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PubMed1997

Immunohistochemical study of c-fos-positive lymphocytes infiltrated into human squamous cell carcinomas of the head and neck during radiation therapy and its clinical significance.

C-fos has been reported to be one of the immediate early genes in signal transduction systems after many kinds of stresses, including ionizing radiation. Changes in c-fos expression induced by radiation therapy in tumor tissues have not yet been reported. In this study, we have attempted to determine whether c-fos expression is induced by radiotherapy in human squamous cell carcinomas of the head and neck and to establish a possible correlation between c-fos expression and the therapeutic effects of radiation therapy. Twenty-seven patients with tumors of the oral cavity, oropharynx, and maxillary sinus were examined, all of which were confirmed as squamous cell carcinomas. After obtaining the patients' informed consent, biopsies were performed before treatment and at doses of 4, 10, and 20 Gy of radiotherapy, and the specimens were preserved in liquid nitrogen for further examination. Serial sectioning of 6 micrometer was performed using a cryostat, and samples were immunohistochemically stained using the streptoavidin-biotin peroxidase method and a monoclonal antibody against c-fos. Three of the 27 patients with squamous cell carcinoma showed slight expression of c-fos in their tumor cells before and/or at 4 or 10 Gy of radiotherapy. The tumors showed high radiosensitivity. Concerning tumor-infiltrating lymphocytes, the rate of moderate or remarkable grades of c-fos-positive lymphocytes before radiotherapy and at radiation doses of 4, 10, and 20 Gy was 8.0, 29.2, 4.8, and 0%, respectively. The relationship between the immunohistochemical findings and the antitumor effect at a radiation dose of 20 Gy was examined on the corresponding H&E-stained sections. In patients whose infiltration of c-fos-positive lymphocytes into tumor tissues were moderate or remarkable at 4 Gy of radiotherapy, the tumors responded significantly well to radiation therapy (P < 0.025, chi2 test), and the patients took a significantly favorable clinical course (P < 0.05, chi2 test). In a sample from one of the patients, c-fos-positive lymphocytes were identified as CD4 positive and CD8 negative. Therefore, the high radiosensitivity of squamous cell carcinomas in our samples could be explained by an overexpression of c-fos in the tumor-infiltrating lymphocytes induced by small doses of radiation therapy, and these activated lymphocytes exerted a cytotoxic effect against the cancer cells.

Adult↗
PubMed1998

Involvement of the spinoparabrachial pathway in inflammatory nociceptive processes: a c-Fos protein study in the awake rat.

The effect of graded inflammatory stimuli (intraplantar-carrageenan, 0.2, 1, and 6 mg/150 microl) on paw edema and c-Fos protein expression at two levels of the spinoparabrachial pathway, the spinal cord and parabrachial area (PB), were studied. The present study, in awake rats, is an extension of previous study (Bester et al. [1997] J. Comp. Neurol. 383:439-458) which evaluated, in anesthetized rats, the effect of graded cutaneous heat stimulation on c-Fos-expression at the same levels. At the spinal level, the c-Fos-protein-like-immunoreactive (c-Fos-LI) neurons were located primarily in superficial laminae ipsilateral to intraplantar carrageenan. The number of c-Fos-LI neurons increased dose dependently (r = 0.973, n = 24) for carrageenan, from a number close to zero for the saline injection. At the PB level, c-Fos was predominantly expressed contralateral to intraplantar carrageenan. c-Fos-LI neurons were located primarily around the pontomesencephalic junction in (i) a restricted pontine area, centered in the lateral crescent, and including an adjacent part of the outer portion of the external lateral subnucleus, and (ii) the mesencephalic superior lateral subnuclei. The number of c-Fos-LI neurons in the PB area was correlated with that in the superficial laminae (r = 0.935, n = 24) and with the paw edema (r = 0.931, n = 24). No significant changes in c-Fos expression were observed in the nucleus of the solitary tract and ventrolateral medulla. The close correlation between c-Fos expression at both the spinal and PB levels and inflammatory edema provides further evidence for the involvement of spinoparabrachial pathway in inflammatory nociceptive processes. The present results are congruent with the existence of electrophysiologically demonstrated spinoparabrachio-amygdaloid and -hypothalamic nociceptive pathways.

Animals↗
PubMed1996

Effects of D2 dopamine receptor antagonists on Fos protein expression in the striatal complex and entorhinal cortex of the nonhuman primate.

Recent studies have reported that acute administration of dopamine D2 receptor antagonists increases expression of the immediate early gene c-fos in the rat striatal complex. There have been no corresponding studies of the effects of D2 antagonists in primate species. Since all clinically effective antipsychotic drugs share D2 receptor antagonism, it is important to define the extent to which these drugs may alter expression of c-fos or its protein product, Fos, in primates. We therefore examined the effects of administration of two D2 receptor antagonists, haloperidol and metoclopramide, on Fos expression in the striatum and temporal cortices of the vervet monkey. Metoclopramide does not appear to possess significant antipsychotic efficacy but potently produces extra-pyramidal side effects, while haloperidol is an effective antipsychotic drug that produces extrapyramidal side effects. Both drugs increased the number of Fos-like immunoreactive (Fos-li) neurons in the caudate nucleus and putamen; the numbers of Fos-li neurons in these regions were increased in both the patch and matrix compartments. Haloperidol but not metoclopramide increased the number of Fos-li neurons in the nucleus accumbens shell. Similarly, haloperidol but not metoclopramide increased the number of Fos-li neurons in the entorhinal cortex. Neither drug altered Fos expression in the inferior temporal cortex. These data suggest that the dorsolateral caudate nucleus and putamen may be sites at which D2 receptor antagonists elicit extrapyramidal side effects, and the nucleus accumbens shell and entorhinal cortex may be loci at which the therapeutic actions of antipsychotic drugs are manifested.

Animals↗
PubMed1996

Influence of the glucocorticoid receptor on c-fos inducibility in activated ras-containing mouse lung cells.

Glucocorticoids inhibit the growth and promote the differentiation of normal lung cells. Transformed A5 mouse lung cells containing an activated Ki-ras gene are not responsive to glucocorticoid-induced growth inhibition and demonstrate increased cell proliferation. Activated ras genes may lead to constitutive activation of genes, such as the activating protein 1 (AP-1) transcription factor components fos and jun, which are downstream in the ras signal-transduction pathway. A5 cells and A5GR, a stable A5 transfectant containing excess copies of the glucocorticoid receptor (GR) gene, were examined for potential alterations in AP-1 that accompany the restoration of glucocorticoid-dependent growth inhibition. The established ability of the GR to antagonize AP-1 activity led us to examine the regulation and inducibility of c-fos and c-jun in these cells. Nontransformed C10 lung cells were found to have higher and more inducible AP-1 activity than the transformed A5 cells. The level of AP-1 activity could be reduced in C10 cells by transient transfection of constitutive fos and jun expression vectors. In A5 cells, stimulation with factors that activate the serum-response element on the fos promoter and induce c-fos mRNA had little effect on AP-1 activity, whereas treatment with 12-O-tetradecanoylphorbol-13-acetate, which acts at the fos-AP-1 binding sequence site on the fos promoter, efficiently induced c-fos mRNA. The c-fos mRNA in A5GR cells, however, was not inducible with all treatments, suggesting that one potential mechanism by which the GR restores glucocorticoid-induced growth inhibition in these cells may involve the desensitization of additional 12-O-tetradecanoylphorbol-13-acetate-inducible elements of the fos promoter.

Animals↗
PubMed1990

fos-jun conspiracy: implications for the cell.

Two nuclear oncoproteins, fos and jun (AP-1), cooperate in forming a very stable heterodimeric complex that binds to the AP-1 site on DNA with high affinity. The 'leucine zipper' domain of both fos and jun is necessary for the formation of this heterodimer. Mutations of single residues within the leucine zipper domain have no effect on protein complex formation. However, results from mutagenesis of the first leucine of the heptad repeat in either fos or jun basic regions and alteration of the spacing between the basic and leucine zipper domains indicate that the basic region of fos plays a crucial role in determining the DNA binding affinity of the transcriptional complex. Mutations of the basic amino acids in fos protein prevent binding to the tumour promoter response element (TRE) in the presence of wild-type jun protein. Thus fos protein appears to be dominant in jun-fos binding to DNA, even though fos alone cannot bind to TRE. Mutants in the basic region of fos and jun can be exploited as dominant-negative mutants to ablate the normal fos cellular function.

Amino Acid Sequence↗
PubMed1989

Expression of c-fos protein in interneurons and projection neurons of the rat spinal cord in response to noxious somatic, articular, and visceral stimulation.

This study used immunocytochemistry to examine the pattern of noxious-stimulus evoked expression of the proto-oncogene c-fos in the spinal cord of the rat. Both noxious somatic and joint stimulation in awake rats evoked the expression of c-fos protein in similar areas of the lumbar spinal cord. C-fos-immunoreactive neurons were found in laminae I and outer II, in the lateral part of the neck of the dorsal horn, and in laminae VII, VIII, and X. All of the labelled neurons were located ipsilateral to the injured hindpaw, except for lamina VIII where bilateral labelling was recorded. The c-fos-immunoreactive neurons in lamina I extended from the L3 segment to the rostral sacral cord; staining in outer lamina II was only found at the L4 segment. The more deeply located cells, of the dorsal and medioventral horns, had the most extensive rostrocaudal spread; they were found from L1 through the rostral sacral segments. The pattern of c-fos-immunoreactivity produced by visceral stimulation, in anesthetized rats, differed in several ways from that produced by somatic stimulation. First, there was considerable bilateral, symmetrical labelling of cells. Second, there was a much more extensive rostrocaudal spread of the labelling, from cervical through sacral cord. Third, the greatest rostrocaudal spread was found for neurons in the superficial dorsal horn; labelled cells in the neck of the dorsal horn and in lamina X were restricted to segments at the thoracolumbar junction, which is also where the superficial dorsal horn cells were most concentrated. Fourth, there were very few labelled neurons in the outer part of the substantia gelatinosa. To determine whether any neurons that express the c-fos protein in response to noxious stimulation project to supraspinal sites, we combined the immunocytochemical localization of c-fos with the localization of a retrogradely transported protein-gold complex that was injected into the thalamic and brainstem targets of the major ascending spinal pathways. In rats that received the somatic noxious stimulus, 90% of all of the c-fos projection neurons were recorded in four major areas of the cord: lamina I (37%), the lateral part of the neck of the dorsal horn (24%), laminae VIII (9%), and X (29%). The remainder were scattered throughout the spinal gray. With the exception of lamina VIII, which contained c-fos projection neurons contralateral to the inflamed paw, all of the c-fos projection neurons were located ipsilateral to the injured paw.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Photic regulation of Fos-like immunoreactivity in the suprachiasmatic nucleus of the mouse.

In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus functions as the primary pacemaker of the circadian system. Light has been shown to induce Fos-like immunoreactivity (Fos-LI) in the SCN of rats and hamsters. The purpose of the present study was to evaluate extensively the effect of light on Fos-LI in the mouse SCN. Brief pulses of light administered to animals otherwise in constant darkness were found to induce Fos-LI. This photic induction was unaffected by the rd mutation, which causes the profound loss of photoreceptors but fails to affect circadian responses to light. Light regulation of Fos-LI was dependent upon the phase of the circadian cycle in which the light pulse was administered. Phases at which light causes phase shifts of the circadian system were permissive for Fos-LI induction (CT 16 and 24), while phases in which light does not cause phase shifts were not permissive (CT 6 and 9). The time course of the induction at CT 16 was also described. In a light/dark cycle, Fos-LI was found to be rhythmically expressed with Fos-LI elevated soon after the lights came on but remaining low throughout the rest of the cycle. However, this rhythm is a direct consequence of the light because in constant darkness Fos-LI was always low. These results have implications regarding the possible functional roles of Fos in the circadian system and add to our understanding of light regulation of circadian physiology in the mouse.

Animals↗
PubMed1993

JUN, FOS, KROX, and CREB transcription factor proteins in the rat cortex: basal expression and induction by spreading depression and epileptic seizures.

The expression of the nuclear c-JUN, JUN B, JUN D, c-FOS, FOS B, KROX-24, and CREB transcription factors was investigated in the cortex of adult rats by immunocytochemistry. The expression patterns were studied in untreated rats and up to 24 hours following topical application of 1 M KCl to the cortical surface (KCl) or i.v. injection of bicuculline (BIC). Topical KCl induced cortical spreading depression and systemic injection of bicuculline evoked generalized tonic-clonic seizures. In untreated rats, JUN B, c-FOS, and FOS B were expressed in a small number of neurons in the piriform, perirhinal, entorhinal, and insular cortex and in layers II, III, and VI of all neocortical areas. In contrast, c-JUN, JUN D, and KROX-24 were expressed in all cortical layers but with different intensities of immunoreactivity (IR): c-JUN-IR was generally weak and predominantly present in layers II, III, and VI. JUN D-IR was equally strong in all layers. KROX-24 showed a prominent expression in layers II, IV, and VI. The CREB protein exhibited a slight preponderance in layer II and piriform cortex. Following KCl or BIC, a strong induction was seen for c-FOS, JUN B, and KROX-24, whereas c-JUN, JUN D, and FOS B showed only a moderate increase compared to basal levels. Changes of CREB-IR could not be detected. The localization of induced JUN, FOS, and KROX proteins reflected the pattern of labelling in untreated animals but demonstrated a higher intensity of labelling and an increased number of immunoreactive nuclei. The intensity and persistence of IR as well as the number of labelled cells following BIC exceeded those following KCl. Following BIC, increased levels of FOS B and JUN D were still present after 24 hours. Counterstaining with cresyl-violet and GFAP, a marker for astrocytes, revealed that JUN, FOS, and KROX proteins were expressed in neurons but not in glial cell populations. The present data demonstrate that CREB, JUN, FOS, and KROX transcription factors exhibit a layer-specific expression in the cerebral cortex with only slight area-specific differences both in untreated rats and following stimulation with KCl and BIC. The expression of transcription factor proteins indicate complex molecular genetic changes in cortical neurons due to pathophysiological events such as seizure activity and spreading depression.

Activating Transcription Factor 1↗
PubMed1989

The product of a novel growth factor activated gene, fos B, interacts with JUN proteins enhancing their DNA binding activity.

We have identified a gene, fos B, encoding a nuclear protein of 338 amino acids presenting a 70% homology with c-fos, whose expression is activated during G0/G1 transition. Growth factor stimulation of quiescent cells leads to a rapid and transient accumulation of fos B mRNA, with kinetics similar to those of c-fos. The induction of fos B mRNA levels is in part due to a dramatic increase in the transcription of the gene. The half-life of fos B mRNA is in the order of 10-15 min. Both transcriptional activation and mRNA stability are substantially increased in the presence of protein synthesis inhibitors. Immunoprecipitation studies showed that fos B as c-fos protein, forms a complex in vitro with c-jun and jun B proteins in the absence of a target binding sequence. Gel retardation assays demonstrated that fos B protein positively influences the binding of c-jun and jun B proteins to an AP-1 binding consensus sequence, suggesting that fos B protein plays a role in control of gene expression.

Amino Acid Sequence↗
PubMed1996

Analysis of signaling pathways used by parathyroid hormone to activate the c-fos gene in human SaOS2 osteoblast-like cells.

We have evaluated the signaling pathways activated by parathyroid hormone (PTH) in SaOS2 human osteoblastlike cells correlating with induction of the c-fos proto-oncogene. Human PTH(1-34) (hPTH[1-34]) and hPTH(1-34) Nle8,18 Tyr34 induced the expression of c-fos mRNA in quiescent SaOS2 cells in a concentration-dependent manner. N-terminal truncations of hPTH(1-34) that fail to activate protein kinase A (PKA) also abolished c-fos mRNA induction. In gel retardation assays hPTH(1-34) led to a change in the mobility of specific, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB)-containing protein-DNA complexes identical to that caused by other activators of PKA. The appearance of this altered mobility complex correlated temporally with the induction of c-fos mRNA. Using a c-fos serum response element probe, a slowed protein DNA complex appeared upon serum, epidermal growth factor, and basic fibroblast growth factor treatment. This slowed complex reflects phosphorylation of the transcription factor ternary complex factor (TCF) mediated via activation of the mitogen-activated protein (MAP) kinase pathway. The MAP kinase cascade is also activated by protein kinase C (PKC), and treatment with phorbol ester led to the induced TCF shift. In contrast, PTH did not produce this shift, ruling out PTH activation of c-fos via PKC and the MAP kinase signaling cascade. Further evidence for this was the lack of effect of the highly selective PKC inhibitor CGP 41251 on c-fos induction by hPTH(1-34). The janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling cascade targets the v-sis-inducible element in the c-fos promoter via the induced binding of STATs. Interferon gamma rapidly induced STAT binding in SaOS2 cells, unlike PTH. Thus, PTH induction of c-fos transcription appears to occur principally through activation of PKA that then targets CREB and the c-fos calcium/cAMP response element.

Gene Expression Regulation↗
PubMed1994

Second messenger signaling of c-fos gene induction by parathyroid hormone (PTH) and PTH-related peptide in osteoblastic osteosarcoma cells: its role in osteoblast proliferation and osteoclast-like cell formation.

The present study was performed to clarify second messenger signaling in parathyroid hormone (PTH)-induced c-fos gene expression, to characterize the participation of the c-fos gene in the regulation of osteoblast proliferation and function as well as osteoclast-like cell formation by PTH and to compare these effects of PTH with those of PTH-related peptide (PTHrP). Both human (h) PTH-(1-34) and hPTHrP-(1-34) at 10(-8) M induced a transient c-fos gene expression to a similar degree in osteoblastic osteosarcoma cells, UMR-106. N6,O2'-dibutyryl adenosine 3',5'-cyclic monophosphate (dbcAMP) as well as Sp-diastereoisomer of adenosine cyclic 3',5'-phosphorothioate (Sp-cAMPS), an activator of cAMP-dependent protein kinase (PKA), induced a weak c-fos gene expression. Although Rp-diastereoisomer of adenosine cyclic 3',5'-phosphorothioate (Rp-cAMPS), an inhibitor of PKA, almost completely antagonized dbCAMP- and Sp-cAMPS-induced expression of c-fos gene, it did not cause an obvious inhibition of PTH- or PTHrP-induced expression. Phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC), induced an intense expression of the c-fos gene, while 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD), incapable of activating PKC, and calcium ionophores (A23187 and ionomycin) did not. Protein kinase C inhibitor (H-7, 50 microM) completely blocked the expression of the c-fos gene by PTH as well as by PTHrP). Antisense oligodeoxynucleotides (as-ODN) complementary to c-fos mRNA, which have been shown to inhibit its mRNA translation, at 1 microM significantly antagonized PTH- and PTHrP-induced inhibition of [3H] thymidine incorporation and stimulation of osteoclast-like cell formation in the presence of osteoblasts, but not an increase in alkaline phosphatase activity, compared to control oligodeoxynucleotides with same nucleotides as as-ODN but with a random sequence. The present study indicates the involvement of PKC system in c-fos gene expression by PTH as well as PTHrP and also indicates the involvement of the c-fos gene in the regulation of bone cell physiology by PTH and PTHrP.

Cell Division↗
PubMed1998

Disruption of c-Fos leads to increased expression of NAD(P)H:quinone oxidoreductase1 and glutathione S-transferase.

Regulation of the basal and induced expression of detoxifying enzymes such as NAD(P)H:quinone oxidoreductasel (NQO1) and glutathione S-transferase (GST) by the antioxidant response element (ARE) is important for cellular protection against oxidative stress. The ARE contains AP1 and AP1-like elements and is known to bind to several leucine zipper proteins including c-Fos. Previous studies (Venugopal, R., and Jaiswal, A.K. (1996) Proc. NatL Acad. Sci. USA 93, 14960-14965) have shown that overexpression of c-Fos in transfected cells leads to repression of ARE-mediated gene expression. In the present report, we used c-Fos-/- mice and investigated the physiological (in vivo) role of c-Fos in repression of the NQO1 and GST genes expression. The analysis of enzyme activity levels showed significant increases in NQO1 and GST activities in several tissues of c-Fos-/- mice, as compared with wild type (c-Fos+/+) mice. The increases in enzyme activities were supported by Wetern analysis of respective proteins. Western analyses showed significant increases in the expression of NQO1 in kidney, liver and skin tissues of c-Fos-/- mice, as compared with wild type (c-Fos+/+) controls. Western analyses also demonstrated an increased expression of the GST Ya gene in kidney and liver tissues of the c-Fos-/-mice. These results confirm a negative (repressive) role for c-Fos in the expression of NQO1, GST Ya, and other detoxifying enzyme genes.

Animals↗
PubMed1994

Retinoic acid inhibition of insulin-like growth factor I stimulation of c-fos mRNA levels in a breast carcinoma cell line.

Retinoic acid (RA) inhibits insulin-like growth factor I (IGF-I)-stimulated growth of the human breast carcinoma cell line MCF-7. RA-mediated inhibition of IGF-I-stimulated growth is not associated with either a decrease in IGF-I receptor number or affinity. Since IGF-I modulation of c-fos gene expression appears to be an important step in IGF-I-mediated cellular proliferation, we investigated whether RA inhibits IGF-I stimulation of c-fos mRNA levels. Treatment of MCF-7 cells with IGF-I resulted in an approximately 10-fold increase in c-fos mRNA levels. Pretreatment of MCF-7 cells with 1 microM RA blocked IGF-I-mediated enhancement of c-fos mRNA levels by approximately 70%. The maximal RA effect (80% inhibition) on IGF-I stimulation of c-fos mRNA levels was noted within 2 h of exposure to RA. IGF-I did not modulate the c-fos gene promoter and appears to increase the stability of the c-fos mRNA. Preexposure of cells to RA results in a significant decrease (P < 0.05) in c-fos mRNA stability. The half-life of c-fos mRNA in the IGF-I-treated cells is 53 +/- 6 6 min while that in RA-pretreated cells is 27 +/- 0.4 min. We conclude that RA-mediated inhibition of IGF-I stimulation of c-fos mRNA may represent a potential mechanism by which RA inhibits IGF-I stimulation of growth.

Breast Neoplasms↗
PubMed2001

Spatiotemporal analysis of Fos expression associated with cocaine- and PTZ-induced seizures in prenatally cocaine-treated rats.

We previously reported that prenatal cocaine exposure (40 mg/kg s.c., E10-E20) increased susceptibility to convulsant-induced seizures later in life, with female rats becoming more sensitive to seizures induced by cocaine and pentylenetetrazol (PTZ), and males more sensitive to PTZ-induced seizures (Snyder-Keller and Keller, 1995, 2000). In order to determine the locus of enhanced seizure susceptibility in the brains of prenatally cocaine-treated rats, we examined the distribution and density of Fos-immunoreactive cells after cocaine- and PTZ-induced seizures in mature rats. Subconvulsive cocaine doses induced c-fos in cortical areas as well as densely dopamine-innervated regions such as striatum and nucleus accumbens. Following cocaine-induced seizures, intense c-fos induction was observed in piriform cortex, amygdala, and hippocampus. Quantification of the number of Fos-immunoreactive cells in the brains of prenatally cocaine-treated versus prenatally saline-treated rats revealed differences in piriform cortex and amygdala that were indicative of a lower threshold in prenatally cocaine-treated female rats. Following PTZ-induced seizures, the same pattern of limbic structures were recruited with increasing seizure severity. Only females exhibited changes in the number of Fos-immunoreactive cells as a result of prenatal cocaine treatment. Pretreatment with the noncompetitive NMDA antagonist MK-801 blocked both cocaine- and PTZ-induced seizures, and Fos expression in limbic areas was also blocked. The dopamine D1 antagonist SCH 23390 blocked cocaine-induced seizures and associated c-fos induction, but not PTZ-induced seizures or Fos. Examination of the pattern of Fos expression at 15-20 min postseizure revealed that the initial site of c-fos induction associated with PTZ-induced seizures appeared to be the piriform cortex, whereas cocaine-induced seizures induced early expression in both piriform cortex and lateral amygdala. These findings suggest that neural alterations residing in the piriform cortex and amygdala are likely to account for the increased seizure susceptibility of prenatally cocaine-treated rats.

Animals↗
PubMed1995

Fos-related protein expression in the midline paraventricular nucleus of the rat thalamus: basal oscillation and relationship with limbic efferents.

The expression of Fos-related protein, encoded by the proto-oncogene c-fos, was investigated by means of immunohistochemistry in the paraventricular nucleus of the thalamic midline (PV) during nighttime and daytime in rats entrained to a 12-h light/12-h dark cycle. In the first step of this study the animal's physiological state preceding perfusion was monitored with electro-encephalographic recording. It was thus detected that the PV contained a considerable number of Fos-like-immunostained neurons during the hours of darkness, when the rats had been awake, and that the number of Fos-like-immunoreactive neurons was significantly lower during the hours of light, after a period of sleep. In the second step of this study Fos immunohistochemistry was combined with the retrograde transport of a gold-labeled tracer injected either in the amygdala or in the nucleus accumbens. This strategy enabled us to determine that in the rats perfused during nighttime Fos-related protein was spontaneously induced in PV cells projecting to these targets, with a significant prevalence of neurons projecting to the amygdala in the anterior portion of the PV and of neurons projecting to the nucleus accumbens in the posterior part of the nucleus. In addition, a significant reduction of Fos-like-immunoreactive cells was detected in the PV ipsilaterally to the injection, indicating that tracer administration and axonal transport may interfere with c-fos expression in neurons. Altogether the present data indicate that Fos-related protein expression undergoes a marked oscillation in the PV during 24 h in basal conditions, and that c-fos is induced in the PV relay neuronal subsets when the animal is awake.(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala↗
PubMed1996

Time course of striatal changes induced by 6-hydroxydopamine lesion of the nigrostriatal pathway, as studied by combined evaluation of rotational behaviour and striatal Fos expression.

Changes taking place after unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal system have been studied by performing spontaneous, amphetamine-induced and apomorphine-induced rotational behaviour testing and tyrosine hydroxylase (TH) and Fos protein immunohistochemistry in the same rats. Apomorphine at a low dosage (0.25 mg/kg) induced contraversive rotation and supersensitive striatal Fos expression that were detected 24-48 h post-lesion and gradually increased in magnitude. Twenty-four hours after lesion, both high (5 mg/kg) and low doses (0.5 mg/kg) of D-amphetamine induced contraversive rotation and intense striatal Fos activation on the denervated side; however, only the higher dose induced Fos on the normal side. Two, 3 and 4 days after lesion, 0.5 mg/kg amphetamine induced contraversive rotation, but 5 mg/kg induced transitory contraversive rotation which switched to ipsiversive. In the normal striatum, only high doses of amphetamine induced Fos, but Fos induction in the denervated striatum was similar with both doses: areas showing severely decreased TH immunoreactivity still showed considerable Fos immunoreactivity, and some areas still showing TH immunoreactivity had higher Fos density than in the normal side. Seven and 14 days after lesion the loss of TH immunoreactivity and apomorphine-induced supersensitive Fos expression were more evenly distributed, and amphetamine induced only ipsiversive rotation and a low density of Fos-positive nuclei in the denervated striatum. These results indicate that the severe and progressive loss of dopaminergic terminals is counteracted by an early and rapidly progressing dopamine supersensitivity, together with a higher susceptibility to drug-induced dopamine release. This explains the apparently paradoxical contraversive rotation induced by amphetamine during the first week post lesion. However, experiments involving successive drug injections indicated that only the first amphetamine injection releases dopamine from the lesioned terminals.

Amphetamine↗
PubMed1991

c-fos protein like immunoreactivity in non-neuronal cells of rat peripheral nerve after transection.

The induction of c-fos protein (Fos) in non-neuronal cells of rat sciatic nerve was studied immunocytochemically after transection. As soon as 1 h after transection a few Fos-positive Schwann cells and fibroblast-like cells were seen around the wound margins. In the epi-perineurial fibroblast-like cells Fos-like immunoreactivity (Fos-LI) was most intense at 3 h postoperation, but no Fos-LI was seen at 6 days postoperation. In Schwann cells Fos-LI was spread throughout the distal nerve segment at 6 days postoperation, when the staining (in these cells) was most intense. Fos-immunoreactive Schwann cells in the distal nerve segment were still detectable at 14 days postoperation. In the proximal nerve segment positively labelled Schwann cells were observed only 1 and 3 h postoperation and were localized near the site of injury. The results show that the loss of nerve fibers induces a long-lasting expression of Fos or Fos-related antigens in a peripheral nerve.

Animals↗
PubMed2004

Changes in c-fos expression in the rat heart during morphine withdrawal. Involvement of alpha2-adrenoceptors.

We previously demonstrated an increase in Fos expression in the heart during morphine withdrawal. In the present study we examined the role of beta- and alpha-adrenoceptors in naloxone-precipitated increases in Fos expression in the heart. Dependence on morphine was induced by 7-day chronic subcutaneous implantation of six morphine pellets (75 mg). Morphine withdrawal was precipitated by administration of naloxone (5 mg/kg subcutaneously) on day 8. Using immunohistochemical staining of Fos, the present results indicate that morphine withdrawal induced marked Fos immunoreactivity (Fos-IR) within the cardiomyocyte nuclei. Moreover, Western blot analysis revealed a peak expression of c-fos in the right and left ventricles after naloxone-precipitated withdrawal in parallel with an increase in noradrenaline (NA) turnover. In the second study, the effects of the administration of adrenoceptor antagonists on withdrawal-induced Fos expression in the heart were studied. Pretreatment with the beta antagonist, propranolol (3 mg/kg intraperitoneally) or alpha1-adrenoceptor antagonist, prazosin (1 mg/kg intraperitoneally) did not block the marked Fos-IR or the hyperactivity of catecholaminergic neurons observed in the heart during withdrawal. However, pre-treatment with alpha2-adrenoceptor antagonist, yohimbine (1 mg/kg intraperitoneally), 20 min before naloxone administration to morphine-dependent rats antagonized Fos expression and the enhancement of NA turnover in the heart. Collectively, these results suggest that noradrenergic neurons in the heart are active during morphine withdrawal, and that activation of transcriptional responses mediated by Fos are dependent upon cardiac alpha2-adrenoceptor.

Adrenergic alpha-2 Receptor Antagonists↗