-dependent stress-specific expression of the c-fos gene correlates with cellular thiol levels in human PDLFs.

Analysis of Variance↗
PubMedDate not supplied

Bone and haematopoietic defects in mice lacking c-fos.

The proto-oncogene c-fos is the cellular homologue of v-fos originally isolated from murine osteosarcoma. Fos protein is a major component of the AP-1 transcription factor complex, which includes members of the jun family. Stable expression of c-fos in mice has been demonstrated in developing bones and teeth, haematopoietic cells, germ cells and in the central nervous system. It has been proposed that c-fos has an important role in signal transduction, cell proliferation and differentiation. We have previously demonstrated that overexpression of c-fos in transgenic and chimaeric mice specifically affects bone, cartilage and haematopoietic cell development. To understand better the function of c-fos in vivo, we used gene targeting in embryonic stem cells to generate cells and mice lacking c-fos. Here we report that heterozygous fos +/- mice appear normal, although females exhibit a distorted transmission frequency. All homozygous fos -/- mice are growth-retarded, develop osteopetrosis with deficiencies in bone remodelling and tooth eruption, and have altered haematopoiesis. These data define the c-Fos protein as an essential molecule for the development of specific cellular compartments.

Animals↗
PubMed1998

Peripheral and/or central effects of racemic-, S(+)- and R(-)-flurbiprofen on inflammatory nociceptive processes: a c-Fos protein study in the rat spinal cord.

1. We have evaluated the effects of intravenous or intraplantar racemic-, S(+)- and R(-)-flurbiprofen on both the carrageenan-evoked peripheral oedema and spinal c-Fos immunoreactivity, an indirect index of neurons involved in spinal nociceptive processes. 2. Three hours after intraplantar injection of carrageenan (6 mg in 150 microl of saline) in awake rats, a peripheral oedema and numerous c-Fos protein-like immunoreactive (c-Fos-LI) neurons in L4 L5 segments were observed. c-Fos-LI neurons were essentially located in the superficial (I-II) and deep (V-VI) laminae of the dorsal horn. 3. Intravenous racemic-flurbiprofen (0.3, 3 and 9 mg kg(-1)) dose-relatedly reduced the carrageenan-evoked oedema and spinal c-Fos expression (r=0.64, r=0.88 and r=0.84 for paw diameter, ankle diameter and number of c-Fos-LI neurons; P<0.05. P<0.001 and P<0.001 respectively). 4. Similar effects to those of intravenous racemic-flurbiprofen were obtained with intravenous S(+)-flurbiprofen (0.3, 3 and 9 mg kg(-1)) which dose-relatedly reduced the number of c-Fos-LI neurons (r=0.69, P<0.01) and diameters of paw and ankle (r=0.56 and r=0.52 respectively, P<0.05 for both). 5. For the dose of 0.3 mg kg(-1) i.v., R(-)-flurbiprofen did not modify the number of c-Fos-LI neurons and produced a weak reduction of oedema at only the ankle level (23+/-12% reduction, P<0.05). However, a ten times higher dose of R(-)-flurbiprofen (3 mg kg(-1) i.v.) was necessary to obtain effects comparable to those of S(+)- or racemic-flurbiprofen (0.3 mg kg(-1) i.v.). 6. Intraplantar racemic-flurbiprofen (1, 10 and 30 microg) dose-relatedly reduced the carrageenan-enhanced ankle diameter (r=0.81, P<0.001) and the number of c-Fos-LI neurons in L4-L5 segments (r=0.83, P<0.001). with a 60+/-3% reduction of the number of c-Fos-LI neurons (P<0.001), and 30+/-3 and 67+/-7% reduction of paw and ankle diameter respectively (P<0.001 for both) for the dose of 30 microg. 7. For intraplantar S(+)-flurbiprofen (1, 10 and 30 microg) the dose-related effects (r=0.77, r=0.60 and r=0.59 for c-Fos-LI neurons, paw and ankle diameters respectively, P<0.001, P<0.01 and P<0.01) were similar to those of racemic-flurbiprofen. In contrast, intraplantar R(-)-flurbiprofen (1, 10 and 30 microg) did not have detectable effects on all studied parameters. 8. The present study provides clear evidence for potent anti-inflammatory and antinociceptive effects of both intravenous or intraplantar racemic- and S(+)-flurbiprofen. These results further demonstrate marked anti-inflammatory and antinociceptive effects of intravenous, but not intraplantar, R(-)-flurbiprofen. These results suggest that the main site of action of racemic- and S(+ )-flurbiprofen is in the periphery and indicate that the site of action of R(-)-flurbiprofen is mainly of central origin.

Analgesics↗
PubMed1997

Bcl-2 inhibits c-fos induction by calcium.

Transient elevation of cytosolic Ca2+ induces the expression of a variety of genes involved in cell growth and transformation, including the early response gene c-fos. Previously, we reported that Bcl-2 inhibits the transient elevation of cytosolic Ca2+ induced by thapsigargin (TG), a selective inhibitor of the endoplasmic reticulum-associated Ca2+-ATPase. Therefore, to determine if the effect of Bcl-2 on cytosolic Ca2+ elevation modulates Ca2+ signaling, we investigated the induction of c-fos by TG in WEHI7.2 mouse lymphoma cells, control transfectants (WEHI7.2-neo), and transfectants that stably express a high level of Bcl-2 (W.Hb12 and W.Hb15). TG induced 20-fold elevation of c-fos mRNA in WEHI7.2 and WEHI7.2-neo cells, but c-fos mRNA induction by TG was only fivefold in W.Hb12 and W.Hb15 cells. In contrast, phorbol 12-myristate acetate induced marked c-fos mRNA elevation in both WEHI7.2 and W.Hb12 cells, indicating that the inhibitory effect of Bcl-2 is selective for induction of c-fos by Ca2+. To measure c-fos promoter activity, WEHI7.2 and W.Hb12 cells were transiently transfected with a c-fos promoter-luciferase reporter plasmid. TG induced c-fos promoter activity in WEHI7.2 cells, but not in W.Hb12 cells. In WEHI7.2 cells, the signal for c-fos induction by TG was cytosolic Ca2+ elevation, as the increase in both c-fos mRNA level and promoter activity were prevented by lowering extracellular Ca2+ concentration, a condition that inhibits cytosolic Ca2+ elevation by reducing the TG-mobilizable Ca2+ pool. In summary, the findings indicate that Bcl-2 regulates Ca2+ signaling.

Animals↗
PubMed2005

Use of c-fos to identify activity-dependent spinal neurons after stepping in intact adult rats.

STUDY DESIGN: An investigation of c-fos activation pattern in spinal neurons of intact adult rats after acute bouts of treadmill locomotion. OBJECTIVES: To map spinal neurons that are involved in quadrupedal treadmill stepping of intact adult rats by using c-fos as a marker. SETTINGS: Los Angeles, CA, USA. METHODS: Spinal cord sections of rats that were not stepped (n = 4) were used to map the FOS-positive (+) neurons under basal conditions. The stepped group (n = 16) was placed on a treadmill to step quadrupedally for varying durations to induce c-fos activity. Spinal cord sections of thoracic and lumbar segments of Stp and Nstp rats were processed using a c-fos antibody, choline acetyl transferase and heat shock protein 27 for identifying motoneurons. RESULTS: Stepping induced a greater number of FOS+ neurons than was observed in rats that did not step on the treadmill. There was a rostrocaudal and a dorsoventral gradient of FOS labeled neurons. The number of FOS+ neurons increased with the duration of treadmill stepping. Significant increases in FOS+ neurons were in the most medial parts of laminae IV, V, and VII. FOS+ motoneurons increased with treadmill stepping, particularly in large motoneurons (> or = 700 microm2). CONCLUSION: These data suggest that FOS can be used to identify activity-dependent neuronal pathways in the spinal cord that are associated with treadmill stepping, specifically in lamina VII and in alpha motoneurons. SPONSORSHIP: NIH NS16333, NS40917, and the Christopher Reeve Paralysis Foundation (CRPF VEC 2002).

Animals↗
PubMed2002

A progestin antagonist blocks vaginocervical stimulation-induced fos expression in neurones containing progestin receptors in the rostral medial preoptic area.

Vaginocervical stimulation (VCS) has a variety of effects on the brain, physiology and behaviour. Previous work demonstrated that a progestin antagonist blocked neuronal response to VCS (i.e. Fos expression) in the absence of progesterone in some neurones, and suggested that some of the effects of VCS on the brain are mediated by ligand-independent activation of progestin receptors (PRs). Although it had been reported previously that some of the cells in which VCS induces Fos expression also contain PRs, it had not been determined if a progestin antagonist blocked Fos expression in these particular neurones. The purpose of this experiment was to determine if a progestin antagonist decreases Fos expression specifically in cells that also express PRs in the preoptic area and ventromedial hypothalamus. As has been shown previously, VCS increased Fos-immunoreactive (ir) expression in the particular areas studied. In the rostral medial preoptic area, VCS increased Fos expression in cells that coexpressed PRs, as well as in cells that do not. However, in the caudal medial preoptic area, VCS only increased Fos expression in cells that did not coexpress PRs. Injection of the progestin antagonist, RU 486, decreased Fos expression in the rostral, but not caudal medial preoptic area, and it decreased Fos expression only in cells that coexpressed PR-ir. In contrast to a previous report, in the present study, the progestin antagonist did not inhibit VCS-induced Fos expression in the ventromedial hypothalamic area. The results of this experiment suggest that the progestin antagonist inhibits VCS-induced Fos expression in some neurones by blocking PRs, and they provide further support for the idea that VCS influences neuronal response in some cells by ligand-independent activation of PRs in those cells.

Animals↗
PubMed2002

Anatomical markers of activity in neuroendocrine systems: are we all 'fos-ed out'?

It has now been nearly 15 years since the immediate early gene, c-fos, and its protein product, Fos, were introduced as tools for determining activity changes within neurones of the nervous system. In the ensuing years, this approach was applied to neuroendocrine study with success. With it have come advances in our understanding of which neuroendocrine neurones respond to various stimuli and how other central nervous system components interact with neuroendocrine neurones. Use of combined tract-tracing approaches, as well as double-labelling for Fos and transmitter markers, have added to characterization of neuroendocrine circuits. The delineation of the signal transduction cascades that induce Fos expression has led to establishment of the relationship between neurone firing and Fos expression. Importantly, we can now appreciate that Fos expression is often, but not always, associated with increased neuronal firing and vice versa. There are remaining gaps in our understanding of Fos in the nervous system. To date, knowledge of what Fos does after it is expressed is still limited. The transience of Fos expression after stimulation (especially if the stimulus is persistent) complicates design of experiments to assess the function of Fos and makes Fos of little value as a marker for long-term changes in neurone activity. In this regard, alternative approaches must be sought. Useful alternative approaches employed to date to monitor neuronal changes in activity include examination of (i) signal transduction intermediates (e.g. phosphorylated CREB); (ii) transcriptional/translational intermediates (e.g. heteronuclear RNA, messenger RNA (mRNA), prohormones); and (iii) receptor translocation. Another capitalizes on the fact that many neuroendocrine systems show striking stimulus-transcription coupling in the regulation of their transmitter or its synthetic enzymes. Together, as we move into the 21st Century, the use of multiple approach to study activity within neuroendocrine systems will further our understanding of these important systems.

Animals↗
PubMed2001

The role of putative intragenic control elements in c-fos regulation by calcium and growth factor signalling pathways.

Sequences in the transcribed region of the c-fos gene have been suggested to control c-fos induction following exposure of cells to mitogens or stimuli that increase intracellular calcium concentrations. Using a mutational analysis we show that putative regulatory elements present in the first intron of the human c-fos gene and the fos-intragenic-regulatory-element (FIRE) are not required for c-fos regulation by growth factor and calcium signalling pathways in AtT20 and PC12 cells. Removal of the c-fos first intron and the FIRE did not increase the basal level of c-fos mRNA and only moderately reduced the magnitude of calcium-induced transcription mediated by either the entire c-fos promoter or the cAMP response element (CRE). Intragenic mutations did not affect serum response element (SRE)-dependent gene expression induced by calcium signals but caused a superinduction of c-fos expression in nerve growth factor-stimulated PC12 cells. These results indicate that c-fos promoter elements, rather than intragenic sequences, are the principal targets of transcription-regulating signalling pathways. This suggests that CRE- and SRE-bound activators of transcription initiation may also enhance, in a signal-dependent manner, c-fos transcript elongation beyond promoter-proximal pause sites.

Animals↗
PubMed1991

Ribozyme-mediated cleavage of c-fos mRNA reduces gene expression of DNA synthesis enzymes and metallothionein.

The c-fos gene product Fos has been implicated in many cellular processes, including signal transduction, DNA synthesis, and resistance to antineoplastic agents. A fos ribozyme (catalytic RNA) was designed to evaluate the effects of suppressing Fos protein synthesis on expression of enzymes involved in DNA synthesis, DNA repair, and drug resistance. DNA encoding the fos ribozyme (fosRb) was cloned into the pMAMneo expression plasmid, and the resultant vector was transfected into A2780DDP cells resistant to the chemotherapeutic agent cisplatin. The parental drug-sensitive A2780S cells were transfected with the pMMV vector containing the c-fos gene. Morphological alterations were accompanied by significant changes in pharmacological sensitivity in both c-fos- and fosRb-transfected cells. pMAMneo fosRb transfectants revealed decreased c-fos gene expression, concomitant with reduced thymidylate (dTMP) synthase, DNA polymerase beta, topoisomerase I, and metallothionein IIA mRNAs. In contrast, c-myc expression was elevated after fos ribozyme action. Insertion of a mutant ribozyme, mainly capable of antisense activity, into A2780DDP cells resulted in smaller reductions in c-fos gene expression and in cisplatin resistance than the active ribozyme. These studies establish a role for c-fos in drug resistance and in mediating DNA synthesis and repair processes by modulating expression of genes such as dTMP synthase, DNA polymerase beta, and topoisomerase I. These studies also suggest the utility of ribozymes in the analysis of cellular gene expression.

Base Sequence↗
PubMed1998

Requirements of focal adhesions and calcium fluxes for interleukin-1-induced ERK kinase activation and c-fos expression in fibroblasts.

Interleukin-1 (IL-1) is an important inflammatory mediator and plays a central role in the destruction of connective tissue matrices in diseases such as arthritis and periodontitis. It is well established that IL-1 activation of the mitogen-activated protein (MAP) kinase pathway and induction of c-fos expression is a required step in the induction of matrix metalloproteinase expression involved in tissue degradation. Previous studies in our laboratory showed that IL-1-induced calcium flux is dependent on focal adhesion formation, suggesting a matrix-dependent restriction system for IL-1 signaling. Therefore, in the present study, we examined the consequences of this restriction on IL-1-mediated activation of the MAP kinase family and on c-fos expression. Treatment of human gingival fibroblasts with IL-1 activated extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 kinase activity and induced c-fos expression in a dose- and time-dependent fashion. Plating cells on poly-L-lysine prevented focal adhesion formation, eliminated IL-1-induced calcium influx, abolished ERK stimulation, and blocked c-fos expression. Cells in suspension and hence with no suitable substratum for focal adhesion formation also showed no ERK activation or enhanced c-fos expression in response to IL-1. In contrast, eliminating focal adhesion formation or calcium depletion in cells plated on fibronectin had no effect on IL-1 stimulation of JNK and p38 kinases, demonstrating that their activation was mediated through pathways independent of focal adhesions and calcium. Calcium depletion abolished IL-1-induced calcium uptake, ERK activation, and c-fos expression. The focal adhesion dependence of IL-1-induced ERK activation and c-fos expression could be circumvented in cells plated on poly-L-lysine by simultaneous incubation with IL-1 and the calcium ionophore ionomycin. In transfection studies, IL-1 stimulation of serum responsive element (SRE) transcriptional activity was dependent on the presence of extracellular calcium. This is consistent with a requirement for calcium in the activation of ERKs and their involvement in the induction of c-fos expression through the SRE site on the 5' promoter of the c-fos gene. Our results demonstrate that in cells attached to substrates by focal adhesions, IL-1-mediated calcium flux is required for ERK activation and c-fos expression but not for JNK or p38 activation. We conclude that cellular interactions with the extracellular matrix play an important role in restricting ERK and c-fos-dependent processes.

Blood↗
PubMed2002

Changes in c-Fos protein expression in the rat cuneate nucleus after electric stimulation of the transected median nerve.

In this study we investigate temporal changes in Fos expression in cuneate neurons after a high-threshold electrical stimulation of the transected median nerve in rats. Two hours after injury of the median nerve when given electrical stimulation, c-Fos-immunoreactive (c-Fos-IR) cells were barely detected in the ipsilateral cuneate nucleus (CN). A few c-Fos-IR cells, however, were observed in the ipsilateral CN at 5 days. A marked increase in c-Fos-IR cells was observed at 2, 3, and 4 weeks, but levels subsided thereafter. Labeled cells were totally diminished by 16 weeks. The statistical analysis showed that the mean density of c-Fos-IR cells throughout the CN at 4 weeks was significantly higher than at other post-surgical time points, except for 3 weeks. Furthermore, the mean density of c-Fos-IR cells in the middle region of the CN was markedly higher than in other areas of the nucleus. The mean density of c-Fos-IR cells in the middle region at 4 weeks (mean density = 35.9 +/- 3.0 cells/section) was considerably higher than at other time points. Combined retrograde Fluorogold (FG) labeling and c-Fos immunocytochemistry showed that throughout the CN about 60% (2270/3652) of the c-Fos-IR cells contained FG, confirming that they were cuneothalamic projection neurons (CTNs). Moreover, the percentage of double-labeled cells in the middle region at 2 weeks (78.9 +/- 0.6%) was significantly greater than at 3 (70.2 +/- 3.4%) and 4 weeks (66.0b +/- 1.4%) after injury. Although the mechanism leading to the vigorous c-Fos expression in the CTNs following the electrical stimulation of the transected median nerve remains unclear the hyperexcitable CTNs may transmit the neuropathic nociceptive sensation to the thalamus after the median nerve injury.

Animals↗
PubMed1990

Transcriptional regulation of early growth response genes in FOS-expressing PC-12 cells.

Deregulated c-fos expression in the rat pheochromocytoma cell line, PC-12, causes pronounced downregulation of nerve growth factor (NGF)-induced c-fos and c-jun activation, accompanied by a block in NGF-induced differentiation of PC-12 cells. The FOS-expressing PC-12 cells were exposed to diverse agents such as NGF, epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), dibutyryl cyclic adenosine 3',5' monophosphate (db cAMP), and Ca-ionophore; and the expression of egr-1, c-fos, c-jun, jun-B, and jun-D was analyzed. Pronounced downregulation of c-fos, c-jun, and--to a lesser extent--jun-B was observed on treatment with NGF, bFGF, db cAMP, and Ca-ionophore, whereas EGF-induced activation of these early response genes was not inhibited in FOS-expressing PC-12 cells. Ca-ionophore- and db cAMP-induced egr-1 activation in PC-12 fos cells was completely inhibited. Both parent and PC-12 fos cells expressed similar high basal levels of jun-D, whose expression was the least regulatable by all of these agents. Transfection of fos promoter-chloramphenicol acetyltransferase (promoter-CAT) plasmid into these stable FOS-expressing PC-12 cells revealed that these effects are exerted at the fos promoter level.

Adrenal Gland Neoplasms↗
PubMed2004

Fos expression is selectively and differentially regulated by endogenous glucocorticoids in the paraventricular nucleus of the hypothalamus and the dentate gyrus.

We examined the extent to which basal levels of corticosterone, which vary in a circadian fashion, influence the pattern of Fos protein expression in the paraventricular nucleus of the hypothalamus (PVN), the hippocampal formation and three different functional cortical areas. Basal and poststress (1 h of restraint) Fos expression, as determined by immunohistochemistry, was examined in male rats with either no previous surgical manipulation or in rats 5 days after: (i) sham adrenalectomy; (ii) adrenalectomy with no corticosterone replacement; or (iii) adrenalectomy with corticosterone (25 microg/ml) in the drinking water replacement. In adrenal-intact rats, restraint produced similar patterns of Fos expression in the PVN, cortical areas and hippocampus (CA1-CA3), with peak levels of expression attained 60-90 min after restraint onset. Surprisingly, in the dentate gyrus, there was a dissociation between the two blades in the pattern of Fos expression after restraint. In the inner blade (suprapyramidal), there was a delayed induction that occurred between 60 and 90 min after restraint onset and, in the outer blade (infrapyramidal), there was a steady decline in Fos expression after restraint. Adrenalectomy had an effect on Fos expression only in the PVN and dentate gyrus, and the nature of the effect was quite different for both brain regions. In the PVN, adrenalectomy had no effect on Fos expression in unstressed rats, but resulted in an enhanced number of Fos positive cells after restraint. In the dentate gyrus, adrenalectomy resulted in an overall reduction of Fos positive cells in both blades, and this reduction was present in unstressed and stressed rats. Corticosterone replacement normalized the adrenalectomy effect on Fos expression in both brain regions. Thus, Fos expression in the rat brain displays specific patterns of dependency on the permissive effects of glucorticoids, and this dependency varies between brain regions.

Adrenalectomy↗
PubMed1995

Reduction of carrageenin oedema and the associated c-Fos expression in the rat lumbar spinal cord by nitric oxide synthase inhibitor.

1. Three hours after intraplantar carrageenin (6 mg/150 microliters of saline) Fos-like immunoreactivity (Fos-LI) was mainly observed in L4 and L5 segments of the dorsal horn. Both superficial (I-II) and deep laminae (V-VI) neurones were labelled. 2. We have studied the effect of systemic administration of a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) on carrageenin evoked c-Fos expression and thus the contribution of nitric oxide to this expression. 3. Pre-administration of L-NAME (10, 25, 50, 100 mg kg-1, i.v.) dose-dependently reduced the number of superificial and deep laminae Fos-LI neurones, 100 mg kg-1 produced a 63 +/- 2% and 72 +/- 4% reduction of Fos-LI neurones respectively, P < 0.0001 for both superficial and deep neurones. 4. Pre-administered L-NAME dose-relatedly reduced the carrageenin-evoked paw and ankle oedema, with 100 mg kg-1 of L-NAME resulting in a 74 +/- 2% and 103 +/- 2% reduction respectively. 5. Post-administration of L-NAME (10 mg kg-1, i.v.) reduced the number of superficial and deep laminae Fos-LI neurones (65 +/- 7% and 53 +/- 8% reduction respectively, P < 0.01 for both superficial and deep neurones). 6. Post-administered L-NAME reduced both the paw and ankle oedema (52 +/- 8% and 62 +/- 10% reduction respectively, P < 0.0001 for both paw and ankle). 7. Pre-administered D-NAME (100 mg kg-1, i.v.), the inactive isomer of L-NAME, produced a weak reduction of the number of superficial laminae Fos-LI neurones (26 +/- 8% reduction, P<0.05), without influencing the deep Fos-LI neurones (5 +/- 8% enhancement) or the oedema.8. Systemic L-arginine (1200 mg kg-1) did not reverse the reduction of the total number of Fos-LI neurones induced by 100mg kg-1 of L-NAME, or the effect of L-NAME on the paw and ankle oedema.9. Intraplantar L-arginine (30 mg) did not reverse the effect of L-NAME (100 mg kg-1) on the total number of Fos-LI neurones. However, the inhibitory effects of L-NAME on the paw and ankle oedema were partially reversed by intraplantar L-Arginine (34 +/- 9% and 45 +/- 11% reduction of carrageenin oedema respectively) with these effects being significant as compared to the effect of L-NAME alone(P<0.05 for both).10. There is a strong correlation between the reduction of the number of Fos-LI neurones and the oedema by L-NAME, clearly demonstrating a predominant role of peripheral NO in the development of one of the signs of carrageenin inflammation.

Amino Acid Oxidoreductases↗
PubMed1996

Intraplantar morphine depresses spinal c-Fos expression induced by carrageenin inflammation but not by noxious heat.

1. We have studied the effects of intraplantar administration of the same doses of morphine on intraplantar carrageenin (6 mg 150 microliters-1 of saline) and noxious heat (52 degrees C for 15 s) induced spinal c-Fos expression and inflammation. 2. Intraplantar carrageenin, in awake rats, induced numerous Fos-like immunoreactive (Fos-LI) neurones in the dorsal horn of L4-L5 lumbar segments of the spinal cord and extensive peripheral oedema. At 1 h 30 min, Fos-LI neurones were preferentially located in the superficial laminae (74 +/- 2%) whereas at 3 h, Fos-LI neurones were observed both in the superficial (45 +/- 2%) and deep (37 +/- 1%) laminae of the spinal dorsal horn. 3. Intraplantar morphine dose-dependently reduced c-Fos expression induced 1 h 30 min after carrageenin (r = 0.605, P < 0.02), these effects were completely blocked by intraplantar methiodide naloxone (20 micrograms) (121 +/- 22% of control carrageenin expression). The systemic injection of the highest dose of intraplantar morphine (50 micrograms) had no significant effect on the number of Fos-LI neurones (88 +/- 9% of control carrageenin expression). None of the drugs influenced unilateral peripheral oedema observed 1 h 30 min after carrageenin. 4. In the second series of experiments, intraplantar morphine dose-dependently reduced the number of superficial and deep Fos-LI neurones induced 3 h after carrageenin (r = 0.794, P < 0.0004 and r = 0.698, P < 0.004, respectively). Furthermore, the effects of the highest dose of intraplantar morphine were completely blocked by co-administration of intraplantar methiodide naloxone (20 micrograms). 5. In addition, intraplantar morphine dose-dependently reduced the ankle (r = 0.747, P < 0.002) and paw (r = 0.682, P < 0.005) oedema observed 3 h after carrageenin, with the effect of the highest dose of intraplantar morphine being completely blocked by co-administration of methiodide naloxone (98 +/- 4% and 102 +/- 8% of control paw and ankle oedema, respectively). 6. Brief noxious heat stimulation, in urethane anaesthetized rats, induced, 2 h after the stimulation, numerous Fos-LI neurones in the dorsal horn of L3-L4 lumbar segments of the spinal cord but no detectable peripheral oedema. Fos-LI neurones were preferentially located in superficial laminae (94 +/- 2%) of the spinal dorsal horn. None of the drugs influenced the noxious heat induced c-Fos expression. 7. Such results illustrate that peripheral effects of morphine preferentially occur during inflammatory states and outline the interest of extending clinical investigations of the possible use of local injection of morphine in various inflammatory pain states.

Animals↗