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Sample records for stimulus-induced fos expression

  1. c-Fos expression during temporal order judgment in mice.

    PubMed

    Wada, Makoto; Higo, Noriyuki; Moizumi, Shunjiro; Kitazawa, Shigeru

    2010-05-05

    The neuronal mechanisms for ordering sensory signals in time still need to be clarified despite a long history of research. To address this issue, we recently developed a behavioral task of temporal order judgment in mice. In the present study, we examined the expression of c-Fos, a marker of neural activation, in mice just after they carried out the temporal order judgment task. The expression of c-Fos was examined in C57BL/6N mice (male, n = 5) that were trained to judge the order of two air-puff stimuli delivered bilaterally to the right and left whiskers with stimulation intervals of 50-750 ms. The mice were rewarded with a food pellet when they responded by orienting their head toward the first stimulus (n = 2) or toward the second stimulus (n = 3) after a visual "go" signal. c-Fos-stained cell densities of these mice (test group) were compared with those of two control groups in coronal brain sections prepared at bregma -2, -1, 0, +1, and +2 mm by applying statistical parametric mapping to the c-Fos immuno-stained sections. The expression of c-Fos was significantly higher in the test group than in the other groups in the bilateral barrel fields of the primary somatosensory cortex, the left secondary somatosensory cortex, the dorsal part of the right secondary auditory cortex. Laminar analyses in the primary somatosensory cortex revealed that c-Fos expression in the test group was most evident in layers II and III, where callosal fibers project. The results suggest that temporal order judgment involves processing bilateral somatosensory signals through the supragranular layers of the primary sensory cortex and in the multimodal sensory areas, including marginal zone between the primary somatosensory cortex and the secondary sensory cortex.

  2. Regional c-Fos and FosB/ΔFosB expression associated with chronic methamphetamine self-administration and methamphetamine-seeking behavior in rats.

    PubMed

    Cornish, J L; Hunt, G E; Robins, L; McGregor, I S

    2012-03-29

    The regional expression of the transcription factors c-Fos and FosB/ΔFosB was examined in rats given acute exposure to intravenous methamphetamine (METH) or repeated intravenous METH self-administration. One group of rats self-administered METH via lever pressing in 2 h sessions every day for 3 weeks and on a final test day received self-administered METH as usual. A second group with the same METH self-administration history received saline infusions on the test day, to induce drug-seeking behavior. Other rats were trained with infusions of intravenous saline that were yoked to the passive delivery of METH in the other two groups. On test day, half of these yoked rats received passive METH infusions for the first time, whereas the others received saline as usual. The results showed that acute METH produced a characteristic signature of Fos expression with elevations in striatal, cortical, and extended amygdala regions. Importantly, rats with a 3-week history of METH self-administration displayed similar regional Fos expression to rats receiving METH for the first time. Rats seeking, but not receiving, METH on the test day had augmented Fos in the lateral hypothalamus, septum, and vertical limb of the diagonal band of Broca, suggesting a primary role for these regions in METH-seeking behavior. Both acute and chronic METH activated orexin-positive cells in the perifornical area of the hypothalamus. FosB/ΔFosB was elevated in the lateral hypothalamus, posterior ventral tegmental area, central amygdala, and dorsal raphe of all the rats with a history of METH self-administration. This occurred regardless of whether they received METH on test day, suggesting presence of the long-lived FosB isoform, ΔFosB. Overall, these results show persistent upregulated regional brain Fos and FosB/ΔFosB expression with chronic METH self-administration and indicate a role for the lateral hypothalamus and lateral septum in METH-seeking behavior.

  3. Correlation of Fos expression and circling asymmetry during gerbil vestibular compensation

    NASA Technical Reports Server (NTRS)

    Kaufman, G. D.; Shinder, M. E.; Perachio, A. A.

    1999-01-01

    Vestibular compensation is a central nervous system process resulting in recovery of functional movement and control following a unilateral vestibular lesion. Small pressure injections of phosphorothioate 20mer oligonucleotides were used to probe the role of the Fos transcription protein during vestibular compensation in the gerbil brainstem. During isoflurane gas anesthesia, antisense probes against the c-fos mRNA sequence were injected into the medial vestibular and prepositus nuclei unilaterally prior to a unilateral surgical labyrinthectomy. Anionic dyes, which did not interact with the oligonucleotides, were used to mark the injection site and help determine the extent of diffusion. The antiFos oligonucleotide injections reduced Fos expression at the injection site in neurons which normally express Fos after the lesion, and also affected circling behavior induced by hemilabyrinthectomy. With both ipsilateral and contralateral medial vestibular and prepositus nuclei injections, less ipsilateral and more contralateral circling was noted in animals injected with antiFos injections as compared to non-injected controls. The degree of change in these behaviors was dependent upon the side of the injection. Histologically, antiFos injections reduced the number of Fos immunolabeled neurons around the injection site, and increased Fos expression contralaterally. The correlation of the number of neurons with Fos expression to turning behavior was stronger for contralateral versus ipsilateral turns, and for neurons in the caudal and ipsilateral sub-regions of the medial vestibular and prepositus nuclei. The results are discussed in terms of neuronal firing activity versus translational activity based on the asymmetrical expression of the Fos inducible transcription factor in the medial vestibular and prepositus nuclei. Although ubiquitous in the brain, transcription factors like Fos can serve localized and specific roles in sensory-specific adaptive stimuli. Antisense

  4. FOS Expression in Blood as a LDL-Independent Marker of Statin Treatment

    PubMed Central

    Kang, Ju-Gyeong; Sung, Ho Joong; Jawed, Sarah I.; Brenneman, Cynthia L.; Rao, Yesoda N.; Sher, Salman; Facio, Flavia M.; Biesecker, Leslie G.; Quyyumi, Arshed A.; Sachdev, Vandana; Hwang, Paul M.

    2010-01-01

    Objectives The expression of FOS, a gene critical for monocyte and macrophage function, can be inhibited by statins through the disruption of a cholesterol independent signaling pathway. In this pilot study, we hypothesized that blood FOS mRNA levels will be sensitive to statin treatment independent of LDL cholesterol levels. Methods Three cohorts at increased risk of or with cardiovascular disease (CVD) were studied. Blood FOS mRNA levels were measured before and after statin treatment or in patients under stable treatment. Results Statin treatment for three months significantly reduced blood FOS mRNA and LDL cholesterol levels. However, in subjects with similar LDL levels achieved by different doses of long term statin treatment, there was an inverse relationship between statin dose and FOS expression. Conclusions FOS mRNA levels appear to be a sensitive marker of statin treatment that is dissociated from cholesterol levels. PMID:20619839

  5. Nitric oxide mediates Fos expression in the spinal cord induced by mechanical noxious stimulation.

    PubMed

    Lee, J H; Wilcox, G L; Beitz, A J

    1992-10-01

    Immunocytochemical localization of Fos protein was used to analyze the involvement of nitric oxide (NO) in the expression of Fos in the spinal cord, induced by mechanical noxious stimulation (NS). Mechanical NS was applied to the left hindpaw 30 minutes after intrathecal administration of the NO synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME) and the resulting Fos expression in the spinal cord dorsal horn was compared with that obtained in rats exposed only to the mechanical NS. Pretreatment with L-NAME but not its stereoisomer N omega-nitro-D-arginine methyl ester (D-NAME), produced a dose-dependent suppression of Fos expression induced by mechanical noxious stimulation. These results indicate that NO modulates the expression of Fos in the dorsal horn induced by mechanical noxious stimulation and further support the hypothesis that NO is involved in nociceptive events occurring in the spinal cord in response to a peripheral noxious stimulus.

  6. Activation of c-fos expression in the rat inferior olivary nucleus by ghrelin.

    PubMed

    Zhang, Weizhen; Lin, Theodore R; Hu, Yuexian; Fan, Yongyi; Zhao, Lili; Mulholland, Michael W

    2003-12-26

    Ghrelin, a novel 28-amino-acid hormone secreted by gastric oxyntic glands, stimulates food intake and induces adiposity. We examined whether ghrelin activates the inferior olivary nucleus. Systemic administration of ghrelin (37 nmol/kg) induced the expression of c-fos immunoreactivity in inferior olive neurons (n=6 rats). The number of neurons containing c-fos staining was significantly increased in the ghrelin-treated rats (65+/-14 vs.11+/-6 positive neurons, n=5). No significant difference in c-fos-positive neurons was observed between left (32+/-5) and right (33+/-6) inferior olivary nuclei. The number of c-fos-positive neurons in rats with bilateral vagotomy was not significantly different from those with intact vagal nerves. The present study demonstrates that ghrelin induces c-fos expression in inferior olivary nucleus via a central mechanism.

  7. Expression of the proto-oncogene Fos after exposure to radiofrequency radiation relevant to wireless communications.

    PubMed

    Whitehead, Timothy D; Brownstein, Bernard H; Parry, Jesse J; Thompson, Dominic; Cha, Bibianna A; Moros, Eduardo G; Rogers, Buck E; Roti Roti, Joseph L

    2005-10-01

    In this study the expression levels of the proto-oncogene Fos were measured after exposure to radiofrequency (RF) radiation at two relatively high specific absorption rates (SARs) of 5 and 10 W/kg for three types of modulated signals: 847.74 MHz code division multiple access (CDMA), 835.62 MHz frequency division multiple access (FDMA), and 836.55 MHz time division multiple access (TDMA). This work was undertaken to confirm a previous report by Goswami et al. (Radiat. Res. 151, 300-309, 1999) that CDMA and FDMA radiation caused small but statistically significant increases in Fos levels as cells entered plateau phase during exposure. No effects on Myc or Jun levels were observed in that study. Therefore, in the present study, analyses were restricted to Fos expression during the transition from exponential growth to plateau phase. Fos expression was measured using the real-time polymerase chain reaction (RT-PCR) technique. Serum-stimulated C3H 10T(1/2) cells were used as a positive control for Fos expression. Possible influences of final cell number or pH variability on Fos expression were evaluated. Expression of Fos mRNA in C3H 10T(1/2) cells was not significantly different from that found after sham exposure at either SAR level for any signal modulation. Therefore, the results of Goswami et al. could not be confirmed.

  8. In vivo correlation between c-Fos expression and corticotroph stimulation by adrenocorticotrophic hormone secretagogues in rat anterior pituitary gland.

    PubMed

    Takigami, Shu; Fujiwara, Ken; Kikuchi, Motoshi; Yashiro, Takashi

    2008-03-01

    In the anterior pituitary gland, c-Fos expression is evoked by various stimuli. However, whether c-Fos expression is directly related to the stimulation of anterior pituitary cells by hypothalamic secretagogues is unclear. To confirm whether the reception of hormone-releasing stimuli evokes c-Fos expression in anterior pituitary cells, we have examined c-Fos expression of anterior pituitary glands in rats administered with synthetic corticotrophin-releasing hormone (CRH) intravenously or subjected to restraint stress. Single intravenous administration of CRH increases the number of c-Fos-expressing cells, and this number does not change even if the dose is increased. Double-immunostaining has revealed that most of the c-Fos-expressing cells contain adrenocorticotrophic hormone (ACTH); corticotrophs that do not express c-Fos in response to CRH have also been found. However, restraint stress evokes c-Fos expression in most of the corticotrophs and in a partial population of lactotrophs. These results suggest that c-Fos expression increases in corticotrophs stimulated by ACTH secretagogues, including CRH. Furthermore, we have found restricted numbers of corticotrophs expressing c-Fos in response to CRH. Although the mechanism underlying the different responses to CRH is not apparent, c-Fos is probably a useful immunohistochemical marker for corticotrophs stimulated by ACTH secretagogues.

  9. A Simple Method for Immunohistochemical Staining of Zebrafish Brain Sections for c-fos Protein Expression.

    PubMed

    Chatterjee, Diptendu; Tran, Steven; Shams, Soaleha; Gerlai, Robert

    2015-12-01

    Immediate early genes (IEGs) are transcription factors whose own transcription is initiated rapidly, for example, in the brain in response to environmental stimuli. c-fos is an IEG often used as a marker of neuronal activation. c-fos mRNA expression has started to be quantified and localized in the zebrafish brain following environmental manipulations but analysis of the expression of c-fos protein in the zebrafish brain has rarely been attempted. Here, we describe an immunofluorescence staining method for quantifying c-fos protein expression in different regions of the zebrafish brain. In addition, we expose zebrafish to caffeine, a positive control for c-fos activation in the brain. To confirm cell nucleus specific binding of the c-fos antibody, we counterstained brain sections with the nuclear fluorescent stain DAPI. Furthermore, we describe a method for reducing background autofluorescence often observed in zebrafish brain tissue. Our analysis showed that exposure to caffeine increased the number of c-fos protein-positive cells in specific zebrafish brain regions detected by the immunofluorescence method. Our results demonstrate the feasibility of immunofluorescence-based methods in the analysis of neuronal activation in the zebrafish brain, and reinforce the utility of the zebrafish in behavioral neuroscience research.

  10. Sustained Fos expression is observed in the developing brainstem auditory circuits of kanamycin-treated rats.

    PubMed

    Lee, Jae Ho; Kim, Hee Jung; Suh, Myung-Whan; Ahn, Seung Cheol

    2011-11-14

    It has been demonstrated that kanamycin treatment during early developmental period induces partial cochlear destruction and enhanced glutamatergic transmission at the medial nucleus of the trapezoid body (MNTB) - the lateral superior olive (LSO) synapses in the superior olivary complex (SOC). As c-fos was expected to be expressed in the SOC by kanamycin-induced cochlear damage, the expression of c-fos protein (Fos) was investigated using immunohistochemistry in kanamycin-treated rat pups. In the control rat pups less than postnatal (P) day 9 in age, Fos-like immunoreactivity (Fos-IR) was transiently observed in the MNTB and LSO on P6, but disappeared on P9, which reflects a physiologic process. In contrast, in kanamycin-treated rats, Fos-IR was consistently observed through P9. Because a significant increase in terminal uridine deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick-end labeling (TUNEL) and glial fibrillary acidic protein (GFAP) IR was not demonstrated in the MNTB and LSO of kanamycin-treated rats, the increased Fos-IR does not appear to indicate an ongoing pathologic process, but may be related to the increased activity caused by the disturbance in excitatory and inhibitory balance between brainstem auditory circuits.

  11. Persistent induction of c-fos and c-jun expression by asbestos

    SciTech Connect

    Heintz, N.H.; Mossman, B.T. ); Janssen, Y.M. Univ. of Limburg, Maastricht )

    1993-04-15

    To investigate the mechanisms of asbestos-induced carcinogenesis, expression of c-fos and c-jun protooncogenes was examined in rat pleural mesothelial cells and hamster tracheal epithelial cells after exposure to crocidolite or chrysotile asbestos. In contrast to phorbol 12-myristate 13-acetate, which induces rapid and transient increases in c-fos and c-jun mRNA, asbestos causes 2- to 5-fold increases in c-fos and c-jun mRNA that persist for at least 24 hr in mesothelial cells. The induction of c-fos and c-jun mRNA by asbestos in mesothelial cells is dose-dependent and is most pronounced with crocidolite, the type of asbestos most pathogenic in the causation of pleural mesothelioma. Induction of c-jun gene expression by asbestos occurs in tracheal epithelial cells but is not accompanied by a corresponding induction of c-fos gene expression. In both cell types, asbestos induces increases in protein factors that bind specifically to the DNA sites that mediate gene expression by the AP-1 family of transcription factors. The persistent induction of AP-1 transcription factors by asbestos suggests a model of asbestos-induced carcinogenesis involving chronic stimulation of cell proliferation through activation of the early response gene pathway that includes c-jun and/or c-fos. 30 refs., 5 figs.

  12. Fos Expression in Rat Brain During Depletion-Induced Thirst and Salt Appetite

    NASA Technical Reports Server (NTRS)

    Thunhorst, R. L.; Xu, Z.; Cicha, M. Z.; Zardetto-Smith, A. M.; Johnson, A. K.

    1998-01-01

    The expression of Fos protein (Fos immunoreactivity, Fos-ir) was mapped in the brain of rats subjected to an angiotensin-dependent model of thirst and salt appetite. The physiological state associated with water and sodium ingestion was produced by the concurrent subcutaneous administration of the diuretic furosemide (10 mg/kg) and a low dose of the angiotensin-converting enzyme (ACE) inhibitor captopril (5 mg/kg; Furo/Cap treatment). The animals were killed 2 h posttreatment, and the brains were processed for Fos-ir to assess neural activation. Furo/Cap treatment significantly increased Fos-ir density above baseline levels both in structures of the lamina terminalis and hypothalamus known to mediate the actions of ANG 2 and in hindbrain regions associated with blood volume and pressure regulation. Furo/Cap treatment also typically increased Fos-ir density in these structures above levels observed after administration of furosemide or captopril separately. Fos-ir was reduced to a greater extent in forebrain than in hindbrain areas by a dose of captopril (100 mg/kg sc) known to block the actions of ACE in the brain. The present work provides further evidence that areas of lamina terminalis subserve angiotensin-dependent thirst and salt appetite.

  13. Delta-9-tetrahydrocannabinol differently affects striatal c-Fos expression following haloperidol or clozapine administration.

    PubMed

    Marchese, Giorgio; Sanna, Angela; Casu, Gianluca; Casti, Paola; Spada, Gabriele Pinna; Ruiu, Stefania; Pani, Luca

    2008-11-19

    It was previously shown that haloperidol, but not clozapine, induced intense rat catalepsy when co-administered with delta-9-tetrahydrocannabinol. The present study investigated whether similar alterations could be observed on striatal c-Fos immunoreactivity after administration of the same drug combinations. Western Blot and immunocytochemistry stereological analyses indicated that delta-9-tetrahydrocannabinol (0.5 mg/kg) increased striatal c-Fos immunoreactivity induced by haloperidol (0.1 mg/kg). Conversely, no significant alterations of striatal c-Fos immunoreactivity were observed after injections of clozapine (10 mg/kg)+vehicle, clozapine+delta-9-tetrahydrocannabinol or vehicle+delta-9-tetrahydrocannabinol. The present results indicate that the behavioral effects induced by delta-9-tetrahydrocannabinol in haloperidol- and clozapine-treated rats are associated with different striatal c-Fos expressions.

  14. c-Fos expression correlates with performance on novel object and novel place recognition tests.

    PubMed

    Mendez, Marta; Arias, Natalia; Uceda, Sara; Arias, Jorge L

    2015-08-01

    In rodents, many studies have been carried out using novelty-preference paradigms. The results show that the perirhinal cortex and the hippocampus are involved in the recognition of a novel object, "what", and its new position, "where", respectively. We employed these two variants of a novelty-preference paradigm to assess whether the expression of the immediate-early gene c-fos in the dorsal hippocampus and perirhinal cortex correlates with the performance discrimination ratio (d2), on the respective versions of the novelty preference tests. A control group (CO) was added to explore c-fos activation not specific to recognition. The results showed different patterns of c-Fos protein expression in the hippocampus and perirhinal cortex. The Where Group presented more c-Fos positive nuclei than the What and CO groups in the CA1 and CA3 regions, whereas in the perirhinal cortex, the What Group showed more c-Fos positive nuclei than the Where and CO groups. The correlation results indicate that levels of c-Fos in the CA1 area and perirhinal cortex correlate with effective exploration, d2, on the respective versions of the novelty preference tests, novel place and novel object recognition. These data suggest that the hippocampal CA1 and perirhinal cortex are specifically related to the level of recognition of place and objects, respectively.

  15. Increased dietary sodium alters Fos expression in the lamina terminalis during intravenous angiotensin II infusion.

    PubMed

    Bealer, Steven L; Metcalf, Cameron S; Heyborne, Ryan

    2007-03-01

    These studies examined the effects of increased dietary sodium on expression of Fos, the protein product of c-fos, in forebrain structures in the rat following intravenous infusion with angiotensin II (AngII). Animals were provided with either tap water (Tap) or isotonic saline solution (Iso) as their sole drinking fluid for 3-5 weeks prior to testing. Rats were then implanted with catheters in a femoral artery and vein. The following day, the conscious, unrestrained animals received iv infusion of either isotonic saline (Veh), AngII, or phenylephrine (Phen) for 2 h. Blood pressure and heart rate were monitored continuously throughout the procedure. Brains were subsequently processed for evaluation of Fos-like immunoreactivity (Fos-Li IR) in the organum vasculosum of the lamina terminalis (OVLT), the subfornical organ (SFO), and the median preoptic nucleus (MnPO). Fos-Li IR was significantly increased in the SFO and OVLT of animals consuming both Tap and Iso following AngII, but not Phen, compared to Veh infusions. Furthermore, Fos-Li IR in the MnPO was increased following AngII infusion in rats consuming a high sodium diet, but not in animals drinking Tap. These data suggest that increased dietary sodium sensitizes the MnPO neurons to excitatory input from brain areas responding to circulating AngII.

  16. c-Fos over-expression promotes radioresistance and predicts poor prognosis in malignant glioma

    PubMed Central

    Feng, Guokai; Chen, Furong; Tu, Ziwei; Liu, Guiyun; Zhao, Yu; Peng, Ming-Jing; He, Zheng-Wen; Chen, Xiao-Yan; Lindsay, Holly; Xia, Yun-Fei; Li, Xiao-Nan

    2016-01-01

    c-Fos is a major component of activator protein (AP)-1 complex. It has been implicated in cell differentiation, proliferation, angiogenesis, invasion, and metastasis. To investigate the role of c-Fos in glioma radiosensitivity and to understand the underlying molecular mechanisms, we downregulated c-Fos gene expression by lentivirus-mediated shRNA in glioma cell lines and subsequently analyzed the radiosensitivity, DNA damage repair capacity, and cell cycle distribution. Finally, we explored its prognostic value in 41 malignant glioma patients by immunohistochemistry. Our results showed that silencing c-Fos sensitized glioma cells to radiation by increasing radiation-induced DNA double strand breaks (DSBs), disturbing the DNA damage repair process, promoting G2/M cell cycle arrest, and enhancing apoptosis. c-Fos protein overexpression correlated with poor prognosis in malignant glioma patients treated with standard therapy. Our findings provide new insights into the mechanism of radioresistance in malignant glioma and identify c-Fos as a potentially novel therapeutic target for malignant glioma patients. PMID:27602752

  17. The atypical dopamine D1 receptor agonist SKF 83959 induces striatal Fos expression in rats.

    PubMed

    Wirtshafter, David; Osborn, Catherine V

    2005-12-28

    The effects of dopamine D1 receptor agonists are often presumed to result from an activation of adenylyl cyclase, but dopamine D1 receptors may also be linked to other signal transduction cascades and the relative importance of these various pathways is currently unclear. SKF 83959 is an agonist at dopamine D1 receptors linked to phospholipase C, but has been reported to be an antagonist at receptors linked to adenylyl cyclase. The current report demonstrates that SKF 83959 induces pronounced, nonpatchy, expression of the immediate-early gene product Fos in the striatum of intact rats which can be converted to a patchy pattern by pretreatment with the dopamine D2-like receptor agonist quinpirole. In rats with unilateral 6-hydroxydopamine lesions SKF 83959 induces strong behavioral rotation and a greatly potentiated Fos response. All of the responses to SKF 83959, in both intact and dopamine-depleted animals, can be blocked by pretreatment with the dopamine D1 receptor antagonist SCH-23390. In intact subjects, SKF 83959 induced Fos expression less potently than the standard dopamine D1 receptor agonist SKF 82958, but the two drugs were approximately equipotent in deinnervated animals. These results demonstrate for the first time that possession of full efficacy at dopamine D1 receptors linked to adenylyl cyclase is not a necessary requirement for the induction of striatal Fos expression in intact animals and suggest that alternative signal transduction pathways may play a role in dopamine agonist induced Fos expression, especially in dopamine-depleted subjects.

  18. Peripheral injection of ghrelin induces Fos expression in the dorsomedial hypothalamic nucleus in rats

    PubMed Central

    Kobelt, Peter; Wisser, Anna-Sophia; Stengel, Andreas; Goebel, Miriam; Inhoff, Tobias; Noetzel, Steffen; Veh, Rüdiger W.; Bannert, Norbert; van der Voort, Ivo; Wiedenmann, Bertram; Klapp, Burghard F.; Taché, Yvette; Mönnikes, Hubert

    2009-01-01

    Peripheral ghrelin has been shown to act as a gut–brain peptide exerting a potent orexigenic effect on food intake. The dorsomedial nucleus of the hypothalamus (DMH) is innervated by projections from other brain areas being part of the network of nuclei controlling energy homeostasis, among others NPY/AgRP-positive fibers arising from the arcuate nucleus (ARC). The aim of the study was to determine if peripherally administered ghrelin affects neuronal activity in the DMH, as assessed by Fos expression. The number of Fos positive neurons was determined in the DMH, paraventricular nucleus of the hypothalamus (PVN), ARC, ventromedial hypothalamic nucleus (VMH), nucleus of the solitary tract (NTS) and in the area postrema(AP) in non-fasted Sprague–Dawley rats in response to intraperitoneally (ip) injected ghrelin (3 nmol/rat) or vehicle (0.15 M NaCl). Peripheral ghrelin induced a significant increase in the number of Fos-ir positive neurons/section compared with vehicle in the ARC (mean±SEM: 49±2 vs. 23±2 neurons/section, p=0.001), PVN (69±5 vs. 34±3, p=0.001), and DMH (142±5 vs. 83±5, p<0.001). Fos-ir positive neurons were mainly localized within the ventral part of the DMH. No change in Fos expression was observed in the VMH (53±8 vs. 48±6, p=0.581), NTS (42±2 vs.40±3, p=0.603), and in the AP (7±1 vs. 5±1, p=0.096). Additional double-labelling with anti-Fos and anti-AgRP revealed that Fos positive neurons in the DMH were encircled by a network of AgRP-ir positive fibers. These data indicate that peripheral ghrelin activates DMH neurons and that NPY-/AgRP-positive fibers may be involved in the response. PMID:18329635

  19. Acute estrogen surge enhances inflammatory nociception without altering spinal Fos expression.

    PubMed

    Ralya, Andrew; McCarson, Kenneth E

    2014-07-11

    Chronic pain is a major neurological disorder that can manifest differently between genders or sexes. The complex actions of sex hormones may underlie these differences; previous studies have suggested that elevated estrogen levels can enhance pain perception. The purpose of this study was to investigate the hypothesis that acute, activational effects of estradiol (E2) increase persistent inflammatory nociception, and anatomically where this modulation occurs. Spinal expression of Fos is widely used as a marker of nociceptive activation. This study used formalin-evoked nociception in ovariectomized (OVX) adult female rats and measured late-phase hindlimb flinching and Fos expression in the spinal cord, and their modification by acute estrogen supplementation similar to a proestrus surge. Six days after ovariectomy, female rats were injected subcutaneously (s.c.) with 10μg/kg E2 or vehicle. Twenty-four hours later, 50μL of 1.25% or 100μL of 5% formalin was injected into the right hindpaw; hindlimb flinches were counted, and spinal cords removed 2h after formalin injection. The numbers of Fos-expressing neurons in sections of the lumbar spinal cord were analyzed using immunohistochemistry. Formalin-induced inflammation produced a dose-dependent increase in late-phase hindlimb flinching, and E2 pretreatment increased flinching following 5%, but not 1.25% formalin injection. Despite the modification of behavior by E2, the number of spinal Fos-positive neurons was not altered by E2 pretreatment. These findings demonstrate that an acute proestrus-like surge in serum estrogen can produce a stimulus-intensity-dependent increase in inflammation-evoked nociceptive behavior. However, the lack of effect on spinal Fos expression suggests that this enhancement of nociceptive signaling by estrogen is independent of changes in peripheral activation of, expression of the immediate early gene Fos by, or signal throughput of spinal nociceptive neurons.

  20. Mechanically induced c-fos expression is mediated by cAMP in MC3T3-E1 osteoblasts

    NASA Technical Reports Server (NTRS)

    Fitzgerald, J.; Hughes-Fulford, M.

    1999-01-01

    In serum-deprived MC3T3-E1 osteoblasts, mechanical stimulation caused by mild (287 x g) centrifugation induced a 10-fold increase in mRNA levels of the proto-oncogene, c-fos. Induction of c-fos was abolished by the cAMP-dependent protein kinase inhibitor H-89, suggesting that the transient c-fos mRNA increase is mediated by cAMP. Down-regulation of protein kinase C (PKC) activity by chronic TPA treatment failed to significantly reduce c-fos induction, suggesting that TPA-sensitive isoforms of PKC are not responsible for c-fos up-regulation. In addition, 287 x g centrifugation increased intracellular prostaglandin E2 (PGE2) levels 2.8-fold (P<0. 005). Since we have previously shown that prostaglandin E2 (PGE2) can induce c-fos expression via a cAMP-mediated mechanism, we asked whether the increase in c-fos mRNA was due to centrifugation-induced PGE2 release. Pretreatment with the cyclooxygenase inhibitors indomethacin and flurbiprofen did not hinder the early induction of c-fos by mechanical stimulation. We conclude that c-fos expression induced by mild mechanical loading is dependent primarily on cAMP, not PKC, and initial induction of c-fos is not necessarily dependent on the action of newly synthesized PGE2.

  1. 'Fluorescent Cell Chip' for immunotoxicity testing: Development of the c-fos expression reporter cell lines

    SciTech Connect

    Trzaska, Dominika; Zembek, Patrycja; Olszewski, Maciej; Adamczewska, Violetta; Ulleras, Erik; Dastych, JarosIaw . E-mail: jdastych@cbm.pan.pl

    2005-09-01

    The Fluorescent Cell Chip for in vitro immunotoxicity testing employs cell lines derived from lymphocytes, mast cells, and monocytes-macrophages transfected with various EGFP cytokine reporter gene constructs. While cytokine expression is a valid endpoint for in vitro immunotoxicity screening, additional marker for the immediate-early response gene expression level could be of interest for further development and refinement of the Fluorescent Cell Chip. We have used BW.5147.3 murine thymoma transfected with c-fos reporter constructs to obtain reporter cell lines expressing ECFP under the control of murine c-fos promoter. These cells upon serum withdrawal and readdition and incubation with heavy metal compounds showed paralleled induction of c-Fos expression as evidenced by Real-Time PCR and ECFP fluorescence as evidenced by computer-supported fluorescence microscopy. In conclusion, we developed fluorescent reporter cell lines that could be employed in a simple and time-efficient screening assay for possible action of chemicals on c-Fos expression in lymphocytes. The evaluation of usefulness of these cells for the Fluorescent Cell Chip-based detection of immunotoxicity will require additional testing with a larger number of chemicals.

  2. d-LSD-induced c-Fos expression occurs in a population of oligodendrocytes in rat prefrontal cortex.

    PubMed

    Reissig, Chad J; Rabin, Richard A; Winter, Jerrold C; Dlugos, Cynthia A

    2008-03-31

    Induction of mRNA or protein for immediate-early genes, such as c-fos, is used to identify brain areas, specific cell types, and neuronal circuits that become activated in response to various stimuli including psychoactive drugs. The objective of the present study was to identify the cell types in the prefrontal cortex in which lysergic acid diethylamide (d-LSD) induces c-Fos expression. Systemic administration of d-LSD resulted in a dose-dependent increase in c-Fos immunoreactivity. Although c-Fos-positive cells were found in all cortical layers, they were most numerous in layers III, IV, and V. d-LSD-induced c-Fos immunoreactivity was found in cells co-labeled with anti-neuron-specific enolase or anti-oligodendrocyte Oligo1. The Oligo1-labeled cells had small, round bodies and nuclear diameters characteristic of oligodendrocytes. Studies using confocal microscopy confirmed colocalization of c-Fos-labeled nuclei in NeuN-labeled neurons. Astrocytes and microglia labeled with glial fibrillary acidic protein antibody and OX-42 antibody, respectively, did not display LSD-induced c-Fos expression. Pyramidal neurons labeled with anti-neurofilament antibody also did not show induction of c-Fos immunoreactivity after systemic d-LSD administration. The present study demonstrates that d-LSD induced expression of c-Fos in the prefrontal cortex occurs in subpopulations of neurons and in oligodendrocytes, but not in pyramidal neurons, astrocytes, and microglia.

  3. Baclofen did not modify sexually dimorphic c-Fos expression during morphine withdrawal syndrome.

    PubMed

    Pedrón, Valeria T; Taravini, Irene R E; Induni, Andrea S; Balerio, Graciela N

    2013-03-01

    In previous studies, we have reported sex-related differences during morphine withdrawal. We have also shown that the GABA(B) agonist baclofen (BAC) was able to prevent the morphine withdrawal syndrome in male as well as in female mice. Considering that early gene expression is induced by drugs of abuse, we evaluated the expression of c-Fos in several brain areas, in mice of either sex during naloxone (NAL)-precipitated withdrawal, and after pretreatment with BAC. Swiss-Webster prepubertal mice were rendered dependent by i.p. injection of morphine (2 mg/kg), twice daily for 9 days. On the 10th day, dependent mice were divided into two groups: the withdrawal group received NAL (6 mg/kg, i.p.) after the last dose of morphine, while the prevention group received BAC (2 mg/kg, i.p.) before NAL. Thirty minutes after NAL, animals were sacrificed by transcardial perfusion. Brains were removed and slices were obtained to perform immunohistochemical studies. Our results show a significant decrease in c-Fos expression in hippocampal dentate gyrus, CA3, and CA1 areas of morphine withdrawn males, vs. their control group. Conversely, in females, the number of c-Fos positive nuclei was not modified in any of the areas studied. BAC pretreatment had no effect on the decreased c-Fos expression in morphine withdrawn males. The sexual dimorphism observed here confirms the greater sensitivity of males over females in their response to morphine. The preventive action of BAC on the expression of morphine withdrawal would not be related to an effect on c-Fos expression.

  4. Imaging C-Fos Gene Expression in Burns Using Lipid Coated Spion Nanoparticles.

    PubMed

    Papagiannaros, Aristarchos; Righi, Valeria; Day, George G; Rahme, Laurence G; Liu, Philip K; Fischman, Alan J; Tompkins, Ronald G; Tzika, A Aria

    2012-10-01

    MR imaging of gene transcription is important as it should enable the non-invasive detection of mRNA alterations in disease. A range of MRI methods have been proposed for in vivo molecular imaging of cells based on the use of ultra-small super-paramagnetic iron oxide (USPIO) nanoparticles and related susceptibility weighted imaging methods. Although immunohistochemistry can robustly differentiate the expression of protein variants, there is currently no direct gene assay technique that is capable of differentiating established to differentiate the induction profiles of c-Fos mRNA in vivo. To visualize the differential FosB gene expression profile in vivo after burn trauma, we developed MR probes that link the T2* contrast agent [superparamagnetic iron oxide nanoparticles (SPION)] with an oligodeoxynucleotide (ODN) sequence complementary to FosB mRNA to visualize endogenous mRNA targets via in vivo hybridization. The presence of this SPION-ODN probe in cells results in localized signal reduction in T2*-weighted MR images, in which the rate of signal reduction (R2*) reflects the regional iron concentration at different stages of amphetamine (AMPH) exposure in living mouse tissue. Our aim was to produce a superior contrast agent that can be administered using systemic as opposed to local administration and which will target and accumulate at sites of burn injury. Specifically, we developed and evaluated a PEGylated lipid coated MR probe with ultra-small super-paramagnetic iron oxide nanoparticles (USPION, a T2 susceptibility agent) coated with cationic fusogenic lipids, used for cell transfection and gene delivery and covalently linked to a phosphorothioate modified oligodeoxynucleotide (sODN) complementary to c-Fos mRNA (SPION-cFos) and used the agent to image mice with leg burns. Our study demonstrated the feasibility of monitoring burn injury using MR imaging of c-Fos transcription in vivo, in a clinically relevant mouse model of burn injury for the first time.

  5. Lysergic acid diethylamide-induced Fos expression in rat brain: role of serotonin-2A receptors.

    PubMed

    Gresch, P J; Strickland, L V; Sanders-Bush, E

    2002-01-01

    Lysergic acid diethylamide (LSD) produces altered mood and hallucinations in humans and binds with high affinity to serotonin-2A (5-HT(2A)) receptors. Although LSD interacts with other receptors, the activation of 5-HT(2A) receptors is thought to mediate the hallucinogenic properties of LSD. The goal of this study was to identify the brain sites activated by LSD and to determine the influence of 5-HT(2A) receptors in this activation. Rats were pretreated with the 5-HT(2A) receptor antagonist MDL 100907 (0.3 mg/kg, i.p.) or vehicle 30 min prior to LSD (500 microg/kg, i.p.) administration and killed 3 h later. Brain tissue was examined for Fos protein expression by immunohistochemistry. LSD administration produced a five- to eight-fold increase in Fos-like immunoreactivity in medial prefrontal cortex, anterior cingulate cortex, and central nucleus of amygdala. However, in dorsal striatum and nucleus accumbens no increase in Fos-like immunoreactivity was observed. Pretreatment with MDL 100907 completely blocked LSD-induced Fos-like immunoreactivity in medial prefrontal cortex and anterior cingulate cortex, but only partially blocked LSD-induced Fos-like immunoreactivity in amygdala. Double-labeled immunohistochemistry revealed that LSD did not induce Fos-like immunoreactivity in cortical cells expressing 5-HT(2A) receptors, suggesting an indirect activation of cortical neurons. These results indicate that the LSD activation of medial prefrontal cortex and anterior cingulate cortex is mediated by 5-HT(2A) receptors, whereas in amygdala 5-HT(2A) receptor activation is a component of the response. These findings support the hypothesis that the medial prefrontal cortex, anterior cingulate cortex, and perhaps the amygdala, are important regions involved in the production of hallucinations.

  6. The neurotensin agonist PD149163 increases Fos expression in the prefrontal cortex of the rat.

    PubMed

    Petrie, Kimberly A; Bubser, Michael; Casey, Cheryl D; Davis, M Duff; Roth, Bryan L; Deutch, Ariel Y

    2004-10-01

    Dopaminergic axons innervating the prefrontal cortex (PFC) target both pyramidal cells and GABAergic interneurons. Many of these dopamine (DA) axons in the rat coexpress the peptide neurotransmitter neurotensin. Previous electrophysiological data have suggested that neurotensin activates GABAergic interneurons in the PFC. Activation of D2-like DA receptors increases extracellular GABA levels in the PFC, as opposed to the striatum, where D2 receptor activation inhibits GABAergic neurons. Because activation of presynaptic D2 release-modulating autoreceptors in the PFC suppresses DA release but increases release of the cotransmitter neurotensin, D2 agonists may enhance the activity of GABAergic interneurons via release of neurotensin. In order to determine if neurotensin can activate GABAergic interneurons, we treated rats with the peptide neurotensin agonist, PD149163, and examined Fos expression in PFC neurons. Systemic administration of PD149163 increased overall Fos expression in the PFC, but not in the dorsal striatum. PD149163 induced Fos in PFC interneurons, as defined by the presence of calcium-binding proteins, and in pyramidal cells. Pretreatment with the high-affinity neurotensin antagonist, SR48692, blocked neurotensin agonist-induced Fos expression. These data suggest that neurotensin activates interneurons in the PFC of the rat.

  7. Context-Induced Reinstatement of Methamphetamine Seeking Is Associated with Unique Molecular Alterations in Fos-Expressing Dorsolateral Striatum Neurons

    PubMed Central

    Rubio, F. Javier; Liu, Qing-Rong; Li, Xuan; Cruz, Fabio C.; Leão, Rodrigo M.; Warren, Brandon L.; Kambhampati, Sarita; Babin, Klil R.; McPherson, Kylie B.; Cimbro, Raffaello; Bossert, Jennifer M.; Shaham, Yavin

    2015-01-01

    Context-induced reinstatement of drug seeking is a well established animal model for assessing the neural mechanisms underlying context-induced drug relapse, a major factor in human drug addiction. Neural activity in striatum has previously been shown to contribute to context-induced reinstatement of heroin, cocaine, and alcohol seeking, but not yet for methamphetamine seeking. In this study, we found that context-induced reinstatement of methamphetamine seeking increased expression of the neural activity marker Fos in dorsal but not ventral striatum. Reversible inactivation of neural activity in dorsolateral but not dorsomedial striatum using the GABA agonists muscimol and baclofen decreased context-induced reinstatement. Based on our previous findings that Fos-expressing neurons play a critical role in conditioned drug effects, we assessed whether context-induced reinstatement was associated with molecular alterations selectively induced within context-activated Fos-expressing neurons. We used fluorescence-activated cell sorting to isolate reinstatement-activated Fos-positive neurons from Fos-negative neurons in dorsal striatum and used quantitative PCR to assess gene expression within these two populations of neurons. Context-induced reinstatement was associated with increased expression of the immediate early genes Fos and FosB and the NMDA receptor subunit gene Grin2a in only Fos-positive neurons. RNAscope in situ hybridization confirmed that Grin2a, as well as Grin2b, expression were increased in only Fos-positive neurons from dorsolateral, but not dorsomedial, striatum. Our results demonstrate an important role of dorsolateral striatum in context-induced reinstatement of methamphetamine seeking and that this reinstatement is associated with unique gene alterations in Fos-expressing neurons. PMID:25855177

  8. Context-induced reinstatement of methamphetamine seeking is associated with unique molecular alterations in Fos-expressing dorsolateral striatum neurons.

    PubMed

    Rubio, F Javier; Liu, Qing-Rong; Li, Xuan; Cruz, Fabio C; Leão, Rodrigo M; Warren, Brandon L; Kambhampati, Sarita; Babin, Klil R; McPherson, Kylie B; Cimbro, Raffaello; Bossert, Jennifer M; Shaham, Yavin; Hope, Bruce T

    2015-04-08

    Context-induced reinstatement of drug seeking is a well established animal model for assessing the neural mechanisms underlying context-induced drug relapse, a major factor in human drug addiction. Neural activity in striatum has previously been shown to contribute to context-induced reinstatement of heroin, cocaine, and alcohol seeking, but not yet for methamphetamine seeking. In this study, we found that context-induced reinstatement of methamphetamine seeking increased expression of the neural activity marker Fos in dorsal but not ventral striatum. Reversible inactivation of neural activity in dorsolateral but not dorsomedial striatum using the GABA agonists muscimol and baclofen decreased context-induced reinstatement. Based on our previous findings that Fos-expressing neurons play a critical role in conditioned drug effects, we assessed whether context-induced reinstatement was associated with molecular alterations selectively induced within context-activated Fos-expressing neurons. We used fluorescence-activated cell sorting to isolate reinstatement-activated Fos-positive neurons from Fos-negative neurons in dorsal striatum and used quantitative PCR to assess gene expression within these two populations of neurons. Context-induced reinstatement was associated with increased expression of the immediate early genes Fos and FosB and the NMDA receptor subunit gene Grin2a in only Fos-positive neurons. RNAscope in situ hybridization confirmed that Grin2a, as well as Grin2b, expression were increased in only Fos-positive neurons from dorsolateral, but not dorsomedial, striatum. Our results demonstrate an important role of dorsolateral striatum in context-induced reinstatement of methamphetamine seeking and that this reinstatement is associated with unique gene alterations in Fos-expressing neurons.

  9. Role of the c-fos gene expression on the mitogenic response in EL2 rat fibroblasts.

    PubMed

    Di Francesco, P; Liboi, E

    1988-01-01

    Stimulation of the growth of quiescent fibroblasts by polypeptide growth factors is accompanied by the rapid induction of the c-fos proto-oncogene. To investigate whether there exists a relationship between mitogenic activity and c-fos expression, we analysed cellular responses (DNA synthesis and cell growth) and c-fos gene induction (mRNA and proteins) in a rat embryo fibroblast line (EL2) stimulated with epidermal growth factor (EGF), fibroblast growth factor (FGF), 12-O-tetradodecanoyl phorbol-13-acetate (TPA) and transforming growth factor beta (TGF beta). Our results suggest that the susceptibility of EL2 cells to a growth factor could be predicted as a function of the c-fos expression caused by the same growth factor. These also indicate that the c-fos gene expression may have contributed to moving our cells out of the quiescent state, but it is not the only essential event required to effect EL2 cell growth.

  10. Problem-Solving Test: The Role of a Micro-RNA in the Regulation of "fos" Gene Expression

    ERIC Educational Resources Information Center

    Szeberenyi, Jozsef

    2009-01-01

    The "fos" proto-oncogene codes for a component of the AP1 transcription factor, an important regulator of gene expression and cell proliferation. Dysregulation of AP1 function may lead to the malignant transformation of the cell. The present test describes an experiment in which the role of a micro-RNA (miR-7b) in the regulation of "fos" gene…

  11. The Changes of c-Fos Expression by Motor Cortex Stimulation in the Deafferentation Pain Model

    PubMed Central

    KUDO, Kanae; TAKAHASHI, Toshio; SUZUKI, Shigeharu

    2014-01-01

    The effect of motor cortex stimulation (MCS) therapy for deafferentation pain was evaluated based on c-Fos, a known pain marker. Nineteen mature cats weighing 1.5–3.5 kg were used. Cats were divided into three groups: a deafferentation pain group in which the left trigeminal ganglion was destroyed, an MCS group in which MCS was used following destruction of the trigeminal ganglion, and a control group. Sites and levels of c-Fos expression were examined immunohistochemically. The percentage of c-Fos-positive cells in the left spinal nucleus of the trigeminus, the bilateral insula, and the bilateral operculum increased in both the deafferentation pain and the MCS groups. There were no statistically significant differences between these groups. In the cingulate gyrus, the percentage of c-Fos-positive cells increased bilaterally in the deafferentation pain group and the MCS group, but the increase was greater in the MCS group. The increase in c-Fos-positive cells in the left spinal nucleus of the trigeminus in the deafferentation group may reflect reported electrical hyperactivity. The cingulate gyrus, insula, and parietal operculum were activated after deafferentation. This change (increase in c-Fos positive cells) is related to the development of deafferentation pain. Pain relief due to MCS is not dependent on the suppression of the activated left spinal nucleus of the trigeminus or the descending analgesic mechanism of the brain stem. Activation of the cingulate gyrus appears to be a factor in the analgesic mechanism of MCS. PMID:24965534

  12. Treatment with neuropeptides attenuates c-fos expression in a mouse model of fetal alcohol syndrome.

    PubMed

    Incerti, Maddalena; Vink, Joy; Roberson, Robin; Abebe, Daniel; Spong, Catherine Y

    2010-10-01

    Fetal alcohol syndrome (FAS) is the most common nongenetic cause of mental retardation and is characterized by neurodevelopmental anomalies. C-FOS is a cellular marker of transcriptional activity in the stress-signal pathway. Previously, we showed the treatment with NAP (NAPVSIPQ) + SAL (SALLRSIPA) reversed the learning deficit after prenatal alcohol exposure in FAS. Our objective was to evaluate if the mechanism of actions of NAP + SAL involves the stress-signal pathway differentiating C-FOS expression in mouse brains after prenatal alcohol exposure. C57Bl6/J mice were treated with alcohol (0.03 mL/g) or placebo on gestational day 8. On postnatal day 40, in utero alcohol-exposed males were treated via gavage with 40 μg D-NAP and 40 μg D-SAL ( N = 6) or placebo ( N = 4); controls were gavaged with placebo daily ( N = 12). After learning evaluation, hippocampus, cerebellum, and cortex were isolated. Calibrator-normalized relative real-time polymerase chain reaction and Western blot analysis were performed. Statistics included analysis of variance and post hoc Fisher analysis. Adult treatment with NAP + SAL restored the down-regulation of C-FOS in the hippocampus after prenatal alcohol exposure ( P < 0.05), but not in the cerebellum. There was no difference in C-FOS expression in the cortex. Adult treatment with NAP + SAL restored the down-regulation of C-FOS expression in hippocampus attenuating the alcohol-induced alteration of the stress-signal pathway.

  13. Identification of temperature-sensitive neural circuits in mice using c-Fos expression mapping.

    PubMed

    Bachtell, Ryan K; Tsivkovskaia, Natalia O; Ryabinin, Andrey E

    2003-01-17

    Expression of the inducible transcription factor c-Fos was mapped in mouse brain to identify neural circuits selectively involved in response to cold and hot external temperatures. Male C57BL/6J mice were exposed acutely or repeatedly (seven sessions) to 10 or 34 degrees C in sound-attenuated chambers. Control mice were acclimated to exposure to the experimental room at 20 degrees C. All animals were sacrificed at 90 min for immunohistochemical analysis. A statistically significant induction of c-Fos was observed in the shell of nucleus accumbens and posterior medial cortical amygdala only following the acute thermal exposure, showing a significant habituation of the response to repeated treatments, a finding arguing against specificity of responses in these nuclei to thermal exposures. In contrast, expression of c-Fos was significantly increased following both acute and repeated thermal exposures in subregions of hypothalamus (the median and medial preoptic nuclei, the paraventricular nucleus of hypothalamus and the posterior hypothalamic area), septum (the ventral and dorsal portions of the lateral septum), midbrain (the periaqueductal gray and the intermediate layers of superior colliculus), as well as in the dentate gyrus and the paraventricular nucleus of thalamus, suggesting specificity of their responses to external temperatures. Expression of c-Fos was also significantly increased in the Edinger-Westphal nucleus following acute thermal exposures versus control mice, but not versus mice repeatedly exposed to cold and hot temperatures, providing modest support for thermal specificity of c-Fos response in this nucleus. While thermal sensitivity of hypothalamic structures has been previously confirmed by many authors, the present study identifies a number of structures previously not found to be responsive to changes in external temperature, and lays ground for future work important for identification of neural circuits involved in thermoregulation.

  14. Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior

    PubMed Central

    Frenois, François; Moreau, Maïté; Connor, Jason O’; Lawson, Marc; Micon, Charlotte; Lestage, Jacques; Kelley, Keith W.; Dantzer, Robert; Castanon, Nathalie

    2007-01-01

    Proinflammatory cytokines induce both sickness behavior and depression, but their respective neurobiological correlates are still poorly understood. The aim of the present study was therefore to identify in mice the neural substrates of sickness and depressive-like behavior induced by lipopolysaccharide (LPS, 830 μg/kg, intraperitoneal). LPS-induced depressive-like behavior was dissociated from LPS-induced sickness by testing mice either at 6 h (at which time sickness was expected to be maximal) or at 24 h post-LPS (at which time sickness was expected to be minimal and not to bias the measurement of depressive-like behavior). Concurrently, the expression of acute and chronic cellular reactivity markers (c-Fos and FosB/ΔFosB respectively) was mapped by immunohistochemistry at these two time points. In comparison to saline, LPS decreased motor activity in a new cage at 6 but not at 24 h. In contrast, the duration of immobility in the tail suspension test was increased at both 6 and 24 h. This dissociation between decreased motor activity and depressive-like behavior was confirmed at 24 h post-LPS in the forced swim test. LPS also decreased sucrose consumption at 24 and 48 h, despite normal food and water consumption by that time. At 24 h post-LPS, LPS-induced depressive-like behavior was associated with a delayed cellular activity (as assessed by FosB/ΔFosB immunostaining) in specific brain structures, particularly within the extended amygdala, hippocampus and hypothalamus, whereas c-Fos labeling was markedly decreased by that time in all the brain areas at 6 h post-LPS. These results provide the first evidence in favor of a functional dissociation between the brain structures that underlie cytokine-induced sickness behavior and cytokine-induced depressive-like behavior, and provide important cues about the neuroanatomical brain circuits through which cytokines could have an impact on affect. PMID:17482371

  15. Regulation of fos-lacZ fusion gene expression in primary mouse epidermal keratinocytes isolated from transgenic mice.

    PubMed Central

    Bollag, W B; Xiong, Y; Ducote, J; Harmon, C S

    1994-01-01

    The expression of a fos-lacZ fusion gene was studied in primary mouse epidermal keratinocytes obtained from transgenic mice. This gene construct contains the entire upstream regulatory sequence of c-fos, and expression of the endogenous and fusion gene was shown by Northern analysis to correlate upon induction with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). Using a chromogenic substrate of beta-galactosidase, we also demonstrated that expression of the fusion gene product, like that of Fos, was localized to the cell nucleus. In addition, we showed that epidermal keratinocytes responded to dialysed fetal bovine serum (FBS), TPA and high-calcium medium with enhanced Fos-lacZ expression and an inhibition of proliferation. The time course of induction of Fos-lacZ expression was similar for dialysed FBS and TPA, with a peak approximately 2 h after exposure. Exposure for approximately 24 h to an elevated extracellular calcium concentration was required to elicit an increase in Fos-lacZ expression. The lack of an immediate effect of raising medium calcium levels on Fos-lacZ expression contrasted with the rapidity of its effect on DNA synthesis, which was significantly inhibited within 6-8 h. In addition, we found that the protein kinase C inhibitor Ro 31-7549 blocked Fos-lacZ expression induced by TPA but had little or no effect on that elicited by high calcium levels. Thus, although our results indicate that the fos gene product may be involved in mediating epidermal keratinocyte growth arrest in response to differentiative agents such as FBS, TPA and high medium calcium levels, the exact role of this gene product remains unclear. Images Figure 1 Figure 2 PMID:8198544

  16. Regulation of fos-lacZ fusion gene expression in primary mouse epidermal keratinocytes isolated from transgenic mice.

    PubMed

    Bollag, W B; Xiong, Y; Ducote, J; Harmon, C S

    1994-05-15

    The expression of a fos-lacZ fusion gene was studied in primary mouse epidermal keratinocytes obtained from transgenic mice. This gene construct contains the entire upstream regulatory sequence of c-fos, and expression of the endogenous and fusion gene was shown by Northern analysis to correlate upon induction with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). Using a chromogenic substrate of beta-galactosidase, we also demonstrated that expression of the fusion gene product, like that of Fos, was localized to the cell nucleus. In addition, we showed that epidermal keratinocytes responded to dialysed fetal bovine serum (FBS), TPA and high-calcium medium with enhanced Fos-lacZ expression and an inhibition of proliferation. The time course of induction of Fos-lacZ expression was similar for dialysed FBS and TPA, with a peak approximately 2 h after exposure. Exposure for approximately 24 h to an elevated extracellular calcium concentration was required to elicit an increase in Fos-lacZ expression. The lack of an immediate effect of raising medium calcium levels on Fos-lacZ expression contrasted with the rapidity of its effect on DNA synthesis, which was significantly inhibited within 6-8 h. In addition, we found that the protein kinase C inhibitor Ro 31-7549 blocked Fos-lacZ expression induced by TPA but had little or no effect on that elicited by high calcium levels. Thus, although our results indicate that the fos gene product may be involved in mediating epidermal keratinocyte growth arrest in response to differentiative agents such as FBS, TPA and high medium calcium levels, the exact role of this gene product remains unclear.

  17. Peripheral obestatin has no effect on feeding behavior and brain Fos expression in rodents

    PubMed Central

    Kobelt, Peter; Wisser, Anna-Sophia; Stengel, Andreas; Goebel, Miriam; Bannert, Norbert; Gourcerol, Guillaume; Inhoff, Tobias; Noetzel, Steffen; Wiedenmann, Bertram; Klapp, Burghard F.; Taché, Yvette; Mönnikes, Hubert

    2009-01-01

    Obestatin is produced in the stomach from proghrelin by post-translational cleavage. The initial report claimed anorexigenic effects of obestatin in mice. Contrasting studies indicated no effect of obestatin on food intake (FI). We investigated influences of metabolic state (fed/fasted), environmental factors (dark/light phase) and brain Fos response to intraperitoneal (ip) obestatin in rats, and used the protocol from the original study assessing obestatin effects in mice. FI was determined in male rats injected ip before onset of dark or light phase, with obestatin (1 or 5 μmol/kg), CCK8S (3.5 nmol/kg) or 0.15 M NaCl, after fasting (16 h, n = 8/group) or ad libitum (n = 10-14/group) food intake. Fos expression in hypothalamic and brainstem nuclei was examined in freely fed rats 90 min after obestatin (5 μmol/kg), CCK8S (1.75 nmol/kg) or 0.15 M NaCl (n = 4/group). Additionally, fasted mice were injected ip with obestatin (1 μmol/kg) or urocortin 1 (2 nmol/kg) 15 min before food presentation. No effect on FI was observed after obestatin administration during the light and dark phase under both metabolic conditions while CCK8S reduced FI irrespectively of the conditions. The number of Fos positive neurons was not modified by obestatin while CCK8S increased Fos expression in selective brain nuclei. Obestatin did not influence the refeeding response to a fast in mice, while urocortin was effective. Therefore, peripheral obestatin has no effect on FI under various experimental conditions and did not induce Fos in relevant central neuronal circuitries modulating feeding in rodents. PMID:18342400

  18. Gonadotropin and kisspeptin gene expression, but not GnRH, are impaired in cFOS deficient mice

    PubMed Central

    Xie, Changchuan; Jonak, Carrie R.; Kauffman, Alexander S.; Coss, Djurdjica

    2015-01-01

    cFOS is a pleiotropic transcription factor, which binds to the AP1 site in the promoter of target genes. In the pituitary gonadotropes, cFOS mediates induction of FSHβ and GnRH receptor genes. Herein, we analyzed reproductive function in the cFOS-deficient mice to determine its role in vivo. In the pituitary cFOS is necessary for gonadotropin subunit expression, while TSHβ is unaffected. Additionally, cFOS null animals have the same sex-steroid levels, although gametogenesis is impeded. In the brain, cFOS is not necessary for GnRH neuronal migration, axon targeting, cell number, or mRNA levels. Conversely, cFOS nulls, particularly females, have decreased Kiss1 neuron numbers and lower Kiss1 mRNA levels. Collectively, our novel findings suggest that cFOS plays a cell-specific role at multiple levels of the hypothalamic–pituitary–gonadal axis, affecting gonadotropes but not thyrotropes in the pituitary, and kisspeptin neurons but not GnRH neurons in the hypothalamus, thereby contributing to the overall control of reproduction. PMID:25958044

  19. Tactile Experience Induces c-fos Expression in Rat Barrel Cortex

    PubMed Central

    Filipkowski, Robert K.; Rydz, Marek; Berdel, Bozena; Morys, Janusz; Kaczmarek, Leszek

    2000-01-01

    Understanding gene expression that is responsive to sensory stimulation is central to elucidate molecular mechanisms underlying neuronal plasticity. In this study we demonstrate two new methods of stimulating whiskers that provide major sensory input to rat neocortex. In the first paradigm, animals were placed on the top of a cylinder and their vibrissae were brushed by hand. In the second paradigm, animals were placed for a brief period of time into a new, wired cage resulting in vibrissae stimulation when they explored the new environment. Both approaches induced c-Fos expression in barrel cortex corresponding to the stimulated vibrissae, especially in layer IV. Layers II/III and V/VI also showed c-Fos induction, but there were no detectable changes in layer VIb. The majority of c-Fos-expressing cells are probably not inhibitory neurons, because they do not show parvalbumin staining. Both paradigms, in contrast to the previous methods, are simple to use and do not require anesthesia, restraint of animals, or elaborate experimental setups. PMID:10753978

  20. Blocking c-Fos Expression Reveals the Role of Auditory Cortex Plasticity in Sound Frequency Discrimination Learning.

    PubMed

    de Hoz, Livia; Gierej, Dorota; Lioudyno, Victoria; Jaworski, Jacek; Blazejczyk, Magda; Cruces-Solís, Hugo; Beroun, Anna; Lebitko, Tomasz; Nikolaev, Tomasz; Knapska, Ewelina; Nelken, Israel; Kaczmarek, Leszek

    2017-03-17

    The behavioral changes that comprise operant learning are associated with plasticity in early sensory cortices as well as with modulation of gene expression, but the connection between the behavioral, electrophysiological, and molecular changes is only partially understood. We specifically manipulated c-Fos expression, a hallmark of learning-induced synaptic plasticity, in auditory cortex of adult mice using a novel approach based on RNA interference. Locally blocking c-Fos expression caused a specific behavioral deficit in a sound discrimination task, in parallel with decreased cortical experience-dependent plasticity, without affecting baseline excitability or basic auditory processing. Thus, c-Fos-dependent experience-dependent cortical plasticity is necessary for frequency discrimination in an operant behavioral task. Our results connect behavioral, molecular and physiological changes and demonstrate a role of c-Fos in experience-dependent plasticity and learning.

  1. c-FOS expression in the visual system of tree shrews after monocular inactivation.

    PubMed

    Takahata, Toru; Kaas, Jon H

    2017-01-01

    Tree shrews possess an unusual segregation of ocular inputs to sublayers rather than columns in the primary visual cortex (V1). In this study, the lateral geniculate nucleus (LGN), superior colliculus (SC), pulvinar, and V1 were examined for changes in c-FOS, an immediate-early gene, expression after 1 or 24 hours of monocular inactivation with tetrodotoxin (TTX) in tree shrews. Monocular inactivation greatly reduced gene expression in LGN layers related to the blocked eye, whereas normally high to moderate levels were maintained in the layers that receive inputs from the intact eye. The SC and caudal pulvinar contralateral to the blocked eye had greatly (SC) or moderately (pulvinar) reduced gene expressions reflective of dependence on the contralateral eye. c-FOS expression in V1 was greatly reduced contralateral to the blocked eye, with most of the expression that remained in upper layer 4a and lower 4b and lower layer 6 regions. In contrast, much of V1 contralateral to the active eye showed normal levels of c-FOS expression, including the inner parts of sublayers 4a and 4b and layers 2, 3, and 6. In some cases, upper layer 4a and lower 4b showed a reduction of gene expression. Layers 5 and sublayer 3c had normally low levels of gene expression. The results reveal the functional dominance of the contralateral eye in activating the SC, pulvinar, and V1, and the results from V1 suggest that the sublaminar organization of layer 4 is more complex than previously realized. J. Comp. Neurol. 525:151-165, 2017. © 2016 Wiley Periodicals, Inc.

  2. Neural Correlates of Birth: Labor Contractions Induce C-Fos Expression In Newborn Rat Brain

    NASA Technical Reports Server (NTRS)

    Ronca, A. E.; Daly, M. E.; Baer, L. A.; Hills, E. M.; Conway, G.; Dalton, Bonnie (Technical Monitor)

    2002-01-01

    At birth, the newborn mammal must make rapid adaptations to the extrauterine environment to survive. We have previously shown that labor contractions augment the appearance of adaptive responses at birth, viz., postpartum breathing and the onset of suckling. Since neuronal activity has been shown to upregulate the activity of immediate early genes (IEGs) in the brain, we analyzed the neural distribution of c-Fos protein expression in newborn rats using immunohistochemistry. Previous studies have reported a burst of c-Fos mRNA expression in mouse and rat brain at birth however relationships to labor and delivery have not been examined. In the present study, we exposed near-term rat fetuses to elements of the vaginal birth process: 1) Simulated labor contractions. 2) Postpartum cooling (22 deg C). 3) Umbilical cord occlusion. and 4) Stroking to mimic postpartum licking by the dam. Cardinally delivered newborns (VG) were compared with those delivered by cesarean section following either prenatal exposure to compressions (C) [simulated labor contractions], or no compressions (NC) [no labor contractions]. Similar patterns of c-fos activation were observed throughout hypothalamic and thalamic nuclei, hippocampus and cerebral cortex in VG and C newborns that were not apparent in NC newborns. Our results indicate that labor contractions play a role in the induction of widespread neural activation in the newborn brain.

  3. Anxiety-like behaviour and c-fos expression in rats that inhaled vetiver essential oil.

    PubMed

    Saiyudthong, Somrudee; Pongmayteegul, Sirinun; Marsden, Charles A; Phansuwan-Pujito, Pansiri

    2015-01-01

    Vetiver essential oil (VEO) has been used in aromatherapy for relaxation. This study aimed to investigate the effects of VEO on an anxiety-related behavioural model (the elevated plus-maze, EPM) and immediate-early gene c-fos in amygdala, known to be involved in anxiety. Male Wistar rats were administered diazepam (1 mg/kg i.p.) for 30 min or inhalated with VEO (1%, 2.5% or 5% w/w) for 7 min prior to exposure to the EPM. Then, the effects of 2.5% VEO, the anxiolytic dose, on c-fos expression in amygdala were investigated. The rats given either 2.5% VEO or diazepam exhibited an anxiolytic-like profile in the EPM. VEO and diazepam significantly increased c-fos expression in the lateral division of the central amygdaloid nucleus (CeL). Therefore, the anxiolytic properties of VEO might be associated with altering neuronal activation in CeL. However, future studies are needed to investigate the precise mechanism of action of VEO.

  4. Amphetamine-elicited striatal Fos expression is attenuated in neurotensin null mutant mice.

    PubMed

    Fadel, Jim; Dobner, Paul R; Deutch, Ariel Y

    2006-07-10

    Neurotensin (NT) has been suggested to interact with dopamine systems in different forebrain sites to exert both antipsychotic- and psychostimulant-like effects. We previously found that genetic or pharmacological manipulations that disrupt endogenous NT signaling attenuate antipsychotic drug-induced Fos expression in the dorsolateral and central striatum but not other striatal regions. To assess the role of NT in psychostimulant responses, we examined the ability of d-amphetamine (AMP) to induce Fos in wild-type and NT null mutant mice. AMP-elicited Fos expression was significantly attenuated in the medial striatum of NT null mutant mice, but was unaffected in other striatal territories. Similar results were obtained in rats and mice pretreated with the high affinity neurotensin receptor (NTR1) antagonist SR 48692. The effect of the NTR1 antagonist was particularly apparent in the striatal patch (striosome) compartment, as defined by mu-opioid receptor immunoreactivity. These data suggest that NT is required for the full activation by AMP of medial striatal neurons.

  5. Forced expression of stabilized c-Fos in dendritic cells reduces cytokine production and immune responses in vivo

    SciTech Connect

    Yoshida, Ryoko; Suzuki, Mayu; Sakaguchi, Ryota; Hasegawa, Eiichi; Kimura, Akihiro; Shichita, Takashi; Sekiya, Takashi; Shiraishi, Hiroshi; Shimoda, Kouji; Yoshimura, Akihiko

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer Dendritic cells expressing stabilized c-Fos produced less inflammatory cytokines. Black-Right-Pointing-Pointer Dendritic cells expressing stabilized c-Fos activated T cells less efficiently. Black-Right-Pointing-Pointer Transgenic mice expressing stabilized c-Fos were resistant to EAE model. -- Abstract: Intracellular cyclic adenosine monophosphate (cAMP) suppresses innate immunity by inhibiting proinflammatory cytokine production by monocytic cells. We have shown that the transcription factor c-Fos is responsible for cAMP-mediated suppression of inflammatory cytokine production, and that c-Fos protein is stabilized by IKK{beta}-mediated phosphorylation. We found that S308 is one of the major phosphorylation sites, and that the S308D mutation prolongs c-Fos halflife. To investigate the role of stabilized c-Fos protein in dendritic cells (DCs) in vivo, we generated CD11c-promoter-deriven c-FosS308D transgenic mice. As expected, bone marrow-derived DCs (BMDCs) from these Tg mice produced smaller amounts of inflammatory cytokines, including TNF-{alpha}, IL-12, and IL-23, but higher levels of IL-10, in response to LPS, than those from wild-type (Wt) mice. When T cells were co-cultured with BMDCs from Tg mice, production of Th1 and Th17 cytokines was reduced, although T cell proliferation was not affected. Tg mice demonstrated more resistance to experimental autoimmune encephalomyelitis (EAE) than did Wt mice. These data suggest that c-Fos in DCs plays a suppressive role in certain innate and adaptive immune responses.

  6. Expression of c-fos gene in central nervous system of adult medaka (Oryzias latipes) after hypergravity stimulation

    NASA Astrophysics Data System (ADS)

    Shimomura, S.; Ijiri, K.

    The immediate-early genes serve as useful neurobiological tools for mapping brain activity induced by a sensory stimulation. In this study, we have examined brain activity related to gravity perception of medaka (Oryzias latipes) by use of c-fos. The gene, which is homologous to the c-fos genes of other vertebrates, was identified in medaka. Functionally important domains are highly conserved among all the vertebrate species analyzed. Intraperitoneal administration of kainic acid transiently induced the c-fos mRNAs in medaka brain. The results indicate that the expression of c-fos can be utilized as a suitable anatomical marker for the increased neural activities in the central nervous system of medaka. Fish were continuously exposed to 3G hypergravity by centrifugation. Investigation of c-fos mRNA expression showed that c-fos mRNA significantly increased 30 minutes after a start of 3G exposure. The distribution of its transcripts within brains was analyzed by an in situ hybridization method. The 3G-treated medakas displayed c-fos positive cells in their brainstem regions, which are related to vestibular function, such as torus semicircularis, posterior octavu nucleus, nucleus tangentialis and inferior olive. Our results established the method to trace the activated area in the fish brain following gravity stimulation. The method will be a useful tool for understanding gravity perception in the brain.

  7. Central expression of c-Fos in neonatal male and female prairie voles in response to treatment with oxytocin.

    PubMed

    Cushing, Bruce S; Yamamoto, Yukiyo; Hoffman, Gloria E; Carter, C Sue

    2003-07-12

    Early postnatal exposure to both exogenous and endogenous oxytocin (OT) can have long-term effects on behavior and physiology, although the mechanisms of these effects are not known. c-Fos expression was used to investigate the immediate neural effects of neonatal manipulations of OT in male and female prairie voles. On the day of birth prairie vole pups received an intraperitoneal injection of OT, a selective OT antagonist (OTA), or saline (vehicle control), while an additional group was handled but not injected. One hour after treatment brains were collected and fixed via spinning immersion and immunocytochemistry was then used to label for c-Fos immunoreactivity (IR). There were significant differences between males and females. Handled only females displayed significantly higher levels of c-Fos IR in the mediodorsal thalamic nucleus (MD) than males while handled males had higher c-Fos IR in the paraventricular nucleus of the hypothalamus than females. Exogenous OT stimulated neuronal activity in the supraoptic nucleus (SON) in males, while treatment with OTA increased Fos IR in the SON and was associated with reduced Fos IR in the MD in females. The results indicate that neuronal activity and responses to OT are sexually dimorphic in newborn prairie voles. In females changes in Fos expression were stimulated by treatment with OTA, suggesting that endogenous OT affects cellular activity while males responded to exogenous OT.

  8. Differential Expression of FosB Proteins and Potential Target Genes in Select Brain Regions of Addiction and Depression Patients.

    PubMed

    Gajewski, Paula A; Turecki, Gustavo; Robison, Alfred J

    2016-01-01

    Chronic exposure to stress or drugs of abuse has been linked to altered gene expression throughout the body, and changes in gene expression in discrete brain regions are thought to underlie many psychiatric diseases, including major depressive disorder and drug addiction. Preclinical models of these disorders have provided evidence for mechanisms of this altered gene expression, including transcription factors, but evidence supporting a role for these factors in human patients has been slow to emerge. The transcription factor ΔFosB is induced in the prefrontal cortex (PFC) and hippocampus (HPC) of rodents in response to stress or cocaine, and its expression in these regions is thought to regulate their "top down" control of reward circuitry, including the nucleus accumbens (NAc). Here, we use biochemistry to examine the expression of the FosB family of transcription factors and their potential gene targets in PFC and HPC postmortem samples from depressed patients and cocaine addicts. We demonstrate that ΔFosB and other FosB isoforms are downregulated in the HPC but not the PFC in the brains of both depressed and addicted individuals. Further, we show that potential ΔFosB transcriptional targets, including GluA2, are also downregulated in the HPC but not PFC of cocaine addicts. Thus, we provide the first evidence of FosB gene expression in human HPC and PFC in these psychiatric disorders, and in light of recent findings demonstrating the critical role of HPC ΔFosB in rodent models of learning and memory, these data suggest that reduced ΔFosB in HPC could potentially underlie cognitive deficits accompanying chronic cocaine abuse or depression.

  9. Differential Expression of FosB Proteins and Potential Target Genes in Select Brain Regions of Addiction and Depression Patients

    PubMed Central

    Gajewski, Paula A.; Turecki, Gustavo; Robison, Alfred J.

    2016-01-01

    Chronic exposure to stress or drugs of abuse has been linked to altered gene expression throughout the body, and changes in gene expression in discrete brain regions are thought to underlie many psychiatric diseases, including major depressive disorder and drug addiction. Preclinical models of these disorders have provided evidence for mechanisms of this altered gene expression, including transcription factors, but evidence supporting a role for these factors in human patients has been slow to emerge. The transcription factor ΔFosB is induced in the prefrontal cortex (PFC) and hippocampus (HPC) of rodents in response to stress or cocaine, and its expression in these regions is thought to regulate their “top down” control of reward circuitry, including the nucleus accumbens (NAc). Here, we use biochemistry to examine the expression of the FosB family of transcription factors and their potential gene targets in PFC and HPC postmortem samples from depressed patients and cocaine addicts. We demonstrate that ΔFosB and other FosB isoforms are downregulated in the HPC but not the PFC in the brains of both depressed and addicted individuals. Further, we show that potential ΔFosB transcriptional targets, including GluA2, are also downregulated in the HPC but not PFC of cocaine addicts. Thus, we provide the first evidence of FosB gene expression in human HPC and PFC in these psychiatric disorders, and in light of recent findings demonstrating the critical role of HPC ΔFosB in rodent models of learning and memory, these data suggest that reduced ΔFosB in HPC could potentially underlie cognitive deficits accompanying chronic cocaine abuse or depression. PMID:27494187

  10. Expression and colocalization of NMDA receptor and FosB/ΔFosB in sensitive brain regions in rats after chronic morphine exposure.

    PubMed

    Zhang, Qiang; Liu, Qi; Li, Tongzhou; Liu, You; Wang, Lei; Zhang, Zhonghai; Liu, Hongzhi; Hu, Min; Qiao, Yuehua; Niu, Haichen

    2016-02-12

    Research in the last decade demonstrated that the NMDA receptor (NMDAR) has an important role in opiate-induced neural and behavioral plasticity. In addition, increased levels of FosB-like proteins (FosB/ΔFosB) were found to be related to morphine withdrawal behaviors. However, the relationship between NMDAR and FosB/ΔFosB in sensitive brain regions during morphine withdrawal is largely unknown. In this study, we aimed to investigate NMDAR dynamics and FosB/ΔFosB levels in multiple brain regions and whether they are related in sensitive brain regions during morphine abstinence. Quantitative immunohistochemistry was adopted to test NMDAR and FosB/ΔfosB levels during morphine withdrawal in rats. Increased NMDAR and FosB/ΔFosB levels were found in the nucleus accumbens core (AcbC), nucleus accumbens shell (AcbSh), central amygdaloid nucleuscapsular part (CeC), ventral tegmental area (VTA) and cingulate cortex (Cg). Double-immunofluorescence labeling indicated that NMDAR colocalized with Fos/ΔFosB in these five regions. These results suggest that multiple phenotypic regions are mediated by NMDAR and Fos/ΔFosB during morphine withdrawal, such as the motivational (AcbC, AcbSh), limbic (CeC, VTA) and executive (Cg) system pathways, and may be the primary targets of NMDAR and Fos/ΔfosB that impact morphine withdrawal behaviors.

  11. Novel spinal pathways identified by neuronal c-Fos expression after urethrogenital reflex activation in female guinea pigs.

    PubMed

    Yuan, S Y; Vilimas, P I; Zagorodnyuk, V P; Gibbins, I L

    2015-03-12

    Pudendal nerve-spinal pathways are involved in urethrogenital sensation, pain and sexual activity. However, details of these pathways and their modulation are unclear. We examined spinal pathways activated by the urethrogenital reflex (UGR) and visualized by c-Fos immunoreactivity in reflexly activated neurons within spinal cord. In anesthetized female guinea pigs, a balloon was inserted into the urethra and inflated with short-repeat or long-continuous distension to activate the UGR. A second balloon recorded reflex contractions of the vagina and uterus. Two control groups had either no balloon or a vaginal balloon (VB) only. Ninety minutes after UGR activation, c-Fos immunoreactivity in L3 and S2 spinal segments was examined. Reflex activated c-Fos immunoreactivity also was investigated in some animals with acute spinal transections at either L4 or T12 levels. There was no significant difference in spinal c-Fos expression between the control groups. Short-repeat distension reliably induced a UGR and a two- to threefold increase in c-Fos-expressing neurons throughout dorsal, intermediate and lateral spinal gray matter at S2 and about twofold increase in superficial dorsal horn at L3. T12 transection had little effect on c-Fos expression at either spinal level. However, after L4 transection, UGR generation was associated with a four- to sixfold increase in c-Fos-expressing neurons in lateral horn (LH) and central canal areas at S2, and but only 20-30% increase at L3. Thus, UGR activates preganglionic neurons projecting to pelvic viscera in both sacral and lumbar spinal cord. The reflex also must activate ascending and descending spinal inhibitory circuits that suppress c-Fos-expression in neurons at both sacral and lumbar spinal levels.

  12. Neuronal expression of c-Fos after epicortical and intracortical electric stimulation of the primary visual cortex.

    PubMed

    Neyazi, Belal; Schwabe, Kerstin; Alam, Mesbah; Krauss, Joachim K; Nakamura, Makoto

    2016-11-01

    Electrical stimulation of the primary visual cortex (V1) is an experimental approach for visual prostheses. We here compared the response to intracortical and epicortical stimulation of the primary visual cortex by using c-Fos immunoreactivity as a marker for neuronal activation. The primary visual cortex of male Sprague Dawley rats was unilaterally stimulated for four hours using bipolar electrodes placed either intracortically in layer IV (n=26) or epicortically (n=20). Four different current intensities with a constant pulse width of 200μs and a constant frequency of 10Hz were used, for intracortical stimulation with an intensity of 0μA (sham-stimulation), 10μA, 20μA and 40μA, and for epicortical stimulation 0μA, 400μA, 600μA and 800μA. Subsequently all animals underwent c-Fos immunostaining and c-Fos expression was assessed in layer I-VI of the primary visual cortex within 200μm and 400μm distance to the stimulation site. C-Fos expression was higher after intracortical stimulation compared to epicortical stimulation, even though ten times lower current intensities were applied. Furthermore intracortical stimulation resulted in more focal neuronal activation than epicortical stimulation. C-Fos expression was highest after intracortical stimulation with 20μA compared to all other intensities. Epicortical stimulation showed a linear increase of c-Fos expression with the highest expression at 800μA. Sham stimulation showed similar expression of c-Fos in both hemispheres. The contralateral hemisphere was not affected by intracortical or epicortical stimulation of either intensities. In summary, intracortical stimulation resulted in more focal neuronal activation with less current than epicortical stimulation. This model may be used as a simple but reliable model to evaluate electrodes for microstimulation of the primary visual cortex before testing in more complex settings.

  13. Effects of monocular deprivation on the spatial pattern of visually induced expression of c-Fos protein.

    PubMed

    Nakadate, K; Imamura, K; Watanabe, Y

    2012-01-27

    We studied the pattern of expression of a protein product (c-Fos) of immediate-early gene (IEG) in the visual cortex of rats and mice. The basal expression of c-Fos was very low and visual exposure revealed a large number of c-Fos immunopositive cells in the visual cortex. We found that monocular deprivation during the sensitive period of ocular dominance (OD) plasticity significantly changed both the amount and pattern of c-Fos expression upon monocular stimulation of either eye. The number of immunopositive cells in layer IV of binocular subfields of the primary visual cortex (Oc1B) ipsilateral to the stimulated eye was found to be the most sensitive index of the effects of monocular deprivation during the sensitive period, that is, opened eye stimulation induced significantly larger numbers of c-Fos immunopositive cells, whereas closed eye stimulation induced significantly smaller numbers compared with those induced by monocular stimulation in control animals. In the lateral geniculate nucleus and superior colliculus, the pattern of expression of c-Fos following monocular stimulation was not affected by preceding monocular deprivation. Monocular deprivation imposed after the sensitive period did not affect the pattern of induction of c-Fos. Notably, in age-matched old animals that had been raised in total darkness and then experienced monocular deprivation, the distribution and numbers of c-Fos-expressing cells in visual cortex exhibited the same alterations as found in young animals during the sensitive period. These findings suggest that the present activity mapping method using c-Fos as a molecular marker is useful for examining the activity-dependent regulation of cortical plasticity, and provides an alternative method to conventional electrophysiological recording. This method is particularly powerful when applied to knockout or transgenic mice in which sampling biases in electrophysiological recording have been considered inevitable. Furthermore, these

  14. Site specific effects of anosmia and cloacal gland anesthesia on Fos expression induced in male quail brain by sexual behavior

    PubMed Central

    Taziaux, Mélanie; Keller, Matthieu; Ball, Gregory F.; Balthazart, Jacques

    2008-01-01

    In rats, expression of the immediate early gene, c-fos observed in the brain following male copulatory behavior relates mostly to the detection of olfactory information originating from the female and to somatosensory feedback from the penis. However, quail, like most birds, are generally considered to have a relatively poorly developed sense of smell. Furthermore, quail have no intromittent organ (e.g., penis). It is therefore intriguing that expression of male copulatory behavior induces in quail and rats a similar pattern of c-fos expression in the medial preoptic area (mPOA), bed nucleus of the stria terminalis (BSTM) and parts of the amygdala. We analyzed here by immunocytochemistry Fos expression in the mPOA/BSTM/amygdala of male quail that had been allowed to copulate with a female during standardized tests. Before these tests, some of the males had either their nostrils plugged, or their cloacal area anesthetized, or both. A control group was not exposed to females. These manipulations did not affect frequencies of male sexual behavior and all birds exposed to a female copulated normally. In the mPOA, the increased Fos expression induced by copulation was not affected by the cloacal gland anesthesia but was markedly reduced in subjects deprived of olfactory input. Both manipulations affected copulation-induced Fos expression in the BSTM. No change in Fos expression was observed in the amygdala. Thus immediate early gene expression in the mPOA and BSTM of quail is modulated at least in part by olfactory cues and/or somatosensory stimuli originating from the cloacal gland. Future work should specify the nature of these stimuli and their function in the expression of avian male sexual behavior. PMID:18638505

  15. Preventive role of social interaction for cocaine conditioned place preference: correlation with FosB/DeltaFosB and pCREB expression in rat mesocorticolimbic areas.

    PubMed

    El Rawas, Rana; Klement, Sabine; Salti, Ahmad; Fritz, Michael; Dechant, Georg; Saria, Alois; Zernig, Gerald

    2012-01-01

    The worsening of drug abuse by drug-associated social interaction is a well-studied phenomenon. In contrast, the molecular mechanisms of the beneficial effect of social interaction, if offered as a mutually exclusive choice to drugs of abuse, are under-investigated. In a rat place preference conditioning (CPP) paradigm, four 15 min episodes of social interaction with a gender- and weight-matched male early-adult conspecific inhibited cocaine-induced reinstatement of cocaine CPP, a model of relapse. These protective effects of social interaction were paralleled by a reduced activation, as assessed by Zif268 expression, in brain areas known to play pivotal roles in drug-seeking behavior. Here we show that social interaction during extinction of cocaine CPP also reduced cocaine-CPP-stimulated FosB expression in the nucleus accumbens shell and core. In addition, social interaction during cocaine CPP extinction increased pCREB (cAMP response element binding protein) expression in the nucleus accumbens shell and the cingulate cortex area 1 (Cg1). Our results show that FosB and pCREB may be implicated in the protective effect of social interaction against cocaine-induced reinstatement of CPP. Thus, social interaction, if offered in a context that is clearly distinct from the previously drug-associated one, may profoundly inhibit relapse to cocaine addiction.

  16. Endomorphins suppress nociception-induced c-Fos and Zif/268 expression in the rat spinal dorsal horn.

    PubMed

    Tateyama, Shingo; Ikeda, Tetsuya; Kosai, Kazuko; Nakamura, Tadashi; Kasaba, Toshiharu; Takasaki, Mayumi; Nishimori, Toshikazu

    2002-09-06

    We evaluated the potency of endomorphin-1 and -2 as endogenous ligands on c-Fos and Zif/268 expression in the spinal dorsal horn by formalin injection to the rat hind paw. Endomorphin-1, -2, or morphine was administered intrathecally or intracerebroventricularly 5 min before formalin injection (5%, 100 microl). All drugs produced marked reductions of formalin-induced c-Fos and Zif/268 immunoreactivity in laminae I and II, and laminae V and VI in the rat lumbar spinal cord. The reductions of Zif/268 expression by endomorphins were greater than those by morphine, while the reductions of c-Fos expression by endomorphins were smaller than those by morphine. These effects of endomorphins were attenuated by pretreatment with naloxone. These results indicate that endomorphin-1 and -2 act as endogenous ligands of mu-opioid receptor in neurons of the spinal dorsal horn and suppress the processing of nociceptive information in the central nervous system.

  17. Fos expression at the cerebellum following non-contact arousal and mating behavior in male rats

    PubMed Central

    Manzo, Jorge; Miquel, Marta; Toledo, Rebeca; Mayor-Mar, Justo Abraham; Garcia, Luis I.; Aranda-Abreu, Gonzalo E.; Caba, Mario; Hernandez, Maria Elena

    2010-01-01

    The cerebellum is considered a center underlying fine movements, cognition, memory and sexual responses. The latter feature led us to correlate sexual arousal and copulation in male rats with neural activity at the cerebellar cortex. Two behavioral paradigms were used in this investigation: the stimulation of males by distant receptive females (non-contact sexual stimulation), and the execution of up to three consecutive ejaculations. The vermis area of the cerebellum was removed following behavioral experiments, cut into sagittal sections, and analyzed with Fos immunohistochemistry to determine neuronal activation. At the mid-vermis region (sections from the midline to 0.1 mm laterally), non-contact stimulation significantly increased the activity of granule neurons. The number of activated cells increased in every lobule, but lobules 1 and 6 to 9 showed the greatest increment. In sexual behavior tests, males reaching one ejaculation had a high number of activated neurons similar to those counted after non-contact stimulation. However, two or three consecutive ejaculations showed a smaller number of Fos-ir cells. In contrast to the mid-vermis region, sections farthest from the midline (0.1 to 0.9 mm laterally) revealed that only lobule 7 expressed activated neurons. These data suggest that a well-delineated group of granule neurons have a sexual biphasic response at the cerebellar vermis, and that Fos in them is under an active degradation mechanism. Thus, they participate as a neural substrate for male rat sexual responses with an activation-deactivation process corresponding with the sensory stimulation and motor performance occurring during copulation. PMID:17936859

  18. AP-1(c-Jun/FosB) mediates xFoxD5b expression in Xenopus early developmental neurogenesis.

    PubMed

    Yoon, Jaeho; Kim, Jung-Ho; Lee, Ok-Joo; Lee, Sung-Young; Lee, Seung-Hwan; Park, Jae-Bong; Lee, Jae-Yong; Kim, Sung-Chan; Kim, Jaebong

    2013-01-01

    AP-1 (activator protein-1) is composed of Jun and Fos proteins and functions in cell proliferation, apoptosis and differentiation. Previous studies have demonstrated that different AP-1 complexes participate in the determination of various cell fates. However, the role of different AP-1 complexes during early vertebrate development is not yet fully understood. In the present study, we demonstrate that AP-1(c-Jun/FosB) regulates neurogenesis via FoxD5b expression. We show that FoxD5 was induced by the inhibition of BMP and that FoxD5b plays roles in neurogenesis. Additionally, we show that the FoxD5b promoter region within -1336 and -1316 contains an AP-1 binding site, which is required for the transcriptional regulation of FoxD5b and is induced by the inhibition of BMP signaling in animal cap explants. Moreover, c-Jun, a component of AP-1, directly binds to the AP-1 binding site of the FoxD5b promoter and induces FoxD5b expression cooperatively with FosB, but not with c-Fos or Fra-1. Altogether, these results suggest that AP-1(c-Jun/FosB) may play a role in neurogenesis via the induction of FoxD5b expression during early vertebrate development.

  19. Striatal dopamine and glutamate receptors modulate methamphetamine-induced cortical Fos expression

    PubMed Central

    Gross, Noah B.; Marshall, John F.

    2009-01-01

    Methamphetamine (mAMPH) is a psychostimulant drug that increases extracellular levels of monoamines throughout the brain. It has previously been observed that a single injection of mAMPH increases immediate early gene (IEG) expression in both the striatum and cerebral cortex. Moreover, this effect is modulated by dopamine and glutamate receptors since systemic administration of dopamine or glutamate antagonists has been found to alter mAMPH-induced striatal and cortical IEG expression. However, because dopamine and glutamate receptors are found in extra-striatal as well as striatal brain regions, studies employing systemic injection of dopamine or glutamate antagonists fail to localize the effects of mAMPH-induced activation. In the present experiments, the roles of striatal dopamine and glutamate receptors in mAMPH-induced gene expression in the striatum and cerebral cortex were examined. The nuclear expression of Fos, the protein product of the IEG c-fos, was quantified in both the striatum and the cortex of animals receiving intrastriatal dopamine or glutamate antagonist administration. Intrastriatal infusion of dopamine (D1 or D2) or glutamate [N-methyl-D-aspartic acid (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)] antagonists affected not only mAMPH-induced striatal, but also cortical, Fos expression. Overall, the effects of the antagonists occurred dose-dependently, in both the infused and non-infused hemispheres, with greater influences occurring in the infused hemisphere. Finally, unilateral intrastriatal infusion of dopamine or glutamate antagonists changed the behavior of the rats from characteristic mAMPH-induced stereotypy to rotation ipsilateral to the infusion. These results demonstrate that mAMPH’s actions on striatal dopamine and glutamate receptors modulate the widespread cortical activation induced by mAMPH. It is hypothesized that dopamine release from nigrostriatal terminals modulates activity within striatal

  20. c-fos modulates brain-derived neurotrophic factor mRNA expression in mouse hippocampal CA3 and dentate gyrus neurons.

    PubMed

    Dong, Mei; Wu, Yongfei; Fan, Yunxia; Xu, Ming; Zhang, Jianhua

    2006-05-29

    Excess neuronal excitation by glutamate induces neuron cell death, which may contribute to the pathogenesis of acute brain injuries and neurodegenerative diseases. Our previous studies using a mouse with hippocampal c-fos gene deletion showed that c-fos regulates neuronal excitability and excitotoxicity. Moreover, a delayed induction of brain-derived neurotrophic factor (BDNF) protein expression in response to kainic acid (KA) treatment was found in c-fos mutant mice compared to wildtype controls, suggesting that c-fos is important in the temporal control of BDNF induction. To further investigate mechanisms of in vivo regulation of c-fos on BDNF expression, we studied the expression of BDNF mRNA and its colocalization with c-Fos protein in the hippocampal formation in the presence and absence of KA. By in situ hybridization, we observed that the c-fos mutant and wildtype mice exhibited similar basal expression of BDNF in the absence of KA. In contrast, the KA-induced BDNF mRNA levels were significantly different in wildtype and c-fos mutant mice in CA3 and dentate gyrus regions. Our findings indicate that c-fos regulates expression of BDNF in distinct neuron populations of the hippocampal formation in vivo.

  1. Spatial memory formation differentially affects c-Fos expression in retrosplenial areas during place avoidance training in rats.

    PubMed

    Malinowska, Monika; Niewiadomska, Monika; Wesierska, Malgorzata

    2016-01-01

    The retrosplenial cortex is involved in spatial memory function, but the contribution of its individual areas is not well known. To elucidate the involvement of retrosplenial cortical areas 29c and 30 in spatial memory, we analyzed the expression of c-Fos in these areas in the experimental group of rats that were trained in a spatial place avoidance task, i.e. to avoid shocks presented in an unmarked sector of a stable arena under light conditions. Control rats were trained in the same context as the experimental rats either without (Control-noUS) or with shocks (Control-US) that were delivered in a random, noncontingent manner for three days. On the first day of place avoidance learning, the experimental group exhibited c-Fos induction in area 29c, similar to both control groups. In area 30, similarly high levels of c-Fos expression were observed in the experimental and Control-US groups. On the third day of training, when the experimental group efficiently avoided c-Fos expression in areas 29c and 30 was lower compared with the first day of training. In area 29c c-Fos level was also lower in the experimental than in comparison to the Control-US group. In area 30, c-Fos expression in the experimental group was lower than in both control groups. In conclusion, areas 29c and 30 appear to be activated during spatial memory acquisition on the first day of training, whereas area 30 seems suppressed during long-term memory functioning on the third day of training when rats effectively avoid.

  2. Fos Expression in Neurons of the Rat Vestibulo-Autonomic Pathway Activated by Sinusoidal Galvanic Vestibular Stimulation

    PubMed Central

    Holstein, Gay R.; Friedrich Jr., Victor L.; Martinelli, Giorgio P.; Ogorodnikov, Dmitri; Yakushin, Sergei B.; Cohen, Bernard

    2012-01-01

    The vestibular system sends projections to brainstem autonomic nuclei that modulate heart rate and blood pressure in response to changes in head and body position with regard to gravity. Consistent with this, binaural sinusoidally modulated galvanic vestibular stimulation (sGVS) in humans causes vasoconstriction in the legs, while low frequency (0.02–0.04 Hz) sGVS causes a rapid drop in heart rate and blood pressure in anesthetized rats. We have hypothesized that these responses occur through activation of vestibulo-sympathetic pathways. In the present study, c-Fos protein expression was examined in neurons of the vestibular nuclei and rostral ventrolateral medullary region (RVLM) that were activated by low frequency sGVS. We found c-Fos-labeled neurons in the spinal, medial, and superior vestibular nuclei (SpVN, MVN, and SVN, respectively) and the parasolitary nucleus. The highest density of c-Fos-positive vestibular nuclear neurons was observed in MVN, where immunolabeled cells were present throughout the rostro-caudal extent of the nucleus. c-Fos expression was concentrated in the parvocellular region and largely absent from magnocellular MVN. c-Fos-labeled cells were scattered throughout caudal SpVN, and the immunostained neurons in SVN were restricted to a discrete wedge-shaped area immediately lateral to the IVth ventricle. Immunofluorescence localization of c-Fos and glutamate revealed that approximately one third of the c-Fos-labeled vestibular neurons showed intense glutamate-like immunofluorescence, far in excess of the stain reflecting the metabolic pool of cytoplasmic glutamate. In the RVLM, which receives a direct projection from the vestibular nuclei and sends efferents to preganglionic sympathetic neurons in the spinal cord, we observed an approximately threefold increase in c-Fos labeling in the sGVS-activated rats. We conclude that localization of c-Fos protein following sGVS is a reliable marker for sGVS-activated neurons of the vestibulo

  3. Detection of molecular alterations in methamphetamine-activated Fos-expressing neurons from a single rat dorsal striatum using fluorescence-activated cell sorting (FACS).

    PubMed

    Liu, Qing-Rong; Rubio, Francisco J; Bossert, Jennifer M; Marchant, Nathan J; Fanous, Sanya; Hou, Xingyu; Shaham, Yavin; Hope, Bruce T

    2014-01-01

    Methamphetamine and other drugs activate a small proportion of all neurons in the brain. We previously developed a fluorescence-activated cell sorting (FACS)-based method to characterize molecular alterations induced selectively in activated neurons that express the neural activity marker Fos. However, this method requires pooling samples from many rats. We now describe a modified FACS-based method to characterize molecular alterations in Fos-expressing dorsal striatal neurons from a single rat using a multiplex pre-amplification strategy. Fos and NeuN (a neuronal marker) immunohistochemistry indicate that 5-6% of dorsal striatum neurons were activated 90 min after acute methamphetamine injections (5 mg/kg, i.p.) while less than 0.5% of neurons were activated by saline injections. We used FACS to separate NeuN-labeled neurons into Fos-positive and Fos-negative neurons and assessed mRNA expression using RT-qPCR from as little as five Fos-positive neurons. Methamphetamine induced 3-20-fold increases of immediate early genes arc, homer-2, c-fos, fosB, and its isoforms (ΔfosB and a novel isoform ΔfosB-2) in Fos-positive but not Fos-negative neurons. Immediate early gene mRNA induction was 10-fold lower or absent when assessed in unsorted samples from single dorsal striatum homogenates. Our modified method makes it feasible to study unique molecular alterations in neurons activated by drugs or drug-associated cues in complex addiction models. Methamphetamine and other drugs activate a small proportion of all neurons in the brain. We here report an improved method to characterize molecular alterations induced selectively in activated neurons that express the neural activity marker Fos. We used FACS along with targeted PCR pre-amplification to assess acute methamphetamine-induced gene expression from as few as 5 Fos-expressing neurons from a single rat dorsal striatum. Methamphetamine induced 3-20-fold increases of immediate early genes (IEGs) in Fos-positive but not

  4. Influence of sleep deprivation on expression of MKK4 and c-fos in the mandibular condylar cartilage of rats.

    PubMed

    Chen, Jinlong; Wu, Gaoyi; Zhu, Guoxiong; Wang, Peihuan; Chen, Hongyu; Zhao, Huaqiang

    2013-12-01

    The aim of this study was to investigate the changes in expression of mitogen-activated protein kinase kinase 4 (MKK4) and c-fos in the mandibular condylar cartilage of rats that had been subjected to sleep deprivation. One hundred and twenty female Wistar rats were randomly divided into 6 groups with 20 in each: sleep deprivation for 2 days, 4 days, 6 days, and 8 days, large-platform controls, and cage controls. After sleep deprivation by the modified multiple platform method the sleep-deprived rats were killed. The large-platform and cage control rats were killed at the same time as the rats deprived of sleep for 8 days. Haematoxylin and eosin were used to record the morphological changes in cartilage, and immunohistochemistry and real-time quantitative polymerase chain reaction (PCR) were used to detect the expression of MKK4 and c-fos. Pathological alterations were apparent after 6 and 8 days of sleep deprivation. Compared with control groups, the expression of MKK4 in the sleep-deprived groups was lower, while that of c-fos was higher. As the duration of sleep deprivation increased, the expression of MKK4 decreased. These results indicate that the variation in expression of MKK4 and c-fos may be correlated with pathological changes induced by sleep deprivation in mandibular condylar cartilage in rats.

  5. c-Fos expression after deep brain stimulation of the pedunculopontine tegmental nucleus in the rat 6-hydroxydopamine Parkinson model.

    PubMed

    Saryyeva, Assel; Nakamura, Makoto; Krauss, Joachim K; Schwabe, Kerstin

    2011-11-01

    Deep brain stimulation (DBS) is used to alleviate motor dysfunction in Parkinson's disease (PD). The pedunculopontine nucleus (PPN) may be a potential target for severe freezing and postural instability with 25 Hz stimulation being considered more effective than 130 Hz stimulation. Here we evaluated the expression of c-Fos after 25 Hz and 130 Hz DBS of the pedunculopontine tegmental nucleus (PPTg, i.e., the rodent equivalent to the human PPN) in the rat 6-hydroxydopamine (6-OHDA) PD model. Anaesthetized male Sprague Dawley rats with unilateral 6-OHDA-induced nigrostriatal lesions were stimulated with 25 Hz, 130 Hz, or 0 Hz sham-stimulation for 4h by electrodes implanted into the ipsilateral PPTg. Thereafter the distribution and number of neurons expressing the immediate early gene c-Fos, a marker for acute neuronal activity, was assessed. DBS of the PPTg induced strong ipsilateral c-Fos expression at the stimulation site, with 25 Hz having a more marked impact than 130 Hz. Additionally, c-Fos was strongly expressed in the central gray. In the dorsal part expression was stronger after 25 Hz stimulation, while in the medial and ventral part there was no difference between 25 Hz and 130 Hz stimulation. Expression in the basal ganglia was negligible. In the rat 6-OHDA PD model stimulation of the PPTg did not affect c-Fos expression in the basal ganglia, but had a strong impact on other functional circuitries. PPN stimulation in humans might therefore also have an impact on other systems than the motor system.

  6. Central Fos expression and conditioned flavor avoidance in rats following intragastric administration of bitter taste receptor ligands.

    PubMed

    Hao, Shuzhen; Dulake, Michelle; Espero, Elvis; Sternini, Catia; Raybould, Helen E; Rinaman, Linda

    2009-03-01

    G protein-coupled receptors that signal bitter taste (T2Rs) are expressed in the mucosal lining of the oral cavity and gastrointestinal (GI) tract. In mice, intragastric infusion of T2R ligands activates Fos expression within the caudal viscerosensory portion of the nucleus of the solitary tract (NTS) through a vagal pathway (Hao S, Sternini C, Raybould HE. Am J Physiol Regul Integr Comp Physiol 294: R33-R38, 2008). The present study was performed in rats to further characterize the distribution and chemical phenotypes of brain stem and forebrain neurons activated to express Fos after intragastric gavage of T2R ligands, and to determine a potential behavioral correlate of this central neural activation. Compared with relatively low brain stem and forebrain Fos expression in control rats gavaged intragastrically with water, rats gavaged intragastrically with T2R ligands displayed significantly increased activation of neurons within the caudal medial (visceral) NTS and caudal ventrolateral medulla, including noradrenergic neurons, and within the lateral parabrachial nucleus, central nucleus of the amygdala, and paraventricular nucleus of the hypothalamus. A behavioral correlate of this Fos activation was evidenced when rats avoided consuming flavors that previously were paired with intragastric gavage of T2R ligands. While unconditioned aversive responses to bitter tastants in the oral cavity are often sufficient to inhibit further consumption, a second line of defense may be provided postingestively by ligand-induced signaling at GI T2Rs that signal the brain via vagal sensory inputs to the caudal medulla.

  7. Fos Expression in Monoaminergic Cell Groups in Response to Sociosexual Interactions in Male and Female Japanese Quail

    PubMed Central

    Iyilikci, Onur; Baxter, Samantha; Balthazart, Jacques; Ball, Gregory F.

    2014-01-01

    Monoaminergic neurotransmitters regulate different components of sexual behaviors, but how the different monoaminergic cell groups selectively regulate these behaviors is not well understood. We examined the potential contribution of these different cell groups in the control of different aspects of sexual behaviors in male and female quail. We used double-label immunohistochemistry, labeling the protein product of the immediate early gene, Fos, along with tyrosine hydroxylase (TH) or tryptophan hydroxylase (TPH), markers for catecholaminergic or indolaminergic cells, respectively. Rhythmic Cloacal Sphincter Movements (RCSM) were recorded as a measure of male appetitive sexual behavior. Consummatory sexual behaviors were evaluated based on the species-typical copulation sequence. Enhanced Fos expression in the medial preoptic nucleus and bed nucleus of the stria terminalis was observed in association with both physical and visual contact to the opposite sex for males, but not for females. Fos induction associated with physical contact was observed in the ventral tegmental area and anterior periaqueductal gray in both sexes. In males only, the number of Fos-immunoreactive (ir) cells increased in the visual contact condition in these two dopaminergic cell groups, however no significant effect was observed for double-labeled TH-Fos-ir cells. In addition, consummatory but not appetitive sexual behavior increased Fos expression in TPH-ir cells in the raphe pallidus of males. This increase following physical but not visual contact agrees with the notion that activation of the serotoninergic system is implicated in the development of sexual satiation but not activated by simply viewing a female, in contrast to the dopaminergic system. PMID:24512065

  8. High ambient temperature increases 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy")-induced Fos expression in a region-specific manner.

    PubMed

    Hargreaves, G A; Hunt, G E; Cornish, J L; McGregor, I S

    2007-03-16

    3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") is a popular drug that is often taken under hot conditions at dance clubs. High ambient temperature increases MDMA-induced hyperthermia and recent studies suggest that high temperatures may also enhance the rewarding and prosocial effects of MDMA in rats. The present study investigated whether ambient temperature influences MDMA-induced expression of Fos, a marker of neural activation. Male Wistar rats received either MDMA (10 mg/kg i.p.) or saline, and were placed in test chambers for 2 h at either 19 or 30 degrees C. MDMA caused significant hyperthermia at 30 degrees C and a modest hypothermia at 19 degrees C. The 30 degrees C ambient temperature had little effect on Fos expression in vehicle-treated rats. However MDMA-induced Fos expression was augmented in 15 of 30 brain regions at the high temperature. These regions included (1) sites associated with thermoregulation such as the median preoptic nucleus, dorsomedial hypothalamus and raphe pallidus, (2) the supraoptic nucleus, a region important for osmoregulation and a key mediator of oxytocin and vasopressin release, (3) the medial and central nuclei of the amygdala, important in the regulation of social and emotional behaviors, and (4) the shell of the nucleus accumbens and (anterior) ventral tegmental area, regions associated with the reinforcing effects of MDMA. MDMA-induced Fos expression was unaffected by ambient temperature at many other sites, and was diminished at high temperature at one site (the islands of Calleja), suggesting that the effect of temperature on MDMA-induced Fos expression was not a general pharmacokinetic effect. Overall, these results indicate that high temperatures accentuate key neural effects of MDMA and this may help explain the widespread use of the drug under hot conditions at dance parties as well as the more hazardous nature of MDMA taken under such conditions.

  9. CREB, AP‐1, ternary complex factors and MAP kinases connect transient receptor potential melastatin‐3 (TRPM3) channel stimulation with increased c‐Fos expression

    PubMed Central

    Rubil, Sandra; Rössler, Oliver G.

    2016-01-01

    Background and Purpose The rise in intracellular Ca2+ stimulates the expression of the transcription factor c‐Fos. Depending on the mode of entry of Ca2+ into the cytosol, distinct signal transducers and transcription factors are required. Here, we have analysed the signalling pathway connecting a Ca2+ influx via activation of transient receptor potential melastatin‐3 (TRPM3) channels with enhanced c‐Fos expression. Experimental Approach Transcription of c‐Fos promoter/reporter genes that were integrated into the chromatin via lentiviral gene transfer was analysed in HEK293 cells overexpressing TRPM3. The transcriptional activation potential of c‐Fos was measured using a GAL4‐c‐Fos fusion protein. Key Results The signalling pathway connecting TRPM3 stimulation with enhanced c‐Fos expression requires the activation of MAP kinases. On the transcriptional level, three Ca2+‐responsive elements, the cAMP‐response element and the binding sites for the serum response factor (SRF) and AP‐1, are essential for the TRPM3‐mediated stimulation of the c‐Fos promoter. Ternary complex factors are additionally involved in connecting TRPM3 stimulation with the up‐regulation of c‐Fos expression. Stimulation of TRPM3 channels also increases the transcriptional activation potential of c‐Fos. Conclusions and Implications Signalling molecules involved in connecting TRPM3 with the c‐Fos gene are MAP kinases and the transcription factors CREB, SRF, AP‐1 and ternary complex factors. As c‐Fos constitutes, together with other basic region leucine zipper transcription factors, the AP‐1 transcription factor complex, the results of this study explain TRPM3‐induced activation of AP‐1 and connects TRPM3 with the biological functions regulated by AP‐1. © 2015 The British Pharmacological Society PMID:26493679

  10. C-fos and IL-2 gene expression in rat brain cells and splenic lymphocytes after nonantigenic and antigenic stimuli.

    PubMed

    Korneva, E A; Barabanova, S V; Golovko, O I; Nosov, M A; Novikova, N S; Kazakova, T B

    2000-01-01

    Immunostimulatory or immunosuppressive stress models were used: (1) rotation stress (RS) and (2) immobilization (restraint) stress (IS). Intravenous injection of tetanus toxoid (anatoxin) (TT) was chosen as the antigenic stimulus (500 micrograms/kg weight), and intravenous injection of saline solution was used as the control. Splenic lymphocytes (CBA mice) or different brain structures (Wistar and Sprague-Dawley rats) were analyzed. The c-fos and interleukin-2 (IL-2) mRNA expression was measured using a digoxigenin (Dig)-labeled cDNA probe by spot or in situ hybridization. Rotation stress stimulated IL-2 mRNA synthesis in lymphocytes in the presence of ConA and rIL-2 by 40%. IL-2 mRNA synthesis in lymphoid cells obtained from animals after IS and after IS in combination with the administration in vitro of the cytotoxic drug CsA to the splenic lymphocytes was inhibited (30% and 99%), accordingly, as compared with control rats. Induction of c-fos mRNA synthesis in rat brain cells was noted 30 minutes after RS in the hypothalamus (lateralis hypothalamic area, LHA), thalamus, corpus collosum, and sensorimotor zone of the brain cortex. IL-2 mRNA synthesis was shown two hours after RS in the same structures. The increased number of c-fos mRNA-positive cells two hours after TT injection was shown in the posterior hypothalamus area (PHA), LHA, dorsomedial nucleus (DMH), ventromedial nucleus (VMH), and anterior hypothalamus area (AHA) as compared to the effect of i.v. saline injection. Moreover, IL-2 mRNA-positive cell induction was noted in the PHA, DMH, and VMH. Six hours after TT injection, c-fos mRNA expression was decreased in the PHA, LHA, and AHA. Activation of c-fos and IL-2 mRNA was detected in the paraventricularis nucleus 6 hours after TT i.v. injection. Thus, inhibition or stimulation of IL-2 gene expression in lymphoid cells depends on the nature of the stressors. RS or antigenic stimuli induce c-fos and IL-2 gene expression in definite structures of the brain

  11. [Antagonistic effects of selenium on the expression of c-fos in central nerval system of rat included by mercury contaminated rice].

    PubMed

    Cheng, Jin-ping; Wang, Wen-hua; Jia, Jin-ping; Qu, Li-ya; Zheng, Min; Shen, Zhe-ming; Shi, Wei

    2005-03-01

    The objective of this paper is to study the antagonisms between selenium and mercury and the effect of different species mercury on the brain injury. The expression of c-fos mRNA and c-FOS protein in rat brain induced by Hg-contaminated rice was observed by using reverse transcriptions polymerase chain reaction (RT-PCR) and immunocytochemical methods. The results show the Hg-contaminated rice induced significantly the expression of c-fos mRNA and c-FOS protein; selenium could antagonize mercury accumulative level in brain. Antagonistic effects of selenium on the expression of c-fos included by mercury and the molecule mechanism of the antagonisms between selenium and mercury was probed, too.

  12. Electrical activation and c-fos mRNA expression in rat neurosecretory neurones after systemic administration of cholecystokinin.

    PubMed Central

    Hamamura, M; Leng, G; Emson, P C; Kiyama, H

    1991-01-01

    1. The expression of c-fos mRNA in the rat hypothalamus was examined by in situ hybridization following systemic administration of cholecystokinin (CCK), a procedure known to activate magnocellular oxytocin neurons but not magnocellular vasopressin neurones. 2. Conscious male rats were given a single I.P. injection of 50 micrograms/kg CCK, c-fos mRNA signal was apparent in the supraoptic and paraventricular nuclei in rats killed 10 min after injection but not in uninjected or saline-(vehicle) injected rats. The density of c-fos mRNA at both sites was further elevated in rats killed 30 min or 60 min following injection, and was absent in rats killed 4 h after injection. 3. In the paraventricular nucleus the most dense expression of c-fos mRNA following CCK administration was in the medial, mainly parvocellular portion of the nucleus, in an area corresponding to the distribution of corticotrophin-releasing factor mRNA determined by in situ hybridization in adjacent sections. 4. The I.P. injection of CCK increased plasma oxytocin concentrations, measured by specific radioimmunoassay from 13 +/- 5 pg/ml in control rats to 107 +/- 9 pg/ml in the rats killed 10 min after injection, a similar response to that observed previously in urethane-anaesthetized rats. 5. In each of six urethane-anaesthetized rats, recordings were made from single neurones in the supraoptic nucleus, identified antidronomically as projecting to the posterior pituitary and identified electrophysiologically as putative oxytocin neurones. Following I.P. injection of 50 micrograms/kg CCK, the neurones increased their firing rate by a mean of 1.3 +/- 0.2 spikes/s averaged over the 10 min following injection. 6. From the appearance of c-fos mRNA in supraoptic neurones following CCK administration we conclude that this message is expressed in magnocellular oxytocin neurones, since vasopressin neuronal activity and vasopressin release is known to be unaffected by this stimulus, and since the supraoptic

  13. c-Fos expression associated with reinstatement of cocaine-seeking behavior by response-contingent conditioned cues.

    PubMed

    Kufahl, Peter R; Zavala, Arturo R; Singh, Akanksha; Thiel, Kenneth J; Dickey, Erin D; Joyce, Jeffrey N; Neisewander, Janet L

    2009-10-01

    The capability of cocaine cues to generate craving in cocaine-dependent humans, even after extended abstinence, is modeled in rats using cue reinstatement of extinguished cocaine-seeking behavior. We investigated neural activity associated with incentive motivational effects of cocaine cues using c-fos mRNA and Fos protein expression as markers. Unlike preceding studies, we used response-contingent presentation of discrete cues to elicit cocaine seeking. Rats were first trained to press a lever, resulting in cocaine reinforcement and light and tone cues. Rats then underwent extinction training, during which lever presses decreased. On the test day, rats either received response-contingent cocaine cues or received no cues. The cues reinstated extinguished cocaine-seeking behavior on the test day. In general, cue-elicited c-fos mRNA and protein expression were similar and both were enhanced in the prefrontal cortex, ventral tegmental area (VTA), dorsal striatum, and nucleus accumbens. Cues elicited more widespread Fos protein expression relative to our previous research in which cues were presented noncontingently without prior extinction training, including increases in the VTA, substantia nigra, ventral subiculum, and lateral entorhinal cortex. We also observed a correlation between cocaine-seeking behavior and Fos in the agranular insula (AgI) and basolateral amygdala (BLA). The findings suggest that connections between BLA and AgI play a role in cue-elicited incentive motivation for cocaine and that reinstatement of cocaine seeking by response-contingent cues activates a similar corticolimbic circuit as that observed with other modes of cue presentation; however, activation of midbrain and ventral hippocampal regions may be unique to reinstatement by response-contingent cues.

  14. The expression of c-Fos and colocalisation of c-Fos and glucocorticoid receptors in brain structures of low and high anxiety rats subjected to extinction trials and re-learning of a conditioned fear response.

    PubMed

    Lehner, Małgorzata; Wisłowska-Stanek, Aleksandra; Taracha, Ewa; Maciejak, Piotr; Szyndler, Janusz; Skórzewska, Anna; Turzyńska, Danuta; Sobolewska, Alicja; Hamed, Adam; Bidziński, Andrzej; Płaźnik, Adam

    2009-11-01

    We designed an animal model to examine the mechanisms of differences in individual responses to aversive stimuli. We used the rat freezing response in the context fear test as a discriminating variable: low responders (LR) were defined as rats with a duration of freezing response one standard error or more below the mean value, and high responders (HR) were defined as rats with a duration of freezing response one standard error or more above the mean value. We sought to determine the colocalisation of c-Fos and glucocorticoid receptors-immunoreactivity (GR-ir) in HR and LR rats subjected to conditioned fear training, two extinction sessions and re-learning of a conditioned fear. We found that HR animals showed a marked decrease in conditioned fear in the course of two extinction sessions (16 days) in comparison with the control and LR groups. The LR group exhibited higher activity in the cortical M2 and prelimbic areas (c-Fos) and had an increased number of cells co-expressing c-Fos and GR-ir in the M2 and medial orbital cortex after re-learning a contextual fear. HR rats showed increased expression of c-Fos, GR-ir and c-Fos/GR-ir colocalised neurons in the basolateral amygdala and enhanced c-Fos and GR-ir in the dentate gyrus (DG) in comparison with LR animals. Our data indicate that recovery of a context-related behaviour upon re-learning of contextual fear is accompanied in HR animals by a selective increase in c-Fos expression and GRs-ir in the DG area of the hippocampus.

  15. Harmful Algal Bloom Toxins: c-Fos Protein Expression in the Brain of Killifish, Fundulus heteroclitus

    DTIC Science & Technology

    2006-04-21

    California coast linked to a toxic diatom bloom. Nature 403, 80–84. Schreiberagus, N., Horner, J., Torres, R., Chiu, F.C., Depinho, R.A., 1993. Zebra fish myc...protein product c-Fos, are known to be induced in neurons of mammals and fish as a result of neuronal timulation. The purpose of this study was to...physical stress on c-Fos induction. Groups of fish were exposed to the different tress agents, brain sections were processed for c-Fos staining, and

  16. Pattern of Fos expression in the brain induced by selective activation of somatostatin receptor 2 in rats

    PubMed Central

    Goebel, Miriam; Stengel, Andreas; Wang, Lixin; Coskun, Tamer; Alsina-Fernandez, Jorge; Rivier, Jean; Taché, Yvette

    2010-01-01

    Central activation of somatostatin (sst) receptors by oligosomatostatin analogs inhibits growth hormone and stress-related rise in catecholamine plasma levels while stimulating grooming, feeding behaviors, gastric transit and acid secretion, which can be mimicked by selective sst2 receptor agonist. To evaluate the pattern of neuronal activation induced by peptide sst receptor agonists, we assessed Fos-expression in rat brain after intracerebroventricular (icv) injection of a newly developed selective sst2 agonist compared to the oligosomatostatin agonist, ODT8-SST, a pan-sst1–5 agonist. Ninety min after injection of vehicle (10µl) or previously established maximal orexigenic dose of peptides (1µg=1nmol/rat), brains were assessed for Fos-immunohistochemistry and doublelabeling. Food and water were removed after injection. The sst2 agonist and ODT8-SST induced a similar Fos distribution pattern except in the arcuate nucleus where only the sst2 agonist increased Fos. Compared to ODT8-SST, the sst2 agonist induced higher Fos-expression by 3.7-fold in the basolateral amygdaloid nucleus, 1.2-fold in the supraoptic nucleus (SON), 1.6-fold in the magnocellular paraventricular hypothalamic nucleus (mPVN), 4.1-fold in the external lateral parabrachial nucleus, and 2.6-fold in both the inferior olivary nucleus and superficial layer of the caudal spinal trigeminal nucleus. Doublelabeling in the hypothalamus showed that ODT8-SST activates 36% of oxytocin, 63% of vasopressin and 79% of sst2 immunoreactive neurons in the mPVN and 28%, 55% and 25% in the SON, respectively. Selective activation of sst2 receptor results in a more robust neuronal activation than the pan-sst1–5 agonist in various brain regions that may have relevance in sst2 mediated alterations of behavioral, autonomic and endocrine functions. PMID:20637739

  17. Water deprivation increases Fos expression in hypothalamic corticotropin-releasing factor neurons induced by right atrial distension in awake rats.

    PubMed

    Benedetti, Mauricio; Rorato, Rodrigo; Castro, Margaret; Machado, Benedito H; Antunes-Rodrigues, Jose; Elias, Lucila L K

    2008-11-01

    Atrial mechanoreceptors, sensitive to stretch, contribute in regulating heart rate and intravascular volume. The information from those receptors reaches the nucleus tractus solitarius and then the paraventricular nucleus (PVN), known to have a crucial role in the regulation of cardiovascular function. Neurons in the PVN synthesize CRF, AVP, and oxytocin (OT). Stimulation of atrial mechanoreceptors was performed in awake rats implanted with a balloon at the junction of the superior vena cava and right atrium. Plasma ACTH, AVP, and OT concentrations and Fos, CRF, AVP, and OT immunolabeling in the PVN were determined after balloon inflation in hydrated and water-deprived rats. The distension of the balloon increased the plasma ACTH concentrations, which were higher in water-deprived than in hydrated rats (P < 0.05). In addition, the distension in the water-deprived group decreased plasma AVP concentrations (P < 0.05), compared with the respective control group. The distension increased the number of Fos- and double-labeled Fos/CRF neurons in the parvocellular PVN, which was higher in the water-deprived than in the hydrated group (P < 0.01). There was no difference in the Fos expression in magnocellular PVN neurons after distension in hydrated and water-deprived groups, compared with respective controls. In conclusion, parvocellular CRF neurons showed an increase of Fos expression induced by stimulation of right atrial mechanoreceptors, suggesting that CRF participates in the cardiovascular reflex adjustments elicited by volume loading. Activation of CRF neurons in the PVN by cardiovascular reflex is affected by osmotic stimulation.

  18. Effect of hypoxia on metabolic rate, core body temperature, and c-fos expression in the naked mole rat.

    PubMed

    Nathaniel, Thomas I; Otukonyong, Effiong; Abdellatif, Ahmed; Soyinka, Julius O

    2012-10-01

    Recent investigations of hypoxia physiology in the naked mole rat have opened up an interesting line of research into the basic physiological and genomic alterations that accompany hypoxia survival. The extent to which such findings connect the effect of hypoxia to metabolic rate (O₂ consumption), core body temperature (Tb), and transcripts encoding the immediate early gene product (such as c-fos) under a constant ambient temperature (Ta) is not well known. We investigated this issue in the current study. Our first sets of experiments measured Tb and metabolic rates during exposure of naked mole rats to hypoxia over a constant Ta. Hypoxia significantly decreased metabolic rates in the naked mole rat. Although core Tb also decreased during hypoxia, the effect of hypoxia in suppressing core Tb was not significant. The second series of experiments revealed that c-fos protein and mRNA expression in the hippocampus neurons (CA1) increased in naked mole rats that were repeatedly exposed to 3% O₂ for 60 min per day for 5 days when compared to normoxia. Our findings provide evidence for the up-regulation of c-fos and suppression of metabolic rate in hypoxia tolerating naked mole rats under constant ambient temperature. Metabolic suppression and c-fos upregulation constitute part of the physiological complex associated with adaptation to hypoxia.

  19. TGF beta induces a sustained c-fos expression associated with stimulation or inhibition of cell growth in EL2 or NIH 3T3 fibroblasts.

    PubMed

    Liboi, E; Di Francesco, P; Gallinari, P; Testa, U; Rossi, G B; Peschle, C

    1988-02-29

    We have previously indicated that epidermal growth factor (EGF) plays a fundamental role in the proliferation control of EL2 rat fibroblast line. It is shown here that transforming growth factor beta (TGF beta) stimulates both DNA synthesis and proliferation of EL2 cells, while exerting an inhibitory effect on the growth of murine NIH-3T3 fibroblasts. We also report the effect of TGF beta and EGF on c-fos expression in EL2 cells, as compared to that of TGF beta in NIH-3T3 fibroblasts. In EL2 cells EGF induces a transient c-fos expression at both mRNA and protein level, as previously observed in NIH-3T3 fibroblasts treated with platelet-derived or fibroblast growth factor (PDGF, FGF). Conversely, TGF beta induces in EL2 cells a sustained expression of fos mRNA and protein, which are still detectable at least 24 and 7 hr after treatment respectively. In NIH-3T3 fibroblasts TGF beta causes a sustained fos RNA expression, which is not associated, however, with detectable fos protein. We conclude that in fibroblasts stimulated by mitogens c-fos expression may be differentially modulated, depending of the growth factor and the cell line. This is seemingly due to differential regulation of fos gene expression, not only at the transcriptional and/or post-transcriptional level (transient or sustained fos RNA induction by EGF or TGF beta in EL2 cells), but also at the translational level (fos protein(s) induction by TGF beta in EL2 but not NIH-3T3 fibroblasts, possibly related to the stimulatory vs inhibitory effect of this factor on the growth of the former vs the latter line).

  20. Papillomavirus-Associated Tumor Formation Critically Depends on c-Fos Expression Induced by Viral Protein E2 and Bromodomain Protein Brd4

    PubMed Central

    Schneider, Markus; Schuetz, Johanna; Leiprecht, Natalie; Hudjetz, Benjamin; Brodbeck, Stephan; Corall, Silke; Dreer, Marcel; Schwab, Roxana Michaela; Grimm, Martin; Wu, Shwu-Yuan; Stubenrauch, Frank; Chiang, Cheng-Ming; Iftner, Thomas

    2016-01-01

    We investigated the mechanism of how the papillomavirus E2 transcription factor can activate promoters through activator protein (AP)1 binding sites. Using an unbiased approach with an inducible cell line expressing the viral transcription factor E2 and transcriptome analysis, we found that E2 induces the expression of the two AP1 components c-Fos and FosB in a Brd4-dependent manner. In vitro RNA interference confirmed that c-Fos is one of the AP1 members driving the expression of viral oncogenes E6/E7. Mutation analysis and in vivo RNA interference identified an essential role for c-Fos/AP1 and also for the bromodomain protein Brd4 for papillomavirus-induced tumorigenesis. Lastly, chromatin immunoprecipitation analysis demonstrated that E2 binds together with Brd4 to a canonical E2 binding site (E2BS) in the promoter of c-Fos, thus activating c-Fos expression. Thus, we identified a novel way how E2 activates the viral oncogene promoter and show that E2 may act as a viral oncogene by direct activation of c-Fos involved in skin tumorigenesis. PMID:26727473

  1. Combined Expression of c-jun, c-fos, and p53 Improves Estimation of Prognosis in Oral Squamous Cell Carcinoma.

    PubMed

    Wang, Shan; Xu, Xin; Xu, Fei; Meng, Yan; Sun, Changsheng; Shi, Lei; Zhao, Eryang

    2016-09-13

    To identify the prognostic value of c-jun, c-fos, and p53 in oral cancer, we examined the impact of immunohistochemical expression of these markers on tumor progression in 157 oral squamous cell carcinoma (OSCC). We found that c-jun or c-fos was significantly associated with lymph node metastasis, and coexpression of c-jun/c-fos, or c-jun/c-fos/p53 were significantly associated with lymph node metastasis, poor differentiation and clinical stage. The coexpression of c-jun/c-fos/p53 was identified as independent prognostic factors for overall survival. Simultaneous coexpression of these markers in OSCCs might prove to be a useful indicator for differentiation of low and high-risk patients.

  2. Caffeine elicits c-Fos expression in horizontal diagonal band cholinergic neurons.

    PubMed

    Reznikov, Leah R; Pasumarthi, Ravi K; Fadel, Jim R

    2009-12-09

    Caffeine is a widely self-administered psychostimulant with purported neuroprotective and procognitive effects in rodent models of aging. The cholinergic basal forebrain is important for arousal and attention and is implicated in age-related cognitive decline. Accordingly, we determined the effects of caffeine on cholinergic neuron activation in the rat basal forebrain. Young adult (age 2 months) male rats were treated with caffeine (0, 10, or 50 mg/kg) and killed 2 h later. Caffeine significantly increased c-Fos expression in cholinergic neurons of the horizontal limb of the diagonal band of Broca but not other basal forebrain regions such as the medial septum or substantia innominata. The horizontal limb of the diagonal band of Broca provides cholinergic innervation to the olfactory bulb, suggesting that deficits in this structure may contribute to diminished olfactory function observed in Alzheimer's disease patients. These results suggest that part of the cognitive-enhancing effects of caffeine may be mediated through activation of this part of the cholinergic basal forebrain.

  3. Inhibition of carcinogen induced c-Ha-ras and c-fos proto-oncogenes expression by dietary curcumin

    PubMed Central

    Limtrakul, Porn-ngarm; Anuchapreeda, Songyot; Lipigorngoson, Suwiwek; Dunn, Floyd W

    2001-01-01

    Background We investigated the chemopreventive action of dietary curcumin on 7,12-dimethylbenz(a)anthracene (DMBA)-initiated and 12,0-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor formation in Swiss albino mice. Curcumin, a yellow coloring matter isolated from roots of Curcuma longa Linn, is a phenolic compound possessing antioxidant, free radical scavenger, and antiinflammatory properties. It has been shown by previously reported work that TPA-induced skin tumors were inhibited by topical application of curcumin, and curcumin has been shown to inhibit a variety of biological activities of TPA. Topical application of curcumin was reported to inhibit TPA-induced c-fos, c-jun and c-myc gene expression in mouse skin. This paper reports the effects of orally administered curcumin, which was consumed as a dietary component at concentrations of 0.2 % or 1 %, in ad libitum feeding. Results Animals in which tumors had been initiated with DMBA and promoted with TPA experienced significantly fewer tumors and less tumor volume if they ingested either 0.2% or 1% curcumin diets. Also, the dietary consumption of curcumin resulted in a significantly decreased expression of ras and fos proto-oncogenes in the tumorous skin, as measured by enhanced chemiluminesence Western blotting detection system (Amersham). Conclusions Whereas earlier work demonstrated that topical application of curcumin to mouse skin inhibited TPA-induced expression of c-fos, c-jun and c-myc oncogenes, our results are the first to show that orally consumed curcumin significantly inhibited DMBA- and TPA-induced ras and fos gene expression in mouse skin. PMID:11231886

  4. Periaqueductal gray c-Fos expression varies relative to the method of conditioned taste aversion extinction employed.

    PubMed

    Mickley, G Andrew; Wilson, Gina N; Remus, Jennifer L; Ramos, Linnet; Ketchesin, Kyle D; Biesan, Orion R; Luchsinger, Joseph R; Prodan, Suzanna

    2011-11-14

    A conditioned taste aversion (CTA) is acquired when an animal consumes a novel taste (CS) and then experiences the symptoms of poisoning (US). Following CTA training, animals will avoid the taste that was previously associated with malaise. This defensive reaction to a learned fear can be extinguished by repeated exposure to the CS alone (CS-only; CSO-EXT). However, following a latency period in which the CS is not presented, the CTA will spontaneously recover (SR). Through the use of an explicitly unpaired extinction procedure (EU-EXT) we have shown that we can speed up extinction and attenuate SR of the CTA. Here we compared and contrasted the ability of CSO and EU extinction procedures to affect c-Fos expression in the periaqueductal gray (PAG). Fluid-deprived Sprague-Dawley rats acquired a strong CTA [via 3 pairings of 0.3% oral saccharin (SAC; the CS) and 81mg/kg i.p. lithium chloride (LiCl; the US)] followed by extinction trials consisting of multiple exposures to either, (a) the CS every-other day (CSO-EXT), or (b) CS and US on alternate days (EU-EXT). A different group of rats did not receive multiple CS exposures and served as a "no extinction" (NE) control. Both extinction procedures resulted in ≥90% reacceptance of SAC (achieving asymptotic extinction). Some of the animals were sacrificed for c-Fos immunohistochemical analysis following asymptotic extinction. Other rats entered a 30-day latency period where they drank water only. These remaining animals were then tested for SR with a final exposure to SAC before being sacrificed for c-Fos immunohistochemistry. As reported previously, rats in the CS-only group exhibited a significant SR of the CTA. However, animals in the EU extinction group reached asymptotic extinction more rapidly than did CSO rats and they did not show SR of the CTA. As compared to rats that retained their CTA, both groups of extinguished rats showed suppression in the number of c-Fos-labeled neurons in all 4 longitudinal columns of

  5. Amphetamine withdrawal modulates FosB expression in mesolimbic dopaminergic target nuclei: effects of different schedules of administration.

    PubMed

    Murphy, Carol A; Russig, Holger; Pezze, Marie-Astrid; Ferger, Boris; Feldon, Joram

    2003-06-01

    Different patterns of psychostimulant intake can elicit widely varying behavioral and neurochemical consequences. Accordingly, rats were studied during withdrawal from either of two schedules of amphetamine administration, one consisting of 6 days of low-dose (1.5 mg/kg, i.p.) daily intermittent (INT) amphetamine (AMPH) injections, and the other of 6 days of moderately high-dose (1-5 mg/kg, i.p.) escalating (ESC) AMPH injections, for the effects of these treatments on numbers of FosB-positive nuclei and monoamine utilization in dopaminergic target areas. Withdrawal from AMPH pretreatment according to the ESC schedule markedly increased FosB expression in the nucleus accumbens shell and basolateral amygdala. In contrast, withdrawal from INT-AMPH administration did not increase FosB expression in any of the regions examined. Post-mortem neurochemical analyses of these same brain regions did not reveal effects of withdrawal from either INT or ESC administration of AMPH. These results suggest that withdrawal from a moderately high-dose AMPH regimen modifies patterns of gene expression in mesocorticolimbic dopaminergic target nuclei without significantly affecting basal monoamine levels. The strength of these effects in the nucleus accumbens shell and basolateral nucleus of the amygdala are consistent with behavioral and clinical data indicating the importance of these areas in the neuroadaptive changes which characterize addiction and withdrawal states.

  6. Inhibitory regulation of osteoclast differentiation by interleukin-3 via regulation of c-Fos and Id protein expression.

    PubMed

    Oh, Jaemin; Lee, Myeung Su; Yeon, Jeong-Tae; Choi, Sik-Won; Kim, Hun Soo; Shim, Hyeok; Lee, Sam Youn; Youn, Byung Soo; Yokota, Yoshifumi; Kim, Jung Ha; Kwak, Han Bok

    2012-05-01

    Interleukin-3 (IL-3) is produced under various pathological conditions and is thought to be involved in the pathogenesis of inflammatory diseases; however, its function in bone homeostasis under normal conditions or nature of the downstream molecular targets remains unknown. Here we examined the effect of IL-3 on osteoclast differentiation from mouse and human bone marrow-derived macrophages (BMMs). Although IL-3 can induce osteoclast differentiation of multiple myeloma bone marrow cells, IL-3 greatly inhibited osteoclast differentiation of human BMMs isolated from healthy donors. These inhibitory effects of IL-3 were only observed at early time points (days 0 and 1). IL-3 inhibited the expression of c-Fos and NFATc1 in BMMs treated with RANKL. However, IL-3-mediated inhibition of osteoclast differentiation was not completely reversed by ectopic expression of c-Fos or NFATc1. Importantly, IL-3 induced inhibitor of DNA binding/differentiation (Id)1 in hBMMs, while Id2 were sustained during osteoclast differentiation of mBMMs treated with IL-3. Ectopic expression of NFATc1 in Id2-deficient BMMs completely reversed the inhibitory effect of IL-3 on osteoclast differentiation. Furthermore, inflammation-induced bone erosion was markedly inhibited by IL-3 administration. Taken together, our results suggest that IL-3 plays an inhibitory role in osteoclast differentiation by regulating c-Fos and Ids, and also exerts anti-bone erosion effects.

  7. Long-term suppression of methamphetamine-induced c-Fos expression in rat striatum by the injection of c-fos antisense oligodeoxynucleotides absorbed in water-absorbent polymer.

    PubMed

    Semba, Jun'ichi; Wakuta, Maki; Suhara, Tetsuya

    2004-10-01

    The use of water-absorbent polymer (WAP) as a hydrogel carrier for the slow delivery of antisense oligodeoxynucleotides (ODN) in the brain, was recently developed. In this experiment, 15-mer phosphorothioate ODN, complementary to c-fos gene absorbed in WAP, was injected in the rat striatum. The expression of c-Fos-immunoreactivity induced by methamphetamine (6 mg/kg, intraperitoneally) around the injection site was suppressed until 5 days after injection. Using this method, it was observed that unilateral injection with c-fos antisense ODN into the rat striatum caused robust ipsilateral rotations after methamphetamine challenge 4 days post injection. This method is simple, and the biological and behavioral effects of antisense ODN in WAP can be maintained for several days even after a single injection into the brain.

  8. Spinal neurons that contain gastrin-releasing peptide seldom express Fos or phosphorylate extracellular signal-regulated kinases in response to intradermal chloroquine

    PubMed Central

    Gutierrez-Mecinas, Maria; Polgár, Erika; Todd, Andrew J

    2016-01-01

    Background Gastrin-releasing peptide (GRP) is thought to play a role in the itch evoked by intradermal injection of chloroquine. Although some early studies suggested that GRP was expressed in pruriceptive primary afferents, it is now thought that GRP in the spinal cord is derived mainly from a population of excitatory interneurons in lamina II, and it has been suggested that these are involved in the itch pathway. To test this hypothesis, we used the transcription factor Fos and phosphorylation of extracellular signal-regulated kinases (ERK) to look for evidence that interneurons expressing GRP were activated following intradermal injection of chloroquine into the calf, in mice that express enhanced green fluorescent protein (EGFP) in these cells. Results Injection of chloroquine resulted in numerous Fos- or phospho-ERK (pERK) positive cells in the somatotopically appropriate part of the superficial dorsal horn. The proportion of all neurons in this region that showed Fos or pERK was 18% and 21%, respectively. However, among the GRP–EGFP, only 7% were Fos-positive and 3% were pERK-positive. As such, GRP–EGFP cells were significantly less likely than other neurons to express Fos or to phosphorylate ERK. Conclusions Both expression of Fos and phosphorylation of ERK can be used to identify dorsal horn neurons activated by chloroquine injection. However, these results do not support the hypothesis that interneurons expressing GRP are critical components in the itch pathway. PMID:27270268

  9. Conditioned fear to context is associated with increased Fos expression in the caudal ventrolateral region of the midbrain periaqueductal gray.

    PubMed

    Carrive, P; Leung, P; Harris, J; Paxinos, G

    1997-05-01

    Immunohistochemical detection of Fos was used to determine which regions of the periaqueductal gray are activated during conditioned fear to a context in the rat. More specifically, the aim of the study was to test the role of its lateral and ventrolateral columns in freezing behaviour during fear. Conditioned fear was evoked by re-exposing rats to the same footshock chamber in which they had received footshocks 4 h earlier. Conditioned Re-exposed rats were compared to Not Conditioned Re-exposed and Conditioned Not Re-exposed rats. Freezing was observed in the Conditioned-Re-exposed group only. It was associated with an overall increase in Fos expression in the entire periaqueductal gray that was significantly greater than in the two other groups. The largest and most significant increase in Fos immunoreactivity was found in the ventrolateral column (especially in its caudal part), whereas only a moderate increase was found in the lateral column. The present results argue in favour of the ventrolateral column as the region of the periaqueductal gray that is preferentially involved in expression of conditioned fear. As previous lesion studies suggested, the ventrolateral periaqueductal gray may play a role in mediating the immobility component of freezing induced by fear. Other lines of evidence suggest that it may also play a role in mediating the quiescence immobility associated with deep pain. We propose that the ventrolateral column of the periaqueductal gray acts as an integrating centre mediating behavioural inhibition.

  10. Imipramine-induced c-Fos expression in the medial prefrontal cortex is decreased in the ACTH-treated rats.

    PubMed

    Li, Bingjin; Suemaru, Katsuya; Kitamura, Yoshihisa; Gomita, Yutaka; Araki, Hiroaki; Cui, Ranji

    2013-11-01

    Previous studies have shown that the antidepressive-like effect of tricyclic antidepressants is blocked by repeated treatments with adrenocorticotropic hormone (ACTH). However, little is known about the neuroanatomy underlying the mechanism of the imipramine treatment-resistant depression model. In the present study, first experimental evidence showed no significant difference of the serum imipramine concentrations between the saline and ACTH-treated rats. In further study, imipramine produced significant increases in the c-Fos expression in the medial prefrontal cortex (mPFC), the dentate gyrus of the hippocampus (DGH), and the central nucleus of the amygdala (CeA), in rats repeatedly treated with saline. The imipramine-increased c-Fos immunoreactivity was suppressed in the mPFC of rats repeatedly treated with ACTH. However, there was no significant difference in c-Fos expression in the DGH and CeA between ACTH- and saline-treated rats. These results suggest that the mPFC is maybe involved in effects of the imipramine in the ACTH-treated rats.

  11. Effect of hypergravity on expression of the immediate early gene, c-fos, in central nervous system of medaka (Oryzias latipes)

    NASA Astrophysics Data System (ADS)

    Sayaka, Shimomura-Umemura; Ijiri, Kenichi

    2006-01-01

    Immediate-early genes serve as useful neurobiological tools for mapping brain activity induced by a sensory stimulation. In this study, we have examined brain activity related to gravity perception of medaka (Oryzias latipes) by use of c-fos. The gene, which is homologous to the c-fos genes of other vertebrates, was identified in medaka. Functionally important domains are highly conserved among all the vertebrate species analyzed. Intraperitoneal administration of kainic acid transiently induced the c-fos mRNAs in medaka brains. The results indicate that the expression of c-fos can be utilized as a suitable anatomical marker for the increased neural activities in the central nervous system of medaka. Fish were continuously exposed to 3 g hypergravity by centrifugation. Investigation of c-fos mRNA expression indicated that c-fos mRNA significantly increased 30 min after a start of 3 g exposure. The distribution of its transcripts within the brains was analyzed by an in situ hybridization method. The 3-g treated medakas displayed c-fos positive cells in their brainstem regions, which are related to vestibular function, such as torus semicircularis, nucleus tangentialis, posterior octavu nucleus, and inferior olive. Our results established a method to follow the effect of gravity stimulation, which can be used to investigate gravity perception.

  12. Social experience induces sex-specific fos expression in the amygdala of the juvenile rat.

    PubMed

    Weathington, Jill M; Strahan, J Alex; Cooke, Bradley M

    2012-07-01

    To compare the response of the medial amygdala and central amygdala to juvenile social subjugation (JSS), we used unbiased stereology to quantify the immediate early gene product Fos in prepubertal rats after aggressive or benign social encounters or handling. We estimated the overall number of neurons and the proportion of Fos immunoreactive neurons in the posterodorsal (MePD) and posteroventral medial amygdala (MePV) and the central amygdala (CeA). Experience elicited Fos in a sex- and hemisphere-dependent manner in the MePD. The left MePD was selective for JSS in both sexes, but the right MePD showed a specific Fos response to JSS in males only. In the MePV, irrespective of hemisphere or sex, JSS elicited the greatest amount of Fos, benign social experience elicited an intermediate level, and handling the least. None of the experiential conditions elicited significant levels of Fos in the CeA. We found a previously unreported sex difference in the number of CeA neurons (M>F) that was highly significant and a strong trend toward a sex difference (M>F) in the MePD. These data show that the posterior MeA subnuclei are more responsive to JSS than to benign social interaction, that sex interacts with hemispheric laterality to determine the response of the MePD to JSS and that the MePV responds to social experience and JSS. Taken together, these findings support the hypothesis that juvenile rats process JSS in a sex-specific manner.

  13. Fluorescence Activated Cell Sorting (FACS) and Gene Expression Analysis of Fos-expressing Neurons from Fresh and Frozen Rat Brain Tissue.

    PubMed

    Rubio, F Javier; Li, Xuan; Liu, Qing-Rong; Cimbro, Raffaello; Hope, Bruce T

    2016-08-27

    The study of neuroplasticity and molecular alterations in learned behaviors is switching from the study of whole brain regions to the study of specific sets of sparsely distributed activated neurons called neuronal ensembles that mediate learned associations. Fluorescence Activated Cell Sorting (FACS) has recently been optimized for adult rat brain tissue and allowed isolation of activated neurons using antibodies against the neuronal marker NeuN and Fos protein, a marker of strongly activated neurons. Until now, Fos-expressing neurons and other cell types were isolated from fresh tissue, which entailed long processing days and allowed very limited numbers of brain samples to be assessed after lengthy and complex behavioral procedures. Here we found that yields of Fos-expressing neurons and Fos mRNA from dorsal striatum were similar between freshly dissected tissue and tissue frozen at -80 ºC for 3 - 21 days. In addition, we confirmed the phenotype of the NeuN-positive and NeuN-negative sorted cells by assessing gene expression of neuronal (NeuN), astrocytic (GFAP), oligodendrocytic (Oligo2) and microgial (Iba1) markers, which indicates that frozen tissue can also be used for FACS isolation of glial cell types. Overall, it is possible to collect, dissect and freeze brain tissue for multiple FACS sessions. This maximizes the amount of data obtained from valuable animal subjects that have often undergone long and complex behavioral procedures.

  14. [Gene c-Fos expression in brain of rats resistant and predisposed to emotional stress after intraperitoneal injection of the ACTH(4-10)analog--semax].

    PubMed

    Umriukhin, P E; Koplik, E V; Grivennikov, I A; Miasoedov, N F; Sudakov, K V

    2001-01-01

    The effect of the ACTH(4-10) analog Semax on immediate early gene c-Fos expression was studied in Wistar rats with high and low resistance to emotional stress under the usual conditions and during psychoemotional loading. Fos-immunoreactive cells in the were counted automatically with the help of a computer. It was shown that under the usual conditions the intraperitoneal Semax injection induced immediate early gene c-Fos expression in the lateral septal region in rats predisposed to emotional stress and in the paraventricular hypothalamus in rats of both groups. Preliminary Semax injection decreased the stress-induced c-Fos expression in the paraventricular hypothalamus and medial septum in rats predisposed to emotional stress and tended to reduce the number of stress-induced c-Fos-immunopositive cells in the lateral septum and basolateral amygdala in both groups of animals. The obtained data suggest that Semax differently affects the immediate early c-Fos gene expression in the brain of rats resistant and predisposed to emotional stress and this effect reflects the antistressor properties of the regulatory peptide.

  15. Blockade of 5-Ht3 receptors in the septal area increases Fos expression in selected brain areas.

    PubMed

    Urzedo-Rodrigues, Lilia S; Ferreira, Hilda S; Santana, Rejane Conceição; Luz, Carla Patrícia; Perrone, Camila F; Fregoneze, Josmara B

    2014-04-01

    Serotonin is widely distributed throughout the brain and is involved in a multiplicity of visceral, cognitive and behavioral responses. It has been previously shown that injections of different doses of ondansetron, a 5-HT3 receptor antagonist, into the medial septum/vertical limb of the diagonal band complex (MS/vDB) induce a hypertensive response in rats. On the other hand, administration of m-CPBG, a 5-HT3 agonist, into the MS/vDB inhibits the increase of blood pressure during restraint stress. However, it is unclear which neuronal circuitry is involved in these responses. The present study investigated Fos immunoreactive nuclei (Fos-IR) in different brain areas following the blockade of 5-HT3 receptors located in the MS/vDB in sham and in sinoaortic denervated (SAD) rats. Ondansetron injection into the MS/vDB increases Fos-IR in different brain areas including the limbic system (central amygdala and ventral part of the bed nucleus of the stria terminalis), hypothalamus (medial parvocellular parts of the paraventricular nucleus, anterodorsal preoptic area, dorsomedial hypothalamic nucleus), mesencephalon (ventrolateral periaqueductal gray region) and rhombencephalon (lateral parabrachial nucleus) in sham rats. Barodenervation results in higher Fos expression at the parvocellular and magnocellular part of the paraventricular nucleus, the lateral parabrachial nucleus, the central nucleus of amygdala, the locus coeruleus, the medial part of the nucleus of the solitary tract, the rostral ventrolateral medulla and the caudal ventrolateral medulla following 5-HT3receptor blockade in the MS/vDB. Based on the present results and previous data showing a hypertensive response to ondansetron injected into the MS/vDB, it is reasonable to suggest that 5-HT3receptors in the MS/vDB exert an inhibitory drive that may oscillate as a functional regulatory part of the complex central neuronal network participating in the control of blood pressure.

  16. Expression of the c-fos gene in spinal cord and brain cells in rats subjected to stress in conditions of exposure to various types of halothane anesthesia.

    PubMed

    Novikova, N S; Kazakova, T B; Rogers, V; Korneva, E A

    2004-05-01

    The influences of different treatments on the expression of the c-fos gene in the spinal cord and brain (hypothalamus) was studied in rats using various types of anesthesia. Synthesis of c-Fos-like proteins occurred only in the spinal cord in conditions of constant 1.5% halothane anesthesia. Use of induction anesthesia with 1.5% halothane allowed detection of c-Fos-like protein expression in cells of the rat spinal cord (lumbar segments) and brain, both when animals were placed in a hammock and when mechanical pain stimulation or electromagnetic irradiation of the skin with UHF currents were applied. The pattern of brain structures reacting to mechanical pain stimulation with expression of c-Fos-like protein was identified. This type of stimulation was shown to induce increases in the quantity of c-Fos-positive cells in the lateral hypothalamic area (LHA), the ventromedial (VMH) and dorsomedial (DMH) hypothalamic nuclei, and in the ventral hypothalamic area (AHA) by 116%, 167%, 101%, and 157% respectively as compared with controls. Skin irradiation with UHF currents decreased the intensity of mechanical pain stimulation-induced synthesis of c-Fos-like protein in most structures (LHA, VMH, DMN, and AHA by 32.8%, 29%, 15%, and 33% respectively). Only induction halothane anesthesia allowed identification of hypothalamic structures reacting to mechanical pain stimulation and the modifying effects of irradiating the skin with UHF currents on the intensity of these reactions.

  17. Activation of peroxisome proliferator activated receptor γ in brain inhibits inflammatory pain, dorsal horn expression of Fos, and local edema

    PubMed Central

    Morgenweck, J.; Abdel-aleem, O.S.; McNamara, K.C.; Donahue, R.R.; Badr, M.Z.; Taylor, B.K.

    2009-01-01

    Systemic administration of thiazolidinediones reduces peripheral inflammation in vivo, presumably by acting at peroxisome proliferator-activated receptor γ (PPARγ) in peripheral tissues. Based on a rapidly growing body of literature indicating the CNS as a functional target of PPARγ actions, we postulated that brain PPARγ modulates peripheral edema and the processing of inflammatory pain signals in the dorsal horn of the spinal cord. To test this in the plantar carrageenan model of inflammatory pain, we measured paw edema, heat hyperalgesia, and dorsal horn expression of the immediate-early gene c-fos after intracerebroventricular (ICV) administration of PPARγ ligands or vehicle. We found that ICV rosiglitazone (0.5–50 µg) or 15d-PGJ2 (50–200 µg), but not vehicle, dose-dependently reduced paw thickness, paw volume and behavioral withdrawal responses to noxious heat. These anti-inflammatory and anti-hyperalgesia effects result from direct actions in the brain and not diffusion to other sites, because intraperitoneal and intrathecal administration of rosiglitazone (50 µg) and 15d-PGJ2 (200 µg) had no effect. PPARγ agonists changed neither overt behavior nor motor coordination, indicating that non-specific behavioral effects do not contribute to PPAR ligand-induced anti-hyperalgesia. ICV administration of structurally dissimilar PPARγ antagonists (either GW9662 or BADGE) reversed the anti-inflammatory and anti-hyperalgesic actions of both rosiglitazone and 15d-PGJ2. To evaluate the effects of PPARγ agonists on a classic marker of noxious stimulus-evoked gene expression, we quantified Fos protein expression in the dorsal horn. The number of carrageenan-induced Fos-like immunoreactive profiles was less in rosiglitazone-treated rats as compared to vehicle controls. We conclude that pharmacological activation of PPARγ in the brain rapidly inhibits local edema and the spinal transmission of noxious inflammatory signals. PMID:19891980

  18. Urocortin 2 increases c-Fos expression in serotonergic neurons projecting to the ventricular/periventricular system

    PubMed Central

    Hale, Matthew W.; Stamper, Christopher E.; Staub, Daniel R.; Lowry, Christopher A.

    2010-01-01

    Serotonin plays an important role in the regulation of anxiety states and physiological responses to aversive stimuli. Intracerebroventricular (i.c.v.) injection of the stress- and anxiety-related neuropeptide urocortin 2 (Ucn 2) increases c-Fos expression in serotonergic neurons in the dorsal (DRD) and caudal (DRC) parts of the dorsal raphe nucleus. These regions contain a subset of serotonergic neurons that projects via the dorsal raphe periventricular tract to periventricular structures, including the subfornical organ and ependymal layer, and to the ventricular system. To determine if Ucn 2 activates ventricle/periventricular-projecting serotonergic neurons in the midbrain raphe complex we made i.c.v. injections of the retrograde tracer Fluoro-Gold into the lateral ventricle, followed 7 days later by i.c.v. injection of Ucn 2. The DRD at −8.18 mm and the DRC at −8.54 mm and −9.16 mm bregma were analyzed using a combined brightfield and immunofluorescence technique. Approximately 40% of the ventricle/periventricular-projecting neurons in the subdivisions sampled were serotonergic. Urocortin 2 increased c-Fos expression in ventricle/periventricular-projecting serotonergic neurons in the DRC and in non-ventricle/periventricular-projecting serotonergic neurons in the DRD and DRC. Of the total population of ventricle/periventricular-projecting serotonergic neurons in the DRC at −8.54 and −9.16 mm bregma, 35% expressed c-Fos following Ucn 2 injections. These data are consistent with previous studies showing that i.c.v. injection of Ucn 2 activates subpopulations of serotonergic neurons restricted to the mid-rostrocaudal DRD and DRC, and further demonstrate that these include both subsets of serotonergic neurons that do and do not project to the ventricle/periventricular system. PMID:20382145

  19. Receptor-Selective Agonists Induce Emesis and Fos Expression in the Brain and Enteric Nervous System of the Least Shrew (Cryptotis parva)

    PubMed Central

    Ray, Andrew P.; Chebolu, Seetha; Darmani, Nissar A.

    2009-01-01

    Research on the mechanisms of emesis has implicated multiple neurotransmitters via both central (dorsal vagal complex) and peripheral (enteric neurons and enterochromaffin cells) anatomical substrates. Taking advantage of advances in receptor-specific agonists, and utilizing Fos expression as a functional activity marker, this study demonstrates a strong, but incomplete, overlap in anatomical substrates for a variety of emetogens. We used cisplatin and specific agonists to 5-HT3 serotonergic, D2/D3 dopaminergic, and NK1 tachykininergic receptors to induce vomiting in the least shrew (Cryptotis parva), and quantified the resulting Fos expression. The least shrew is a small mammal whose responses to emetic challenges are very similar to its human counterparts. In all cases, the enteric nervous system, nucleus of the solitary tract, and dorsal motor nucleus of the vagus demonstrated significantly increased Fos immunoreactivity (Fos-IR). However, Fos-IR induction was notably absent from the area postrema following the dopaminergic and NK1 receptor-specific agents. Two brain nuclei not usually discussed regarding emesis, the dorsal raphe nucleus and paraventricular thalamic nucleus, also demonstrated increased emesis-related Fos-IR. Taken together, these data suggest the dorsal vagal complex is part of a common pathway for a variety of distinct emetogens, but there are central emetic substrates, both medullary and diencephalic, that can be accessed without directly stimulating the area postrema. PMID:19699757

  20. Multiple Color Stimulus Induced Steady State Visual Evoked Potentials

    DTIC Science & Technology

    2007-11-02

    MULTIPLE COLOR STIMULUS INDUCED STEADY STATE VISUAL EVOKED POTENTIALS M. Cheng, X. Gao, S. Gao, D. Xu Institute of Biomedical Engineering...characteristics of high SNR and effectiveness in short-term identification of evoked responses. In most of the SSVEP experiments, single high...frequency stimuli are used. To characterize the complex rhythms in SSVEP, a new multiple color stimulus pattern is proposed in this paper. FFT and

  1. A circulating ghrelin mimetic attenuates light-induced phase delay of mice and light-induced Fos expression in the suprachiasmatic nucleus of rats.

    PubMed

    Yi, Chun-Xia; Challet, Etienne; Pévet, Paul; Kalsbeek, Andries; Escobar, Carolina; Buijs, Ruud M

    2008-04-01

    Anatomical evidence suggests that the ventromedial arcuate nucleus (vmARC) is a route for circulating hormonal communications to the suprachiasmatic nucleus (SCN). Whether this vmARC-SCN connection is involved in the modulation of circadian activity of the SCN is not yet known. We recently demonstrated, in rats, that intravenous (i.v.) injection of a ghrelin mimetic, GHRP-6, during the daytime activated neurons in the vmARC and reduced the normal endogenous daytime Fos expression in the SCN. In the present study we show that i.v. administration of GHRP-6 decreases light-induced Fos expression at ZT13 in the rat SCN by 50%, indicating that light-induced changes in the SCN Fos expression can also be reduced by GHRP-6. Because it is difficult to study light-induced phase changes in rats, we examined the functional effects of GHRP-6 on light-induced phase shifts in mice and demonstrated that peripherally injected GHRP-6 attenuates light-induced phase delays at ZT13 by 45%. However, light-induced Fos expression in the mice SCN was not blocked by GHRP-6. These results illustrate that acute stimulation of the ghrelinergic system may modulate SCN activity, but that its effect on light-induced phase shifts and Fos expression in the SCN might be species related.

  2. Effect of blonanserin on methamphetamine-induced disruption of latent inhibition and c-Fos expression in rats.

    PubMed

    Kuramashi, Aki; Abe, Hiroshi; Koganemaru, Go; Matsuo, Hisae; Ikeda, Tetsuya; Ebihara, Kosuke; Funahashi, Hideki; Takeda, Ryuichiro; Nishimori, Toshikazu; Ishida, Yasushi

    2013-08-09

    To clarify the psychopharmacological profile of blonanserin, a novel antipsychotic, we examined its effect on the methamphetamine-induced disruption of latent inhibition (LI) and the neural activation related to this effect in rats. To evaluate the LI, we used a conditioned emotional response in which a tone (conditioned stimulus) was paired with a mild foot shock (unconditioned stimulus). This paradigm was presented to rats licking water. Methamphetamine-induced (1.0mg/kg, i.p.) disruption of LI was significantly improved by the administration of a higher dose (3.0mg/kg, i.p.) of blonanserin and tended to be improved by 1.0-mg/kg blonanserin and 0.2-mg/kg haloperidol but not by a lower dose (0.3mg/kg) of blonanserin. Immunohistochemical examination showed blonanserin (3.0mg/kg, i.p.) increased c-Fos expression in the shell area but not in the core area of the nucleus accumbens while methamphetamine (3.0mg/kg, i.p.) produced the opposite expression pattern. Blonanserin also increased the number of c-Fos expressions in the central amygdala nucleus but not in the basolateral amygdala nucleus or the prefrontal cortex. Blonanserin ameliorates the methamphetamine-induced disruption of LI, as other antipsychotics do, and a neuronal activation and/or modulation of neurotransmission in the nucleus accumbens is related to the disruption of LI by methamphetamine and to its amelioration by blonanserin.

  3. Effects of treadmill running exercise on neuronal expression of c-Fos protein in the medulla oblongata after unilateral phrenicotomy in Wistar rats.

    PubMed

    Tomita, Kazuhide; Takayama, Kiyoshige

    2008-08-08

    The purpose of this study was to examine whether treadmill running exercise after phrenicotomy resulted in change in neuronal expression of c-Fos protein in the medulla oblongata in Wistar rats. All rats were subjected to left-sided unilateral phrenicotomy. In test experiments, rats were trained with treadmill running for 4 weeks, while in control experiments rats were not provided with the opportunity to exercise. c-Fos protein, a transient transcription factor, was immunohistochemically stained by the ABC method, and surveyed in the medulla oblongata. Numbers of c-Fos-immunoreactive (c-Fos-ir) neurons were counted microscopically, and their distribution in the medulla oblongata was mapped. In the dorsal respiratory group (DRG), numbers of c-Fos-ir neurons were found to be significantly increased in the test rats compared with control rats, while in the ventral respiratory group (VRG) no significant differences were found in numbers of c-Fos-ir neurons between test and control rats. These findings suggest that DRG neurons may play more important roles than VRG neurons in recovery of respiration in treadmill exercise after unilateral phrenicotomy in Wistar rats.

  4. Differential involvement of 3', 5'-cyclic adenosine monophosphate-dependent protein kinase in regulation of Fos and tyrosine hydroxylase expression in the heart after naloxone induced morphine withdrawal.

    PubMed

    Almela, Pilar; Cerezo, Manuela; González-Cuello, A; Milanés, M Victoria; Laorden, M Luisa

    2007-01-01

    We previously demonstrated that morphine withdrawal induced hyperactivity of the heart by the activation of noradrenergic pathways innervating the left and right ventricle, as evaluated by noradrenaline (NA) turnover and Fos expression. We investigated whether cAMP-dependent protein kinase (PKA) plays a role in this process by estimating changes in PKA immunoreactivity and the influence of inhibitor of PKA on Fos protein expression, tyrosine hydroxylase (TH) immunoreactivity levels and NA turnover in the left and right ventricle. Dependence on morphine was induced by a 7-day s.c. implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by an injection of naloxone (5 mg/kg). When opioid withdrawal was precipitated, an increase in PKA immunoreactivity and phospho-CREB (cyclic AMP response element protein) levels were observed in the heart. Moreover, morphine withdrawal induces Fos expression, an enhancement of NA turnover and an increase in the total TH levels. When the selective PKA inhibitor HA-1004 was infused, concomitantly with morphine pellets, it diminished the increase in NA turnover and the total TH levels observed in morphine-withdrawn rats. However, this inhibitor neither modifies the morphine withdrawal induced Fos expression nor the increase of nonphosphorylated TH levels. The present findings indicate that an up-regulated PKA-dependent transduction pathway might contribute to the activation of the cardiac catecholaminergic neurons in response to morphine withdrawal and suggest that Fos is not a target of PKA at heart levels.

  5. Effects of electroacupuncture on ethanol-induced impairments of spatial learning and memory and Fos expression in the hippocampus in rats.

    PubMed

    Lu, Bin; Ma, Zhao; Cheng, Fei; Zhao, Yan; Zhang, Xin; Mao, Huijuan; Shen, Xueyong; Liu, Sheng

    2014-07-25

    It is well established that alcohol impairs spatial learning and memory. Here, we investigated the effects of electroacupuncture (EA) at ST36 or nonacupoint on ethanol-induced learning and memory impairment and the expression of Fos in the hippocampus. Ethanol (5g/kg) was administered intragastrically once a day for 5 consecutive days; 2Hz EA was administered immediately after ethanol exposure. After a 2-day ethanol abstinence, for 6 consecutive days, the rats were submitted to Morris water maze training. Probe trials were performed on 1 day after the final training session. We also applied immunohistochemistry to detect Fos-positive nuclei in the hippocampus. We found that 5-day ethanol exposure markedly decreased spatial learning and memory abilities in the Morris water maze task as indicated by escape latency and time in the target quadrant. EA treatment shortened the time of reaching platform and increased times traveled in the target quadrant (P<0.05). Animals administered with ethanol emitted significantly fewer Fos expression in the hippocampal CA1 area. EA increased Fos expression in the hippocampal CA1 area. Significant correlations were obtained between Fos protein expression in CA1 and time in the target quadrant. Altogether, these results suggest that EA protects against ethanol-induced impairments of spatial learning and memory, which may be involved in the hippocampal CA1 area. EA treatment may provide a novel nonpharmacological strategy for ethanol-induced learning and memory impairment.

  6. Novel cues reinstate cocaine-seeking behavior and induce Fos protein expression as effectively as conditioned cues.

    PubMed

    Bastle, Ryan M; Kufahl, Peter R; Turk, Mari N; Weber, Suzanne M; Pentkowski, Nathan S; Thiel, Kenneth J; Neisewander, Janet L

    2012-08-01

    Cue reinstatement of extinguished cocaine-seeking behavior is a widely used model of cue-elicited craving in abstinent human addicts. This study examined Fos protein expression in response to cocaine cues or to novel cues as a control for activation produced by test novelty. Rats were trained to self-administer cocaine paired with either a light or a tone cue, or received yoked saline and cue presentations, and then underwent daily extinction training. They were then tested for reinstatement of extinguished cocaine-seeking behavior elicited by response-contingent presentations of either the cocaine-paired cue or a novel cue (that is, tone for those trained with a light or vice versa). Surprisingly, conditioned and novel cues both reinstated responding and increased Fos similarly in most brain regions. Exceptions included the anterior cingulate, which was sensitive to test cue modality in saline controls and the dorsomedial caudate-putamen, where Fos was correlated with responding in the novel, but not conditioned, cue groups. In subsequent experiments, we observed a similar pattern of reinstatement in rats trained and tested for sucrose-seeking behavior, whereas rats trained and tested with the cues only reinstated to a novel, and not a familiar, light or tone. The results suggest that novel cues reinstate responding to a similar extent as conditioned cues regardless of whether animals have a reinforcement history with cocaine or sucrose, and that both types of cues activate similar brain circuits. Several explanations as to why converging processes may drive drug and novel cue reinforcement and seeking behavior are discussed.

  7. The effects of apomorphine and D-amphetamine on striatal c-Fos expression in Sprague-Dawley and Long Evans rats and their F1 progeny.

    PubMed

    Saint Marie, Richard L; Neary, Alaina C; Shoemaker, Jody M; Swerdlow, Neal R

    2006-11-13

    We previously reported that Sprague-Dawley (SD) rats are significantly more sensitive than Long Evans (LE) rats to disruption of prepulse inhibition (PPI) of the startle reflex by the dopamine agonists, apomorphine (APO) and D-amphetamine (AMPH). This susceptibility is inherited through F1 (SD x LE) and N2 backcross (F1 x SD) generations via an orderly pattern (SD>N2>F1>LE). Here we examined systemic APO (0.5 mg/kg) and AMPH (4.5 mg/kg) modulation of neural activity in four regions of the striatum suspected to be involved in the dopaminergic regulation of PPI - dorsolateral (dlCPu) and medial (mCPu) caudate/putamen and core (NACc) and medial shell (NACms) regions of nucleus accumbens - under conditions that mimicked those used to assess PPI. Immunohistochemical quantification of c-Fos protein expression was used as the surrogate measure of neural activity in SD and LE rats and their F1 crosses. Vehicle-treatment showed significant regional differences in Fos expression, particularly between the dlCPu and the other three areas, but no strain-related differences were observed. Three of four brain areas examined (dlCPu, mCPu and NACc) exhibited drug-induced changes in Fos expression--APO decreased and AMPH increased Fos expression in each region. The aggregate effect across these three regions revealed Fos expression to be significantly greater in LE compared to SD rats for both drugs, with F1 rats intermediate. This pattern of inheritance (LE>F1>SD) reveals an inverse relationship between striatal Fos expression and PPI sensitivity for these drugs; and a positive relationship with reported heritable differences in D2-linked G-protein binding in the CPu and NACc, and with locomotor activation/suppression by AMPH and APO.

  8. Delta 9-tetrahydrocannabinol suppresses vomiting behavior and Fos expression in both acute and delayed phases of cisplatin-induced emesis in the least shrew.

    PubMed

    Ray, Andrew P; Griggs, Lisa; Darmani, Nissar A

    2009-01-03

    Cisplatin chemotherapy frequently causes severe vomiting in two temporally separated clusters of bouts dubbed the acute and delayed phases. Cannabinoids can inhibit the acute phase, albeit through a poorly understood mechanism. We examined the substrates of cannabinoid-mediated inhibition of both the emetic phases via immunolabeling for serotonin, Substance P, cannabinoid receptors 1 and 2 (CB(1), CB(2)), and the neuronal activation marker Fos in the least shrew (Cryptotis parva). Shrews were injected with cisplatin (10mg/kg i.p.), and one of vehicle, Delta(9)-THC, or both Delta(9)-THC and the CB(1) receptor antagonist SR141716A (2mg/kg i.p.), and monitored for vomiting. Delta(9)-THC-pretreatment caused concurrent decreases in the number of shrews expressing vomiting and Fos-immunoreactivity (Fos-IR), effects which were blocked by SR141716A-pretreatment. Acute phase vomiting induced Fos-IR in the solitary tract nucleus (NTS), dorsal motor nucleus of the vagus (DMNX), and area postrema (AP), whereas in the delayed phase Fos-IR was not induced in the AP at all, and was induced at lower levels in the other nuclei when compared to the acute phase. CB(1) receptor-IR in the NTS was dense, punctate labeling indicative of presynaptic elements, which surrounded Fos-expressing NTS neurons. CB(2) receptor-IR was not found in neuronal elements, but in vascular-appearing structures. All areas correlated with serotonin- and Substance P-IR. These results support published acute phase data in other species, and are the first describing Fos-IR following delayed phase emesis. The data suggest overlapping but separate mechanisms are invoked for each phase, which are sensitive to antiemetic effects of Delta(9)-THC mediated by CB(1) receptors.

  9. Schisandra chinensis and Rhodiola rosea exert an anti-stress effect on the HPA axis and reduce hypothalamic c-Fos expression in rats subjected to repeated stress.

    PubMed

    Xia, Nan; Li, Jie; Wang, Hongwei; Wang, Jian; Wang, Yangtian

    2016-01-01

    The aim of the present study was to investigate the effects of Schisandra chinensis (S. chinensis) and Rhodiola rosea (R. rosea) on rats subjected to 5 h of stress, induced by water-floating followed by treadmill exercise. Hypothalamus-pituitary-adrenal (HPA) activity and c-Fos and Fos-related antigen 2 (Fra-2) mRNA expression levels in the hypothalamus of the rats were evaluated. Rats were distributed into four groups: S. chinensis (n=12), R. rosea (n=10), stress control (n=10) and quiet control (n=8). Following a training period of 6 consecutive days, the S. chinensis, R. rosea and stress control groups underwent a 3-h water-floating session in the presence of feline predators immediately followed by 2 h treadmill running to induce psychological and physical stress. Following compound stress induction, the serum levels of corticosterone (CORT), adrenocorticotropic hormone and interleukin-1β and the mRNA expression levels of hypothalamic corticotropin-releasing hormone (CRH), neuropeptide-Y, c-Fos and Fra-2 were evaluated using enzyme-linked immunosorbent assay, radioimmunoassay and quantitative polymerase chain reaction, respectively. The results indicated that S. chinensis and R. rosea markedly decreased the stress-induced elevation of CRH and peripheral CORT levels. The mRNA expression levels of c-Fos and Fra-2 in the hypothalamus were significantly increased after 5 h compound stress, and reduced levels of c-Fos expression were detected in rats treated with R. rosea. Thus, S. chinensis and R. rosea exert an anti-stress effect in rats subjected to stress by balancing the HPA axis, and possibly by reducing the expression of c-Fos in the hypothalamus.

  10. [Influence of dexamethasone on the expression of immediate early genes c-fos and c-jun in different regions of the neonatal brain].

    PubMed

    Sukhareva, E V; Dygalo, N N; Kalinina, T S

    2016-01-01

    The ratio of the expression levels of the immediate early genes c-jun and c-fos that encode components of the AP-1 transcription complex determines the direction of changes in the expression of genes controlled by the complex, including changes induced by glucocorticoids. The aim of the present work was to assess the levels of mRNA encoded by genes c-jun and c-fos and the ratio of expression levels of these genes in various regions of the neonatal rat brain after the administration of dexamethasone, a selective ligand of the glucocorticoid receptor. The level of mRNA encoded by the immediate early gene c-fos in the hippocampus and prefrontal cortex of 3-day-old rat pups was elevated at 30, 60, and 120 min after dexamethasone administration. The basal level of c-fos gene expression in the brainstem was higher than in the cortex and hippocampus, and administration of the hormone was followed by a reduction in the amount of transcript detectable in the brainstem after 2 h. As a result, the ratio of c-jun to c-fos transcript levels in the brainstem of neonatal rats was doubled after dexamethasone administration. The dexamethasone-induced shift of the ratio of c-jun to c-fos transcript levels in the brainstem of neonatal rats towards a predominance of c-jun reported for the first time in the present work may induce the expression of genes that contain AP-1 response elements in the promoters, since the glucocorticoid receptor can be involved in protein-protein interactions with the Jun/Jun homodimer of the AP-1 complex.

  11. Schisandra chinensis and Rhodiola rosea exert an anti-stress effect on the HPA axis and reduce hypothalamic c-Fos expression in rats subjected to repeated stress

    PubMed Central

    XIA, NAN; LI, JIE; WANG, HONGWEI; WANG, JIAN; WANG, YANGTIAN

    2016-01-01

    The aim of the present study was to investigate the effects of Schisandra chinensis (S. chinensis) and Rhodiola rosea (R. rosea) on rats subjected to 5 h of stress, induced by water-floating followed by treadmill exercise. Hypothalamus-pituitary-adrenal (HPA) activity and c-Fos and Fos-related antigen 2 (Fra-2) mRNA expression levels in the hypothalamus of the rats were evaluated. Rats were distributed into four groups: S. chinensis (n=12), R. rosea (n=10), stress control (n=10) and quiet control (n=8). Following a training period of 6 consecutive days, the S. chinensis, R. rosea and stress control groups underwent a 3-h water-floating session in the presence of feline predators immediately followed by 2 h treadmill running to induce psychological and physical stress. Following compound stress induction, the serum levels of corticosterone (CORT), adrenocorticotropic hormone and interleukin-1β and the mRNA expression levels of hypothalamic corticotropin-releasing hormone (CRH), neuropeptide-Y, c-Fos and Fra-2 were evaluated using enzyme-linked immunosorbent assay, radioimmunoassay and quantitative polymerase chain reaction, respectively. The results indicated that S. chinensis and R. rosea markedly decreased the stress-induced elevation of CRH and peripheral CORT levels. The mRNA expression levels of c-Fos and Fra-2 in the hypothalamus were significantly increased after 5 h compound stress, and reduced levels of c-Fos expression were detected in rats treated with R. rosea. Thus, S. chinensis and R. rosea exert an anti-stress effect in rats subjected to stress by balancing the HPA axis, and possibly by reducing the expression of c-Fos in the hypothalamus. PMID:26889268

  12. Differential expression of Fos and Zif268 in the nigrostriatal system after methamphetamine administration in a rat model of Parkinson's disease.

    PubMed

    Ishida, Yasushi; Kawai, Keiichi; Magata, Yasuhiro; Ebihara, Kosuke; Takeda, Ryuichiro; Abe, Hiroshi; Yoshimoto, Mitsuyoshi; Hashiguchi, Hiroyuki; Odagiri, Kei; Matsuo, Hisae; Nishimori, Toshikazu

    2008-12-01

    The goal of this study was to examine the topological specificity of methamphetamine-induced activation of the immediate-early gene proteins, Fos and Zif268, in the nigrostriatal system in a unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease with or without intrastriatal grafts of fetal ventral mesencephalon. Methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity (FLI) dominantly in the striatum and the globus pallidus (GP) on the intact side as well as in the substantia nigra pars reticulata (SNr) on the lesioned side in the 6-OHDA rats. Lower levels of methamphetamine-induced FLI in the striatum and GP on the lesioned side were restored by intrastriatal grafts which could completely suppress the methamphetamine-induced rotation. In the striatum, a similar tendency could be observed between Fos and Zif268 immunoreactivity following methamphetamine. However, sparse immunoreactivity of Zif268 could be detected in the GP and SNr on both sides in the 6-OHDA rats. Intrastriatal grafts had little influence on Zif268 expression in these two regions. The differential expression of Fos and Zif268 was observed among the three regions of the nigrostriatal system following methamphetamine in the 6-OHDA rats. This may suggest that Fos and Zif268 therefore possess gene-specific and region-specific functions in the basal ganglia nuclei.

  13. Induction of Fos expression in the rat forebrain after intragastric administration of monosodium L-glutamate, glucose and NaCl.

    PubMed

    Otsubo, H; Kondoh, T; Shibata, M; Torii, K; Ueta, Y

    2011-11-24

    l-glutamate, an umami taste substance, is a key molecule coupled to a food intake signaling pathway. Furthermore, recent studies have unveiled new roles for dietary glutamate on gut-brain axis communication via activation of gut glutamate receptors and subsequent vagus nerve. In the present study, we mapped activation sites of the rat forebrain after intragastric load of 60 mM monosodium l-glutamate (MSG) by measurement of Fos protein, a functional marker of neuronal activation. The same concentration of d-glucose (sweet) and NaCl (salty) was used as controls. MSG administration exclusively produced enhanced Fos expression in four hypothalamic regions (the medial preoptic area, lateral hypothalamic area, dorsomedial nucleus, and arcuate nucleus). On the other hand, glucose administration exclusively enhanced Fos induction in the nucleus accumbens. Both MSG and glucose enhanced Fos induction in three brain regions (the habenular nucleus, paraventricular nucleus, and central nucleus of the amygdala). However, MSG induced Fos inductions were more potent than those of glucose in the habenular nucleus and paraventricular nucleus. Importantly, the present study identified for the first time two brain areas (the paraventricular and arcuate hypothalamic nuclei) that are more potently activated by intragastric MSG loads compared with glucose and NaCl. Overall, our results suggest significant activation of a neural network comprising the habenular nucleus, amygdala, and the hypothalamic subnuclei following intragastric load with glutamate.

  14. Baclofen prevented the changes in c-Fos and brain-derived neutrophic factor expressions during mecamylamine-precipitated nicotine withdrawal in mice.

    PubMed

    Varani, Andrés P; Moutinho Machado, Lirane; Balerio, Graciela N

    2014-11-01

    Previous studies from our laboratory showed that baclofen (BAC, GABAB receptor agonist) prevented the behavioral and neurochemical alterations of nicotine (NIC) withdrawal syndrome. To further investigate the mechanisms underlying these effects, we analyzed the c-Fos and brain-derived neutrophic factor (BDNF) expression during NIC withdrawal and its prevention with BAC. Swiss-Webster mice received NIC (2.5 mg/kg, sc) four times daily, for 7 days. On the 8th day, NIC-treated mice received the nicotinic antagonist mecamylamine (MEC; 2 mg/kg, i.p.) 1 h after the last dose of NIC. A second group of NIC-treated mice received BAC (2 mg/kg, i.p.) prior to MEC administration. Thirty minutes after MEC, mice were sacrificed and the immunohistochemistry assays (c-Fos and BDNF) were performed at different anatomical levels. c-Fos expression decreased in the dentate gyrus of the hippocampus (DG) and the bed nucleus of the stria terminalis (BST), and increased in the habenular (Hb), accumbens shell (AcbSh) nuclei during NIC withdrawal. BAC re-established the modified c-Fos expression only in the DG, BST and AcbSh during NIC withdrawal. Conversely, BDNF expression decreased in the CA1 and CA3 area of the hippocampus, the Hb, and caudate putamen (CPu) during NIC withdrawal. Finally, BAC restored the decreased BDNF expression during NIC withdrawal in the CA1, CA3, Hb, and CPu. The results suggest a relationship between BAC's preventive effect of the expression of NIC withdrawal signs, and its ability to restore the changes in c-Fos and BDNF expression, observed in specific brain areas of NIC-withdrawn mice.

  15. [Visual input affects the expression of the early genes c-Fos and ZENK in auditory telencephalic centers of pied flycatcher nestlings during the acoustically-guided freezing].

    PubMed

    Korneeva, E V; Tiunova, A A; Aleksandrov, L I; Golubeva, T B; Anokhin, K V

    2014-01-01

    The present study analyzed expression of transcriptional factors c-Fos and ZENK in 9-day-old pied flycatcher nestlings' (Ficedula hypoleuca) telencephalic auditory centers (field L, caudomedial nidopallium and caudomedial mesopallium) involved in the acoustically-guided defense behavior. Species-typical alarm call was presented to the young in three groups: 1--intact group (sighted control), 2--nestlings visually deprived just before the experiment for a short time (unsighted control) 3--nestlings visually deprived right after hatching (experimental deprivation). Induction of c-Fos as well as ZENK in nestlings from the experimental deprivation group was decreased in both hemispheres as compared with intact group. In the group of unsighted control, only the decrease of c-Fos induction was observed exclusively in the right hemisphere. These findings suggest that limitation of visual input changes the population of neurons involved into the acoustically-guided behavior, the effect being dependant from the duration of deprivation.

  16. The orexin-1 receptor antagonist SB-334867 decreases anxiety-like behavior and c-Fos expression in the hypothalamus of rats exposed to cat odor.

    PubMed

    Vanderhaven, M W; Cornish, J L; Staples, L G

    2015-02-01

    Increasing evidence suggests that the orexin system is involved in modulating anxiety, and we have recently shown that cat odor-induced anxiety in rats is attenuated by the orexin receptor antagonist SB-334867. In the current experiment, c-Fos expression was used to map changes in neuronal activation following SB-334867 administration in the cat odor anxiety model. Male Wistar rats were exposed to cat odor with or without SB-334867 pre-treatment (10 mg/kg, i.p.). A naïve control group not exposed to cat odor was also used. Following cat odor exposure, brains were processed for c-Fos expression. Vehicle-treated rats showed an increase in anxiety-like behaviors (increased hiding and decreased approach toward the cat odor), and increased c-Fos expression in the posteroventral medial amygdala (MePV), paraventricular hypothalamus (PVN) and dorsal premammillary nucleus (PMd). In rats pretreated with SB-334867, approach scores increased and c-Fos expression decreased in the PVN and PMd. These results provide both behavioral and neuroanatomical evidence for the attenuation of cat odor-induced anxiety in rats via the orexin system.

  17. Effect of postnatal treadmill exercise on c-Fos expression in the hippocampus of rat pups born from the alcohol-intoxicated mothers.

    PubMed

    Sim, Young-Je; Kim, Hong; Shin, Mal-Soon; Chang, Hyun-Kyung; Shin, Min-Chul; Ko, Il-Gyu; Kim, Ki-Jeong; Kim, Tea-Soo; Kim, Bo-Kyun; Rhim, Yong-Taek; Kim, Sangho; Park, Ho-Yoon; Yi, Jae-Woo; Lee, Sam-Jun; Kim, Chang-Ju

    2008-02-01

    Maternal alcohol-intoxication during pregnancy exerts detrimental effects on fetal development and is known to influence learning ability and memory capability by altering neuronal activity in the hippocampus. c-Fos expression represents neuronal activity and plays a crucial role in the brain development. Physical exercise is known to enhance neuronal plasticity and activity. In the present study, we investigated the influence of postnatal treadmill running on the c-Fos expression in the hippocampus of rat pups born from the alcohol-intoxicated mothers. The results obtained show that maternal alcohol-intoxication suppressed c-Fos expression in the hippocampus of rat pups and that postnatal treadmill exercise enhanced c-Fos expression in the hippocampus of these rat pups. The present study suggests that exercise should be considered as a therapeutic means of countering the effects of maternal alcohol-intoxication, and that it may provide a useful strategy for enhancing the neuronal activity of children born from the mothers who abuse alcohol during pregnancy.

  18. Environmental Novelty is Associated with a Selective Increase in Fos Expression in the Output Elements of the Hippocampal Formation and the Perirhinal Cortex

    ERIC Educational Resources Information Center

    VanElzakker, Michael; Fevurly, Rebecca D.; Breindel, Tressa; Spencer, Robert L.

    2008-01-01

    If the hippocampus plays a role in the detection of novel environmental features, then novelty should be associated with altered hippocampal neural activity and perhaps also measures of neuroplasticity. We examined Fos protein expression within subregions of rat hippocampal formation as an indicator of recent increases in neuronal excitation and…

  19. c-fos sequence necessary for basal expression and induction by epidermal growth factor, 12-O-tetradecanoyl phorbol-13-acetate and the calcium ionophore.

    PubMed Central

    Fisch, T M; Prywes, R; Roeder, R G

    1987-01-01

    We have investigated the sequence requirements for induction of the human c-fos gene by epidermal growth factor (EGF), 12-O-tetradecanoyl-13-acetate (TPA), and the calcium ionophore A23187 by transfecting c-fos promoter mutants into HeLa and A431 cells. Induction by both EGF and TPA in HeLa cells required the presence of the c-fos enhancer located at -317 to -298 relative to the mRNA cap site. A23187, however, did not induce expression of the transfected gene, even though it strongly induced expression of the endogenous gene, suggesting that it has different requirements for induction than do EGF and TPA. We have also investigated the role of promoter sequences downstream of the enhancer in general expression and induction of c-fos. A sequence between -97 and -76, which includes an 8-base-pair perfect direct repeat, was needed for efficient general expression but not for induction of the gene. A factor in nuclear extracts that bound specifically to this sequence was detected by a gel mobility shift assay. A 7-base-pair sequence, located between -63 and -57 relative to the mRNA cap site and previously shown to be important for general expression of mouse c-fos, was also important for general expression of the human gene. In addition, this element was important for inducibility by EGF and TPA, since induction was significantly reduced when internal deletion mutants that retained the enhancer but lacked the -63 to -57 sequence element were analyzed in transfecting assays. Images PMID:3119989

  20. Role of thalamic nuclei in the modulation of Fos expression within the cerebral cortex during hypertonic saline-induced muscle nociception.

    PubMed

    Xiao, Y; Lei, J; Ye, G; Xu, H; You, H-J

    2015-09-24

    It has been proposed that thalamic mediodorsal (MD) and ventromedial (VM) nuclei form thalamic 'nociceptive discriminators' in discrimination of nociceptive afferents, and specifically govern endogenous descending facilitation and inhibition. The present study conducted in rats was to explore the role of thalamic MD and VM nuclei in modulation of cerebral neuronal activities by means of detection of spatiotemporal variations of Fos expression within the cerebral cortex. Following a unilateral intramuscular injection of 5.8% saline into the gastrocnemius muscle, Fos expression within the bilateral, different areas of the cerebral cortex except S2 was significantly increased (P<0.05). Particularly, the increases in Fos expression within the cingulate cortex and the insular cortex occurred at 0.5h, 4h and reached the peak level at 4h, 16h, respectively. Electrolytic lesion of the contralateral thalamic MD and VM nuclei significantly blocked the 5.8% saline intramuscularly induced increases in Fos expression within the bilateral cingulate and insular cortices, respectively. Additionally, the 5.8% saline-induced Fos expression in the cingulate cortex and the insular cortex were dose-dependently attenuated by microinjection of μ-opioid antagonist β-funaltrexamine hydrochloride into the thalamic MD and VM nuclei. It is suggested that (1) the neural circuits of 'thalamic MD nucleus - cingulate cortex' and 'thalamic VM nucleus - insular cortex' form two distinct pathways in the endogenous control of nociception, (2) mirror or contralateral pain is hypothesized to be related to cross-talk of neuronal activities within the bilateral cerebral cortices modulated by μ-opioid receptors within the thalamic MD and VM nuclei.

  1. Immediate expression of c-fos and c-jun mRNA in a model of intestinal autotransplantation and ischemia-reperfusion in situ

    PubMed Central

    Santos, Maria Mercês; Tannuri, Ana Cristina Aoun; Coelho, Maria Cecilia Mendonça; de Oliveira Gonçalves, Josiane; Serafini, Suellen; da Silva, Luiz Fernando Ferraz; Tannuri, Uenis

    2015-01-01

    OBJECTIVE: Intestinal ischemia-reperfusion injury occurs in several clinical conditions and after intestinal transplantation. The aim of the present study was to investigate the phenomena of apoptosis and cell proliferation in a previously described intestinal ischemia-reperfusion injury autograft model using immunohistochemical markers. The molecular mechanisms involved in ischemia-reperfusion injury repair were also investigated by measuring the expression of the early activation genes c-fos and c-jun, which induce apoptosis and cell proliferation. MATERIALS AND METHODS: Thirty adult male Wistar rats were subjected to surgery for a previously described ischemia-reperfusion model that preserved the small intestine, the cecum and the ascending colon. Following reperfusion, the cecum was harvested at different time points as a representative segment of the intestine. The rats were allocated to the following four subgroups according to the reperfusion time: subgroup 1: 5 min; subgroup 2: 15 min; subgroup 3: 30 min; and subgroup 4: 60 min. A control group of cecum samples was also collected. The expression of c-fos, c-jun and immunohistochemical markers of cell proliferation and apoptosis (Ki67 and TUNEL, respectively) was studied. RESULTS: The expression of both c-fos and c-jun in the cecum was increased beginning at 5 min after ischemia-reperfusion compared with the control. The expression of c-fos began to increase at 5 min, peaked at 30 min, and exhibited a declining tendency at 60 min after reperfusion. A progressive increase in c-jun expression was observed. Immunohistochemical analyses confirmed these observations. CONCLUSION: The early activation of the c-fos and c-jun genes occurred after intestinal ischemia-reperfusion injury, and these genes can act together to trigger cell proliferation and apoptosis. PMID:26039956

  2. Differential expression of AP-1 transcription factor genes c-fos and c-jun in the helminth parasites Taenia crassiceps and Taenia solium.

    PubMed

    Morales-Montor, J; Escobedo, G; Rodriguez-Dorantes, M; Téllez-Ascencio, N; Cerbón, M A; Larralde, C

    2004-08-01

    Homologues of c-fos and c-jun from total DNA of Taenia crassiceps and Taenia solium were cloned and sequenced. The amino acid alignment analysis revealed that c-fos DNAs from T. crassiceps and T. solium were highly homologous (96%), and both have high homology compared to several mammalian c-fos proteins (93% to mouse, 96% to rat and 86% to human). The c-jun protein alignment showed higher homology (T. crassiceps and T. solium have 98%), when compared with mouse, rat and human, being 92%, 98% and 93% respectively. RT-PCR amplification of the parasite's total RNA, showed that T. crassiceps expressed both AP-1 complex genes, while T. solium only expressed c-fos. Southern blot hybridization analysis confirmed the true origin of each amplified gene. AP-1 transcription gene expression is regulated by oestradiol in the same fashion as their mammalian counterparts only in T. crassiceps. To study if AP-1 genes are involved in a physiological function of the cyst, reproduction was studied in vitro. Oestradiol treatment stimulated reproduction in T. crassiceps but not in T. solium cysticerci. This is the first report of the detection and functionality of AP-1 transcription factor genes in any species of helminth parasite.

  3. Stimulus-induced drop episodes in Coffin-Lowry syndrome.

    PubMed

    Hahn, Jin S; Hanauer, André

    2012-05-01

    The Coffin-Lowry syndrome (CLS) is a rare but well-defined X-linked semidominant syndrome characterized by psychomotor and growth retardation, and progressive skeletal changes. CLS is caused by loss of function mutations in the Rps6ka3 gene encoding the ribosomal S6 kinase 2 (RSK2) protein. A distinctive paroxysmal disorder has been described in some CLS patients, characterized by episodes of sudden falling, without apparent alteration of consciousness, usually induced by unexpected tactile or auditory stimuli. Duration of episodes is very short, usually lasting a few seconds. The appellation "Stimulus-induced drop episodes" (SIDEs) was proposed for these non-epileptic events in CLS patients. SIDEs are clinically heterogeneous; with some patients exhibiting cataplexy-like events characterized by sudden hypotonia and collapse, and others hyperekplexia-like episodes with a startle response. The pathophysiology of SIDEs is not well understood.

  4. Androgen receptors and estrogen receptors are colocalized in male rat hypothalamic and limbic neurons that express Fos immunoreactivity induced by mating.

    PubMed

    Gréco, B; Edwards, D A; Michael, R P; Clancy, A N

    1998-01-01

    Conversion of testosterone into estradiol is important for male rat sexual behavior, and both steroids probably contribute to mating. The distributions of neurons containing androgen receptors (AR) and estrogen receptors (ER) overlap, and many AR-immunoreactive (AR-ir) neurons express Fos immunoreactivity (Fos-ir) induced by mating. Because mating-induced Fos-ir in the male rat occurs mainly in AR-ir neurons, and because both steroids are important for mating, we hypothesized that (i) AR-ir and ER-ir are colocalized and that (ii) some of these neurons are activated during mating. We examined, in adjacent sections from the medial preoptic area (MPN) through the central tegmental field (CTF), the expression of ER-ir in: (i) AR-ir-containing neurons, and (ii) Fos-ir-expressive neurons. PG21 anti-AR, OA-11-824 anti-c-fos, H222 or 1D5 anti-ER primary antibodies were visualized, respectively, with cyanine-conjugated, fluorescein- or cyanine-conjugated, and fluorescein-conjugated secondary antibodies in male rats which were killed 1 h after ejaculating with a receptive female. In MPN, bed nucleus of the stria terminalis (BNST), and medial amygdala (MEA), 80-90% of ER-ir labeling occurred in AR-ir-positive neurons but only about 30% of AR-ir neurons were ER-ir-positive. No ER-ir was found in the CTF. This suggests the presence of three types of brain neurons sensitive to gonadal steroid hormones: neurons sensitive to androgens only, neurons sensitive to both androgens and estrogens, and neurons sensitive to estrogens only. About 50% of ER-ir labeling occurred in cells expressing mating-induced Fos-ir but only about 30% of Fos-ir neurons were ER-ir-positive. These findings suggest that, in the MPN, at least two different neuronal populations are activated during mating: the first contains AR-ir only and the second contains AR-ir and ER-ir. In the BNST and MEA, at least three hormonally sensitive populations are activated during mating: the two described above plus a third

  5. Incubation of methamphetamine craving is associated with selective increases in expression of Bdnf and trkb, glutamate receptors, and epigenetic enzymes in cue-activated fos-expressing dorsal striatal neurons.

    PubMed

    Li, Xuan; Rubio, F Javier; Zeric, Tamara; Bossert, Jennifer M; Kambhampati, Sarita; Cates, Hannah M; Kennedy, Pamela J; Liu, Qing-Rong; Cimbro, Raffaello; Hope, Bruce T; Nestler, Eric J; Shaham, Yavin

    2015-05-27

    Cue-induced methamphetamine seeking progressively increases after withdrawal (incubation of methamphetamine craving), but the underlying mechanisms are largely unknown. We determined whether this incubation is associated with alterations in candidate genes in dorsal striatum (DS), a brain area implicated in cue- and context-induced drug relapse. We first measured mRNA expression of 24 candidate genes in whole DS extracts after short (2 d) or prolonged (1 month) withdrawal in rats following extended-access methamphetamine or saline (control condition) self-administration (9 h/d, 10 d). We found minimal changes. Next, using fluorescence-activated cell sorting, we compared gene expression in Fos-positive dorsal striatal neurons, which were activated during "incubated" cue-induced drug-seeking tests after prolonged withdrawal, with nonactivated Fos-negative neurons. We found significant increases in mRNA expression of immediate early genes (Arc, Egr1), Bdnf and its receptor (Trkb), glutamate receptor subunits (Gria1, Gria3, Grm1), and epigenetic enzymes (Hdac3, Hdac4, Hdac5, GLP, Dnmt3a, Kdm1a) in the Fos-positive neurons only. Using RNAscope to determine striatal subregion and cell-type specificity of the activated neurons, we measured colabeling of Fos with Drd1 and Drd2 in three DS subregions. Fos expression was neither subregion nor cell-type specific (52.5 and 39.2% of Fos expression colabeled with Drd1 and Drd2, respectively). Finally, we found that DS injections of SCH23390 (C17H18ClNO), a D1-family receptor antagonist known to block cue-induced Fos induction, decreased incubated cue-induced methamphetamine seeking after prolonged withdrawal. Results demonstrate a critical role of DS in incubation of methamphetamine craving and that this incubation is associated with selective gene-expression alterations in cue-activated D1- and D2-expressing DS neurons.

  6. Incubation of Methamphetamine Craving Is Associated with Selective Increases in Expression of Bdnf and Trkb, Glutamate Receptors, and Epigenetic Enzymes in Cue-Activated Fos-Expressing Dorsal Striatal Neurons

    PubMed Central

    Rubio, F. Javier; Zeric, Tamara; Bossert, Jennifer M.; Kambhampati, Sarita; Cates, Hannah M.; Kennedy, Pamela J.; Liu, Qing-Rong; Cimbro, Raffaello; Hope, Bruce T.; Nestler, Eric J.

    2015-01-01

    Cue-induced methamphetamine seeking progressively increases after withdrawal (incubation of methamphetamine craving), but the underlying mechanisms are largely unknown. We determined whether this incubation is associated with alterations in candidate genes in dorsal striatum (DS), a brain area implicated in cue- and context-induced drug relapse. We first measured mRNA expression of 24 candidate genes in whole DS extracts after short (2 d) or prolonged (1 month) withdrawal in rats following extended-access methamphetamine or saline (control condition) self-administration (9 h/d, 10 d). We found minimal changes. Next, using fluorescence-activated cell sorting, we compared gene expression in Fos-positive dorsal striatal neurons, which were activated during “incubated” cue-induced drug-seeking tests after prolonged withdrawal, with nonactivated Fos-negative neurons. We found significant increases in mRNA expression of immediate early genes (Arc, Egr1), Bdnf and its receptor (Trkb), glutamate receptor subunits (Gria1, Gria3, Grm1), and epigenetic enzymes (Hdac3, Hdac4, Hdac5, GLP, Dnmt3a, Kdm1a) in the Fos-positive neurons only. Using RNAscope to determine striatal subregion and cell-type specificity of the activated neurons, we measured colabeling of Fos with Drd1 and Drd2 in three DS subregions. Fos expression was neither subregion nor cell-type specific (52.5 and 39.2% of Fos expression colabeled with Drd1 and Drd2, respectively). Finally, we found that DS injections of SCH23390 (C17H18ClNO), a D1-family receptor antagonist known to block cue-induced Fos induction, decreased incubated cue-induced methamphetamine seeking after prolonged withdrawal. Results demonstrate a critical role of DS in incubation of methamphetamine craving and that this incubation is associated with selective gene-expression alterations in cue-activated D1- and D2-expressing DS neurons. PMID:26019338

  7. BONLAC: A Combinatorial Proteomic Technique to Measure Stimulus-induced Translational Profiles in Brain Slices

    PubMed Central

    Bowling, Heather; Bhattacharya, Aditi; Zhang, Guoan; Lebowitz, Joseph Z.; Alam, Danyal; Smith, Peter T.; Kirshenbaum, Kent; Neubert, Thomas A.; Vogel, Christine; Chao, Moses V.; Klann, Eric

    2015-01-01

    Stimulus-triggered protein synthesis is critical for brain health and function. However, due to technical hurdles, de novo neuronal translation is predominantly studied in cultured cells, whereas electrophysiological and circuit analyses often are performed in brain slices. The different properties of these two experimental systems create an information gap about stimulus-induced alterations in the expression of new proteins in mature circuits. To address this, we adapted two existing techniques, BONCAT and SILAC, to a combined proteomic technique, BONLAC, for use in acute adult hippocampal slices. Using BDNF-induced protein synthesis as a proof of concept, we found alterations in expression of proteins involved in neurotransmission, trafficking, and cation binding that differed from those found in a similar screen in cultured neurons. Our results indicate important differences between cultured neurons and slices, and suggest that BONLAC could be used to dissect proteomic changes underlying synaptic events in adult circuits. PMID:26205778

  8. Characterization of the transduction pathway involved in c-fos and c-jun expression induced by Aggregatibacter actinomycetemcomitans lipopolysaccharides in human gingival fibroblasts.

    PubMed

    Gutiérrez-Venegas, Gloria; Castillo-Alemán, Ramiro

    2008-11-01

    Periodontal disease is an inflammatory disease caused by infection with oral bacteria that results in tooth exfoliation. Lipopolysaccharides (LPS) are a major component of the outer membrane of Gram-negative microorganisms and are involved in the inflammatory response. c-fos and c-jun are involved in pathological conditions such as inflammatory disorders. Inflammatory signaling cascades leading to c-fos activation in human gingival fibroblasts (HGFs) are not well characterized. Thus, we have investigated the kinase pathways involved in c-fos and c-jun activation induced by LPS in human gingival fibroblasts. LPS promoted a dose- and time-dependent increase in c-fos transcription. Phosphoinositide-phospholipase C inhibitor (U-73122), protein kinase A inhibitor (H89), MEK1 inhibitor (PD 98,059), p38 inhibitor (SB203580), and tyrosine kinase inhibitors (genistein and herbimycin) attenuated the LPS effect, while the PI-3 K inhibitor (Wortmannin) had no effect on LPS-induced c-fos transcription. Protein kinase C inhibitors (Ro 31-8220, calphostin C, staurosporine, and chelerythrine chloride) also inhibited LPS-induced c-fos transcription. However, long-term treatment (24 -h) with the PKC activator tetradecanoyl phorbol-13-acetate (PMA) had no significant effect on LPS-induced transcription in HGFs. We also found an increase in c-jun expression in HGF stimulated with LPS. In addition, experiments using pharmacological inhibitors of individual mitogen-activated protein kinases (MAPK) and of protein kinase C (PKC) revealed that p38, ERK 1/2, and PKC are involved in LPS-induced c-jun expression. Our results indicate that LPS-induced c-fos and c-jun expressions are mediated by two different signaling pathways: one through phosphoinositide-phospholipase C via an upstream protein tyrosine kinase, which activates PKC isoforms that are insensitive to phorbol stress, and the second through activation of protein kinase A (PKA). Both kinases regulate the phosphorylation of the

  9. Rhythmic cFos expression in the ventral subparaventricular zone influences general activity rhythms in the Nile grass rat, Arvicanthis niloticus.

    PubMed

    Schwartz, M D; Nuñez, A A; Smale, L

    2009-10-01

    Circadian rhythms in behavior and physiology are very different in diurnal and nocturnal rodents. A pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus is responsible for generating and maintaining circadian rhythms in mammals, and cellular and molecular rhythms within the SCN of diurnal and nocturnal rodents are very similar. The neural substrates determining whether an animal has a diurnal or nocturnal phase preference are thus likely to reside downstream of the SCN. The ventral subparaventricular zone (vSPVZ), a major target of the SCN that is important for the expression of circadian rhythmicity in nocturnal lab rats (Rattus norvegicus), exhibits different rhythms in cFos expression in diurnal Nile grass rats compared to lab rats. We examined the effects of chemotoxic lesions of the cFos-expressing cells of the vSPVZ on activity rhythms of grass rats to evaluate the hypothesis that these cells support diurnality in this species. Male grass rats housed in a 12:12 light:dark (LD) cycle were given bilateral injections of the neurotoxin n-methyl-D-L-aspartic acid (NMA) or vehicle aimed at the vSPVZ; cells in the SCN are resistant to NMA, which kills neurons in other brain regions, but leaves fibers of passage intact. vSPVZ-damaged grass rats exhibited highly unstable patterns of activity in constant darkness (DD) and in the LD cycle that followed. However, crepuscular bouts of activity could be seen in all animals with vSPVZ lesions. Damage to the vSPVZ reduced cFos expression in this area but not in the SCN. Using correlational analyses, we found that the number of cFos-ir cells in the vSPVZ was unrelated to several parameters of the activity rhythms during the initial post-surgical period, when animals were in LD. However, the number of cells expressing cFos in the vSPVZ was positively correlated with general activity during the subjective day relative to the subjective night when the animals were switched to DD, and this pattern persisted

  10. Stress-Induced Locomotor Sensitization to Amphetamine in Adult, but not in Adolescent Rats, Is Associated with Increased Expression of ΔFosB in the Nucleus Accumbens

    PubMed Central

    Carneiro de Oliveira, Paulo E.; Leão, Rodrigo M.; Bianchi, Paula C.; Marin, Marcelo T.; Planeta, Cleopatra da Silva; Cruz, Fábio C.

    2016-01-01

    While clinical and pre-clinical evidence suggests that adolescence is a risk period for the development of addiction, the underlying neural mechanisms are largely unknown. Stress during adolescence has a huge influence on drug addiction. However, little is known about the mechanisms related to the interaction among stress, adolescence and addiction. Studies point to ΔFosB as a possible target for this phenomenon. In the present study, adolescent and adult rats (postnatal day 28 and 60, respectively) were restrained for 2 h once a day for 7 days. Three days after their last exposure to stress, the animals were challenged with saline or amphetamine (1.0 mg/kg i.p.) and amphetamine-induced locomotion was recorded. Immediately after the behavioral tests, rats were decapitated and the nucleus accumbens was dissected to measure ΔFosB protein levels. We found that repeated restraint stress increased amphetamine-induced locomotion in both the adult and adolescent rats. Furthermore, in adult rats, stress-induced locomotor sensitization was associated with increased expression of ΔFosB in the nucleus accumbens. Our data suggest that ΔFosB may be involved in some of the neuronal plasticity changes associated with stress induced-cross sensitization with amphetamine in adult rats. PMID:27672362

  11. Stimulus-induced reflex epileptic spasms in 5p- syndrome.

    PubMed

    Shirai, Kentaro; Saito, Yoshiaki; Yokoyama, Atushi; Nishimura, Yoko; Tamasaki, Akiko; Maegaki, Yoshihiro

    2016-02-01

    Here we describe two patients with 5p- syndrome who suffered from epilepsy characterised by stimulus-induced epileptic spasms manifesting as head nodding. In patient 1, a series of spasms were exclusively triggered by eating, and were associated with diffuse high-voltage slow waves on ictal EEG, particularly presenting as a positive slow potential at the left mid-temporal area. Clusters of sharp waves with negative polarity emerged in the same area during the inter-spasm periods during eating. In patient 2, spasms were provoked by either eating or micturition. Ictal EEG of clustered spasms after micturition showed positive slow or triphasic waves, which correlated with each spasm, over the bifrontal and vertex areas. These findings suggest that the focal cortical areas act as trigger regions in reflex epilepsies, and that a spasm-generator responsible for the execution of reflex spasms exists either in other cortical areas or in the subcortical structures. Although epilepsy is an unusual complication of 5p- syndrome, this syndrome may have a propensity to develop reflex epilepsy, particularly epileptic spasms. However, identification of responsible genes and their roles in this phenotype requires further investigations.

  12. Electrical Stimulation Normalizes c-Fos Expression in the Deep Cerebellar Nuclei of Depressive-like Rats: Implication of Antidepressant Activity.

    PubMed

    Huguet, Gemma; Kadar, Elisabet; Temel, Yasin; Lim, Lee Wei

    2017-04-01

    The electrical stimulation of specific brain targets has been shown to induce striking antidepressant effects. Despite that recent data have indicated that cerebellum is involved in emotional regulation, the mechanisms by which stimulation improved mood-related behaviors in the cerebellum remained largely obscure. Here, we investigated the stimulation effects of the ventromedial prefrontal cortex (vmPFC), nucleus accumbens (NAc), and lateral habenular nucleus on the c-Fos neuronal activity in various deep cerebellar and vestibular nuclei using the unpredictable chronic mild stress (CMS) animal model of depression. Our results showed that stressed animals had increased number of c-Fos cells in the cerebellar dentate and fastigial nuclei, as well as in the spinal vestibular nucleus. To examine the stimulation effects, we found that vmPFC stimulation significantly decreased the c-Fos activity within the cerebellar fastigial nucleus as compared to the CMS sham. Similarly, there was also a reduction of c-Fos expression in the magnocellular part of the medial vestibular nucleus in vmPFC- and NAc core-stimulated animals when compared to the CMS sham. Correlational analyses showed that the anxiety measure of home-cage emergence escape latency was positively correlated with the c-Fos neuronal activity of the cerebellar fastigial and magnocellular and parvicellular parts of the interposed nuclei in CMS vmPFC-stimulated animals. Interestingly, there was a strong correlation among activation in these cerebellar nuclei, indicating that the antidepressant-like behaviors were possibly mediated by the vmPFC stimulation-induced remodeling within the forebrain-cerebellar neurocircuitry.

  13. Maternal separation in early life modifies anxious behavior and Fos and glucocorticoid receptor expression in limbic neurons after chronic stress in rats: effects of tianeptine.

    PubMed

    Trujillo, Verónica; Durando, Patricia E; Suárez, Marta M

    2016-01-01

    Early-life adversity can lead to long-term consequence persisting into adulthood. Here, we assess the implications of an adverse early environment on vulnerability to stress during adulthood. We hypothesized that the interplay between early and late stress would result in a differential phenotype regarding the number of neurons immunoreactive for glucocorticoid receptor (GR-ir) and neuronal activity as assessed by Fos immunoreactivity (Fos-ir) in brain areas related to stress responses and anxiety-like behavior. We also expected that the antidepressant tianeptine could correct some of the alterations induced in our model. Male Wistar rats were subjected to daily maternal separation (MS) for 4.5 h during the first 3 weeks of life. As adults, the rats were exposed to chronic stress for 24 d and they were treated daily with tianeptine (10 mg/kg intraperitoneal) or vehicle (isotonic saline). Fos-ir was increased by MS in all structures analyzed. Chronic stress reduced Fos-ir in the hippocampus, but increased it in the paraventricular nucleus. Furthermore, chronic stress increased GR-ir in hippocampus (CA1) and amygdala in control non-MS rats. By contrast, when MS and chronic stress were combined, GR-ir was decreased in these structures. Additionally, whereas tianeptine did not affect Fos-ir, it regulated GR-ir in a region-dependent manner, in hippocampus and amygdala opposing in some cases the stress or MS effects. Furthermore, tianeptine reversed the MS- or stress-induced anxious behavior. The interplay between MS and chronic stress observed indicates that MS rats have a modified phenotype, which is expressed when they are challenged by stress in later life.

  14. Distinct Fos-Expressing Neuronal Ensembles in the Ventromedial Prefrontal Cortex Mediate Food Reward and Extinction Memories

    PubMed Central

    Warren, Brandon L.; Mendoza, Michael P.; Cruz, Fabio C.; Leao, Rodrigo M.; Caprioli, Daniele; Rubio, F. Javier; Whitaker, Leslie R.; McPherson, Kylie B.; Bossert, Jennifer M.; Shaham, Yavin

    2016-01-01

    reward seeking, whereas the ventral mPFC inhibits reward seeking. In this paper, we use the Daun02 chemogenetic inactivation procedure to demonstrate that Fos-expressing neuronal ensembles mediating both food reward and extinction memories intermingle within the same ventral mPFC area. PMID:27335401

  15. Thapsigargin induces rapid, transient growth inhibition and c-fos expression followed by sustained growth stimulation in mouse keratinocyte cultures.

    PubMed

    Harmon, C S; Ducote, J; Xiong, Y

    1996-08-01

    Although the sesquiterpene lactone thapsigargin has been shown to possess hyperplastic and tumor-promoting activities when applied topically to mouse skin in vivo, the cellular mechanism(s) which underlie these effects are unclear. We show here that thapsigargin treatment of Primary mouse epidermal keratinocytes increased intracellular free Ca2+ concentration (Cai) in a concentration-dependent manner. Thapsigargin induced a rapid, transient elevation in keratinocyte Cai, in part due to the release of Ca2+ from intracellular stores. This response was followed by a sustained elevation in Ca2+, resulting entirely from calcium influx. Thapsigargin elicited a biphasic effect on keratinocyte DNA synthesis: a rapid inhibitory effect (50-60% inhibition at 4-8 h), followed by a very marked and sustained elevation. Prolonged treatment of keratinocytes with thapsigargin at relatively high concentrations resulted in cytotoxicity (inhibition of neutral red uptake). The rapid antiproliferative effect of thapsigargin was not associated with cytotoxicity, as determined by either neutral red uptake or by trypan blue exclusion, and was not blocked by pretreatment with Ro 31-7349, a selective inhibitor of protein kinase C. The rapid antiproliferative effect of thapsigargin was associated with rapid, transient activation of keratinocyte c-fos expression and rapid inhibition of total protein synthesis. Taken together, these findings raise the possibility that the hyperplastic and tumor-promoting activities of thapsigargin on epidermis in vivo result from direct keratinocyte growth stimulation as a consequence of a prolonged elevation in levels of Cai.

  16. Newly paired zebra finches have higher dopamine levels and immediate early gene Fos expression in dopaminergic neurons.

    PubMed

    Banerjee, Sunayana B; Dias, Brian G; Crews, David; Adkins-Regan, Elizabeth

    2013-12-01

    Most birds are socially monogamous, yet little is known about the neural pathways underlying avian monogamy. Recent studies have implicated dopamine as playing a role in courtship and affiliation in a socially monogamous songbird, the zebra finch (Taeniopygia guttata). In the present study, we sought to understand the specific contribution to pair formation in zebra finches of the mesolimbic dopaminergic pathway that projects from the midbrain ventral tegmental area to the nucleus accumbens. We observed that paired birds had higher levels of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid in the ventral medial striatum, where the nucleus accumbens is situated, than unpaired birds. Additionally, we found that the percentage of dopaminergic neurons expressing immediate early gene Fos, a marker of neuronal activity, was higher in the ventral tegmental area of paired birds than in that of unpaired birds. These data are consistent with a role for the mesolimbic dopaminergic pathway in pair formation in zebra finches, suggesting the possibility of a conserved neural mechanism of monogamy in birds and mammals.

  17. IP{sub 3}-dependent intracellular Ca{sup 2+} release is required for cAMP-induced c-fos expression in hippocampal neurons

    SciTech Connect

    Zhang, Wenting; Tingare, Asmita; Ng, David Chi-Heng; Johnson, Hong W.; Schell, Michael J.; Lord, Rebecca L.; Chawla, Sangeeta

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer cAMP-induced c-fos expression in hippocampal neurons requires a submembraneous Ca{sup 2+} pool. Black-Right-Pointing-Pointer The submembraneous Ca{sup 2+} pool derives from intracellular ER stores. Black-Right-Pointing-Pointer Expression of IP{sub 3}-metabolizing enzymes inhibits cAMP-induced c-fos expression. Black-Right-Pointing-Pointer SRE-mediated and CRE-mediated gene expression is sensitive to IP{sub 3}-metabolizing enzymes. Black-Right-Pointing-Pointer Intracellular Ca{sup 2+} release is required for cAMP-induced nuclear translocation of TORC1. -- Abstract: Ca{sup 2+} and cAMP are widely used in concert by neurons to relay signals from the synapse to the nucleus, where synaptic activity modulates gene expression required for synaptic plasticity. Neurons utilize different transcriptional regulators to integrate information encoded in the spatiotemporal dynamics and magnitude of Ca{sup 2+} and cAMP signals, including some that are Ca{sup 2+}-responsive, some that are cAMP-responsive and some that detect coincident Ca{sup 2+} and cAMP signals. Because Ca{sup 2+} and cAMP can influence each other's amplitude and spatiotemporal characteristics, we investigated how cAMP acts to regulate gene expression when increases in intracellular Ca{sup 2+} are buffered. We show here that cAMP-mobilizing stimuli are unable to induce expression of the immediate early gene c-fos in hippocampal neurons in the presence of the intracellular Ca{sup 2+} buffer BAPTA-AM. Expression of enzymes that attenuate intracellular IP{sub 3} levels also inhibited cAMP-dependent c-fos induction. Synaptic activity induces c-fos transcription through two cis regulatory DNA elements - the CRE and the SRE. We show here that in response to cAMP both CRE-mediated and SRE-mediated induction of a luciferase reporter gene is attenuated by IP{sub 3} metabolizing enzymes. Furthermore, cAMP-induced nuclear translocation of the CREB coactivator TORC1 was inhibited by

  18. Nalfurafine prevents 5'-guanidinonaltrindole- and compound 48/80-induced spinal c-fos expression and attenuates 5'-guanidinonaltrindole-elicited scratching behavior in mice.

    PubMed

    Inan, S; Dun, N J; Cowan, A

    2009-09-29

    The aims of the present study were to establish if nalfurafine, a kappa opioid agonist, inhibits compulsive scratching in mice elicited by the s.c. administration (behind the neck) of 5'-guanidinonaltrindole (GNTI), a kappa opioid antagonist; to assess if nalfurafine prevents c-fos expression provoked by GNTI or compound 48/80, two chemically diverse pruritogens; and to distinguish on the basis of neuroanatomy, those neurons in the brainstem activated by either GNTI-induced itch or formalin-induced pain (both compounds given s.c. to the right cheek). Pretreatment of mice with nalfurafine (0.001-0.03 mg/kg s.c.) attenuated GNTI (0.3 mg/kg)-evoked scratching dose-dependently. A standard antiscratch dose of nalfurafine (0.02 mg/kg) had no marked effect on the spontaneous locomotion of mice. Tolerance did not develop to the antiscratch activity of nalfurafine. Both GNTI and compound 48/80 provoked c-fos expression on the lateral side of the superficial layer of the dorsal horn of the cervical spinal cord and pretreating mice with nalfurafine inhibited c-fos expression induced by both pruritogens. In contrast to formalin, GNTI did not induce c-fos expression in the trigeminal nucleus suggesting that pain and itch sensations are projected differently along the sensory trigeminal pathway. Our data indicate that the kappa opioid system is involved, at least in part, in the pathogenesis of itch; and that nalfurafine attenuates excessive scratching and prevents scratch-induced neuronal activity at the spinal level. On the basis of our results, nalfurafine holds promise as a potentially useful antipruritic in human conditions involving itch.

  19. Dopamine D1-like receptors agonist SKF 38393 increases cFOS expression in the paraventricular nucleus of the hypothalamus--impact of acute and chronic cocaine.

    PubMed

    Chocyk, A; Czyrak, A; Wedzony, K

    2008-09-01

    The present study indicates that activation of dopamine D1-like receptors by administration of SKF 38393 leads to dose-dependent (doses: 5, 10 and 20 mg/kg) increases in the expression of cFos proteins in the rat paraventricular nucleus of the hypothalamus (PVN). This effect was abolished by administration of SCH 23390, a dopamine D1-like receptor antagonist (0.5 and 1 mg/kg, given 30 min before SKF 38393--10 mg/kg), suggesting that the apparent effect is specific for activation of dopamine D1-like receptors. Expression of cFos after SKF 38393 (10 mg/kg) was observed in some, but not all, CRF-immunoreactive neurons, as well as in small portion of oxytocin- but not vasopressin-immunoreactive neurons (double-immunofluorescence experiments). There were also certain populations of nuclei that showed expression of cFos but did not co-localize with the above markers. We also found that both acute and repeated (once daily for 5 consecutive days) exposure to cocaine (25 mg/kg) attenuated the induction of cFos expression triggered by SKF 38393 when administered 24 hours after single or the last dose of cocaine (25 mg/kg). Attenuation was observed at the same level after single and chronic exposure to cocaine, indicating a rapid functional down-regulation of dopamine D1-like receptors that are resistant to subsequent doses of cocaine. These data provide evidence for the functional role of dopamine D1-like receptors in the PVN and indicate a functional adaptation of dopamine D1-like receptors following a single dose of cocaine without further progression of adaptation or resistance of D1-like receptor-mediated genomic function in the course of repeated cocaine intake.

  20. Decline in c-myc mRNA expression but not the induction of c-fos mRNA expression is associated with differentiation of SH-SY5Y human neuroblastoma cells

    SciTech Connect

    Jalava, A.M.; Heikkilae, J.E.; Akerman, K.E.O. )

    1988-11-01

    The induction of differentiation in SH-SY5Y human neuroblastoma cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is accompanied by a rapid and a transient expression of c-fos mRNA and a down-regulation of c-myc RNA. The TPA-induced expression of c-fos mRNA was inhibited by H-7, a specific inhibitor of protein kinase C (PK-C). Dioctanoylglycerol (DiC{sub 8}) failed to induce differentiation of SH-SY5Y cells or to down-regulate c-myc mRNA but it did induce the expression of c-fos mRNA. Treatment of IMR-32 human neuroblastoma cells with TPA did not cause differentiation although c-fos mRNA was induced. Since PK-C in SH-SY5Y cells was activated by both TPA and DiC{sub 8} it is suggested that the activation of PK-C alone is not sufficient to induce differentiation in SH-SY5Y cells. The down-regulation of c-myc mRNA rather than the induction of c-fos mRNA seems to be associated with differentiation process in SH-SY5Y cells.

  1. Contribution of REM sleep to Fos and FRA expression in the vestibular nuclei of rat leading to vestibular adaptation during the STS-90 Neurolab Mission.

    PubMed

    Pompeiano, O

    2007-01-01

    1. Electrophysical studies performed in ground-based experiments have shown that VN neurons respond to labyrinthine signals following stimulation of macular gravity receptors. Additional evidence indicates that VN neurons may also respond to extralabyrinthine signals of pontine origin, which occur during the PGO waves typical of REM sleep (Bizzi et al., 1964a, b; cf. also Pompeiano, 1967, 1970, 1974 for ref.). 2. In a previous study (Pompeiano et al., 2002) changes in Fos and FRA expression were used to identify the short-term (Fos) and the long-term (FRA) molecular changes which affect the VN neurons at different time points of the space flight. In particular, while Fos protein persists in the brain tissue only for a few hours (6-8 hrs) after its induction, FRA proteins, which can also be induced in the same experimental conditions, persist in the brain tissue for longer periods of time (i.e. from 12/24 hrs to days). 3. In order to relate the changes in gene expression which occurred in the VN during the space flight either to gravity changes or to REM sleep, we investigated in a recent study (Centini et al, 2006) the changes in Fos and FRA expression which occurred in different phases of the sleep-waking cycle, thus being indicative of the animal state. We could then compare the results obtained during the space lab Mission with those previously observed either in ground-based experiments during the physiological state of waking and slow-wave (SWS) or during neurochemically induced episodes of PS, as obtained after microinjection of appropriate agents in dorsal pontine structures of rats. 4. Our findings indicated that a waking state possibly associated with episodes of SWS, occurred at FD2 and FD14, i.e. at launch and after exposure of the animal to microgravity. It appeared also that at the reentry (R + 1) rather than at launch (FD2), an increase in Fos and FRA expression affected the noradrenergic LC neurons, as well as several related structures. These

  2. Differential expression of the two Drosophila fos/kayak transcripts during oogenesis and embryogenesis.

    PubMed

    Souid, Sami; Yanicostas, Constantin

    2003-05-01

    The Dfos/kayak gene encodes a bZIP protein, DFos, required in a large variety of differentiation and morphogenetic processes throughout Drosophila development. The recent availability of an expressed sequence tag (EST) sequence led us to identify a novel kay mRNA encoding a deduced DFos isoform showing a specific NH(2)-terminal region. To gain further insight into the function and the regulation of this gene, we have investigated the expression pattern of the two kay mRNA isoforms, kay-RA and kay-RB, during oogenesis and embryogenesis by whole-mount in situ hybridization. Results show that, although the two kay RNA isoforms display fully distinct patterns of transcription during oogenesis, they show partially overlapping expression profiles in embryos. These data reveal a previously unsuspected level of complexity in the regulation of the expression of the kay gene. In addition, they suggest a possible requirement for this gene in the invagination processes during early gastrula stages.

  3. Immediate early gene expression in cat visual cortex during and after the critical period: differences between EGR-1 and Fos proteins.

    PubMed

    Kaplan, I V; Guo, Y; Mower, G D

    1996-02-01

    Immediate early gene (IEG) expression in the cat visual cortex is highly responsive to visual input and may initiate genetic mechanisms responsible for neuronal plasticity. The present study used immunohistochemical methods to address two issues regarding IEG expression in response to visual input. One was to define the differential response of distinct IEG families by comparing EGR-1 (also termed zif-268, NGFI-A, and Krox-24) and Fos proteins. The second was to determine whether IEG expression, in addition to reflecting neural activity, is related to the state of plasticity by comparing young and adult visual cortex. Immunoreactivity of the two IEG proteins was compared between 5-week-old and adult cats under three conditions of visual input: ambient light to assess basal levels of expression, 1 week of darkness to assess the effect of reduced activity, and exposure to light after 1 week of darkness to determine rapid changes in expression as a result of visual input. At both ages, there were marked differences in the expression of the two IEG proteins. EGR-1 responded to visual input with sustained changes in its level of expression. It showed high basal levels, reduced expression in darkness, and a rapid return to high constitutive levels with the introduction of light. Fos showed a markedly different profile. It had very low basal expression which was not demonstrably affected by darkness and its principal response was a marked transient induction upon exposure to light after darkness. These unique changes in expression highlight the complex response across IEGs to environmental input and suggest a genetic "on/off' signaling mechanism. There were marked differences in the laminar distribution of EGR-1 and Fos proteins between young and adult cats. In young animals, cells in all visual cortical layers showed high levels of EGR-1 and Fos proteins. In adults, immunostaining was largely specific to cells located above and below layer IV and only very faint labeling

  4. Delayed wave of c-Fos expression in the dorsal hippocampus involved specifically in persistence of long-term memory storage

    PubMed Central

    Katche, Cynthia; Bekinschtein, Pedro; Slipczuk, Leandro; Goldin, Andrea; Izquierdo, Ivan A.; Cammarota, Martin; Medina, Jorge H.

    2009-01-01

    Memory formation is a temporally graded process during which transcription and translation steps are required in the first hours after acquisition. Although persistence is a key characteristic of memory storage, its mechanisms are scarcely characterized. Here, we show that long-lasting but not short-lived inhibitory avoidance long-term memory is associated with a delayed expression of c-Fos in the hippocampus. Importantly, this late wave of c-Fos is necessary for maintenance of inhibitory avoidance long-term storage. Moreover, inhibition of transcription in the dorsal hippocampus 24 h after training hinders persistence but not formation of long-term storage. These findings indicate that a delayed phase of transcription is essential for maintenance of a hippocampus-dependent memory trace. Our results support the hypothesis that recurrent rounds of consolidation-like events take place late after learning in the dorsal hippocampus to maintain memories. PMID:20018662

  5. Expression of c-fos in auditory and non-auditory brain regions of the gerbil after manipulations that induce tinnitus.

    PubMed

    Wallhäusser-Franke, E; Mahlke, C; Oliva, R; Braun, S; Wenz, G; Langner, G

    2003-12-01

    Subjective tinnitus is a phantom sound sensation that does not result from acoustic stimulation and is audible to the affected subject only. Tinnitus-like sensations in animals can be evoked by procedures that also cause tinnitus in humans. In gerbils, we investigated brain activation after systemic application of sodium salicylate or exposure to loud noise, both known to be reliable tinnitus-inductors. Brains were screened for neurons containing the c-fos protein. After salicylate injections, auditory cortex was the only auditory area with consistently increased numbers of immunoreactive neurons compared to controls. Exposure to impulse noise led to prolonged c-fos expression in auditory cortex and dorsal cochlear nucleus. After both manipulations c-fos expression was increased in the amygdala, in thalamic midline, and intralaminar areas, in frontal cortex, as well as in hypothalamic and brainstem regions involved in behavioral and physiological defensive reactions. Activation of these non-auditory areas was attributed to acute stress, to aversive-affective components and autonomous reactions associated with the treatments and a resulting tinnitus. The present findings are in accordance with former results that provided evidence for suppressed activation in auditory midbrain but enhanced activation of the auditory cortex after injecting high doses of salicylate. In addition, our present results provide evidence that acute stress coinciding with a disruption of hearing may evoke activation of the auditory cortex. We interpret these results in favor of our model of central tinnitus generation.

  6. Effects of intracerebroventricular losartan on angiotensin II-mediated pressor responses and c-fos expression in near-term ovine fetus.

    PubMed

    Shi, Lijun; Mao, Caiping; Thornton, Simon N; Sun, Wanping; Wu, Jiawei; Yao, Jiaming; Xu, Zhice

    2005-12-26

    The renin-angiotensin system plays an important role in cardiovascular control. Intracerebroventricular (i.c.v.) angiotensin (ANG) II causes a reliable pressor response in the fetus at 90% gestation. To determine the roles of brain AT1 and AT2 receptors in this response, the effects of the central AT1 and AT2 receptor antagonists losartan and PD123319 were investigated in chronically prepared near-term ovine fetuses. Losartan at 0.5 mg/kg (i.c.v.) abolished central ANG II-induced pressor responses. High-dose losartan (5 mg/kg, i.c.v.) showed a potentiation of the pressor response to i.c.v. ANG II, accompanied by bradycardia. Associated with the pressor responses, c-fos expression in the cardiovascular controlling areas was significantly different between the low and high doses of losartan. These areas included the subfornical organ, median preoptic nucleus, organum vasculosum of the lamina terminalis, and paraventricular nuclei in the forebrain, and the tractus solitarius nuclei, lateral parabrachial nuclei in the hindbrain. Low-dose losartan markedly reduced c-fos in these areas after i.c.v. ANG II, while the high-dose losartan together with ANG II elicited a much stronger FOS-immunoreactivity in these areas than that induced by i.c.v. ANG II alone. This is a novel finding, that c-fos expression in the brain can be both activated and inhibited under the same condition. Central ANG II-induced fetal pressor responses were not altered by PD123319 (0.8 mg/kg). These results indicate that i.c.v. losartan at a high and a low dose has strikingly different effects on central ANG II-induced pressor responses in fetuses at late gestation, and that the AT1 mechanism plays an important role in fetal cardiovascular regulation.

  7. Chronic light deprivation inhibits appetitive associative learning induced by ethanol and its respective c-Fos and pCREB expression.

    PubMed

    Varela, Patrícia; Escosteguy-Neto, João Carlos; Coelho, Carolina Tesone; Mello, Luiz Eugênio; da Silveira, Dartiu Xavier; Santos-Junior, Jair Guilherme

    2014-11-01

    To address the role of mixed anxiety/mood disorder on appetitive associative learning, we verify whether previous chronic light deprivation changes ethanol-induced conditioned place preference and its respective expression of c-Fos and pCREB, markers of neuronal activity and plasticity. The experimental group was maintained in light deprivation for 24 h for a period of 4 wk. Subsequently, it was adapted to a standard light-dark cycle for 1 wk. As a control, some mice were maintained in standard cycle for a period of 4 wk (Naïve group). Then, all animals were submitted to behavioral tests to assess emotionality: elevated plus maze; open field; and forced swim. After that, they were submitted to ethanol-induced conditioned place preference. Ninety minutes after the place preference test, they were perfused, and their brains processed for c-Fos and pCREB immunohistochemistry. Light deprivation induced anxiety-like trait (elevated plus maze), despair (forced swim), and hyperlocomotion (open field), common features seen in other animal models of depression. Ethanol-induced conditioned place preference was accompanied by increases on c-Fos and pCREB in the hippocampus, prefrontal cortex and striatum. Interestingly, mice previously submitted to light deprivation did not develop either acquisition and/or expression of ethanol-induced conditioned place preference or increases in c-Fos and pCREB. Therefore, chronic light deprivation mimics several behavioral aspects of other animal models of depression. Furthermore, it could be useful to study the neurochemical mechanisms involved in the dual diagnosis. However, given its likely deleterious effects on appetitive associative memory, it should be used with caution to investigate the cognitive aspects related to the dual diagnosis.

  8. Beta-adrenoceptor Activation by Norepinephrine Enhances Lipopolysaccharide-induced Matrix Metalloproteinase-9 Expression Through the ERK/JNK-c-Fos Pathway in Human THP-1 Cells

    PubMed Central

    Yin, Xiang; Zhou, Linli; Han, Fei; Han, Jie; Zhang, Yuanyuan; Sun, Zewei; Zhao, Wenting; Wang, Zhen

    2017-01-01

    Aim: Atherosclerosis is a chronic inflammatory disease, which leads to thrombosis and acute coronary syndrome. Matrix metalloproteinase-9 (MMP-9) is involved in the stability of the extracellular matrix (ECM) and atherosclerosis plaque. Until now, it is established that lipopolysaccharide (LPS) and norepinephrine (NE) are associated with the pathological process of atherosclerosis. However, the combined effect of LPS and NE on MMP-9 is unclear. We investigated the combined effect of LPS and NE on MMP-9 expression in human monocytes and the mechanism involved in the process. Methods: THP-1 cells were cultured and treated with LPS and/or NE. MMP-9 and TIMP-1 gene and protein expression were detected by real time PCR and ELISA, respectively. MMP-9 activity was detected by gelatin zymography. Adrenoceptor antagonists and MAPKs inhibitors were used to clarify the mechanism. Pathway-related proteins were detected by Western blot. Results: We found that NE enhances LPS-induced MMP-9 and TIMP-1 expression as well as MMP-9 activity in THP-1 cells. This effect is reversed by the beta (β)-adrenoceptor antagonist propranolol, extracellular signal-regulated kinases (ERK) inhibitor U0126, and c-Jun N-terminal kinase (JNK) inhibitor SP600125. NE enhances LPS-induced ERK/JNK phosphorylation. NE up-regulates LPS-induced c-Fos expression, which is counteracted by propranolol, U0126, and SP600125. Furthermore, c-Fos silence reverses the effect of NE on MMP-9 activity. Conclusions: Our results suggest that NE enhances LPS-induced MMP-9 expression through β-adrenergic receptor and downstream ERK/JNK-c-Fos pathway. This study may help us to understand the combined effect and mechanism of NE/LPS on MMP-9 expression. PMID:27237101

  9. Effect of NMDA receptor antagonist MK-801 on light-induced Fos expression in the suprachiasmatic nuclei and on melatonin production in the Syrian hamster.

    PubMed

    Vuillez, P; Jacob, N; Teclemariam-Mesbah, R; Van Rossum, A; Vivien-Roels, B; Pévet, P

    1998-09-01

    In mammals, circadian rhythms generated by the suprachiasmatic nuclei (SCN) are daily synchronized by a light-dark cycle. Photic information is transmitted to the SCN mainly through the direct retinohypothalamic tract, the neurotransmitters involved being excitatory amino acids. It is also commonly accepted that photoperiodic information coming from the retina via the SCN is transduced by the pineal into a nocturnal signal, i.e. melatonin production. Light exposure at night induces (1) an inhibition of melatonin synthesis and (2) an expression of c-fos in numerous cells of SCN. To determine the role of the NMDA receptor in these effects, we treated Syrian hamsters with ip injections of MK-801, a noncompetitive NMDA receptor antagonist. Several subpopulations of light-sensitive cells in the SCN are affected by MK-801. According to previous studies, MK-801 inhibits light-induced Fos immunoreactivity mainly in the most ventral part of the SCN. However, we observed that numerous other cells are still activated by light. When light is applied in the middle of the night, MK-801 pretreatment does not reduce Fos-ir in the dorsal SCN. At the beginning of the night, labeled cells in this part of the nucleus appear even more numerous after MK-801. We also found that MK-801 fails to reduce the light-induced inhibition of melatonin synthesis. Moreover, in control animals, which received no light stimulation, ip injection of MK-801 induces by itself a dose-dependent inhibition of melatonin production.

  10. Hypovolemic hemorrhage induces Fos expression in the rat hypothalamus: Evidence for involvement of the lateral hypothalamus in the decompensatory phase of hemorrhage.

    PubMed

    Göktalay, G; Millington, W R

    2016-05-13

    This study tested the hypothesis that the hypothalamus participates in the decompensatory phase of hemorrhage by measuring Fos immunoreactivity and by inhibiting neuronal activity in selected hypothalamic nuclei with lidocaine or cobalt chloride. Previously, we reported that inactivation of the arcuate nucleus inhibited, but did not fully prevent, the fall in arterial pressure evoked by hypotensive hemorrhage. Here, we report that hemorrhage (2.2 ml/100g body weight over 20 min) induced Fos expression in a high percentage of cells in the paraventricular, supraoptic and arcuate nuclei of the hypothalamus as shown previously. Lower densities of Fos immunoreactive cells were also found in the medial preoptic area (mPOA), anterior hypothalamus, lateral hypothalamus (LH), dorsomedial hypothalamus, ventromedial hypothalamus (VMH) and posterior hypothalamus. Bilateral injection of lidocaine (2%; 0.1 μl or 0.3 μl) or cobalt chloride (5mM; 0.3 μl) into the tuberal portion of the LH immediately before hemorrhage was initiated reduced the magnitude of hemorrhagic hypotension and bradycardia significantly. Lidocaine injection into the VMH also attenuated the fall in arterial pressure and heart rate evoked by hemorrhage although inactivation of the mPOA or rostral LH was ineffective. These findings indicate that hemorrhage activates neurons throughout much of the hypothalamus and that a relatively broad area of the hypothalamus, extending from the arcuate nucleus laterally through the caudal VMH and tuberal LH, plays an important role in the decompensatory phase of hemorrhage.

  11. UV-induced DNA damage is an intermediate step in UV-induced expression of human immunodeficiency virus type 1, collagenase, c-fos, and metallothionein

    SciTech Connect

    Stein, B.; Rahmsdorf, H.J.; Steffen, A.; Litfin, M.; Herrlich, P. )

    1989-11-01

    UV irradiation of human and murine cells enhances the transcription of several genes. Here we report on the primary target of relevant UV absorption, on pathways leading to gene activation, and on the elements receiving the UV-induced signal in the human immunodeficiency virus type 1 (HIV-1) long terminal repeat, in the gene coding for collagenase, and in the cellular oncogene fos. In order to induce the expression of genes, UV radiation needs to be absorbed by DNA and to cause DNA damage of the kind that cannot be repaired by cells from patients with xeroderma pigmentosum group A. UV-induced activation of the three genes is mediated by the major enhancer elements (located between nucleotide positions -105 and -79 of HIV-1, between positions -72 and -65 of the collagenase gene, and between positions -320 and -299 of fos). These elements share no apparent sequence motif and bind different trans-acting proteins; a member of the NF kappa B family binds to the HIV-1 enhancer, the heterodimer of Jun and Fos (AP-1) binds to the collagenase enhancer, and the serum response factors p67 and p62 bind to fos. DNA-binding activities of the factors recognizing the HIV-1 and collagenase enhancers are augmented in extracts from UV-treated cells. The increase in activity is due to posttranslational modification. While AP-1 resides in the nucleus and must be modulated there, NF kappa B is activated in the cytoplasm, indicating the existence of a cytoplasmic signal transduction pathway triggered by UV-induced DNA damage. In addition to activation, new synthesis of AP-1 is induced by UV radiation.

  12. Exposure to an open-field arena increases c-Fos expression in a distributed anxiety-related system projecting to the basolateral amygdaloid complex.

    PubMed

    Hale, M W; Hay-Schmidt, A; Mikkelsen, J D; Poulsen, B; Shekhar, A; Lowry, C A

    2008-08-26

    Anxiety states and anxiety-related behaviors appear to be regulated by a distributed and highly interconnected system of brain structures including the basolateral amygdala. Our previous studies demonstrate that exposure of rats to an open-field in high- and low-light conditions results in a marked increase in c-Fos expression in the anterior part of the basolateral amygdaloid nucleus (BLA) compared with controls. The neural mechanisms underlying the anatomically specific effects of open-field exposure on c-Fos expression in the BLA are not clear, however, it is likely that this reflects activation of specific afferent input to this region of the amygdala. In order to identify candidate brain regions mediating anxiety-induced activation of the basolateral amygdaloid complex in rats, we used cholera toxin B subunit (CTb) as a retrograde tracer to identify neurons with direct afferent projections to this region in combination with c-Fos immunostaining to identify cells responding to exposure to an open-field arena in low-light (8-13 lux) conditions (an anxiogenic stimulus in rats). Adult male Wistar rats received a unilateral microinjection of 4% CTb in phosphate-buffered saline into the basolateral amygdaloid complex. Rats were housed individually for 11 days after CTb injections and handled (HA) for 2 min each day. On the test day rats were either, 1) exposed to an open-field in low-light conditions (8-13 lux) for 15 min (OF); 2) briefly HA or 3) left undisturbed (control). We report that dual immunohistochemical staining for c-Fos and CTb revealed an increase in the percentage of c-Fos-immunopositive basolateral amygdaloid complex-projecting neurons in open-field-exposed rats compared with HA and control rats in the ipsilateral CA1 region of the ventral hippocampus, subiculum and lateral entorhinal cortex. These data are consistent with the hypothesis that exposure to the open-field arena activates an anxiety-related neuronal system with convergent input to the

  13. Effect of teicoplanin on the expression of c-myc and c-fos proto-oncogenes in MCF-7 breast cancer cell line

    PubMed Central

    Ashouri, Saeideh; Khujin, Maryam Hosseindokht; Kazemi, Mohammad; Kheirollahi, Majid

    2016-01-01

    Background: Teicoplanin is a member of vancomycin-ristocetin family of glycopeptide antibiotics. It mediated wound healing by increasing neovascularization possibly through activation of MAP kinase signaling pathway. The aim of this study is an evaluation of c-myc and c-fos genes expression after treatment of cells by teicoplanin and determines whether this glycopeptide antibiotic exerts its proliferation effects by influencing the expression of these genes. Hence, this study was designed to elucidate one possible mechanism underlying teicoplanin effects on cell proliferation using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Materials and Methods: Breast cancer cell line, MCF-7, was cultured, and three different concentrations of teicoplanin were added to the plates. We measured the cell proliferation rate by MTT assay. After cell harvesting, total RNA was extracted to synthesize single-stranded cDNA. Real-time polymerase chain reaction was performed, and the data were analyzed. Results: It was observed that the level of c-fos and c-myc genes’ expressions was decreased at all three different concentrations of teicoplanin. Conclusion: it could be concluded that although teicoplanin is considered as an enhancing cell growth and proliferation, but probably its effect is not through MAP kinase signaling pathway or perhaps even has inhibitory effect on the expression of some genes such as c-myc and c-fos in this pathway. Hence, the mechanism of action of teicoplanin for increasing cell propagation, through cell signaling pathways or chromosomal abnormalities, remains unclear, and further studies should be conducted. PMID:28028512

  14. Cue-Induced Food Seeking After Punishment Is Associated With Increased Fos Expression in the Lateral Hypothalamus and Basolateral and Medial Amygdala.

    PubMed

    Campbell, Erin J; Barker, David J; Nasser, Helen M; Kaganovsky, Konstantin; Dayas, Christopher V; Marchant, Nathan J

    2017-02-20

    In humans, relapse to unhealthy eating habits following dieting is a significant impediment to obesity treatment. Food-associated cues are one of the main triggers of relapse to unhealthy eating during self-imposed abstinence. Here we report a behavioral method examining cue-induced relapse to food seeking following punishment-induced suppression of food taking. We trained male rats to lever press for food pellets that were delivered after a 10-s conditional stimulus (CS) (appetitive). Following training, 25% of reinforced lever presses resulted in the presentation of a compound stimulus consisting of a novel CS (aversive) and the appetitive CS followed by a pellet and footshock. After punishment-imposed abstinence, we tested the rats in an extinction test where lever pressing resulted in the presentation of either the appetitive or aversive CS. We then compared activity of lateral hypothalamus (LH) and associated extrahypothalamic regions following this test. We also assessed Fos expression in LH orexin and GABA neurons. We found that cue-induced relapse of food seeking on test was higher in rats tested with the appetitive CS compared to the aversive CS. Relapse induced by the appetitive CS was associated with increased Fos expression in LH, caudal basolateral amygdala (BLA), and medial amygdala (MeA). This relapse was also associated with increased Fos expression in LH orexin and VGAT-expressing neurons. These data show that relapse to food seeking can be induced by food-associated cues after punishment-imposed abstinence, and this relapse is associated with increased activity in LH, caudal BLA, and MeA. (PsycINFO Database Record

  15. Fluorescent visualisation of the hypothalamic oxytocin neurones activated by cholecystokinin-8 in rats expressing c-fos-enhanced green fluorescent protein and oxytocin-monomeric red fluorescent protein 1 fusion transgenes.

    PubMed

    Katoh, A; Shoguchi, K; Matsuoka, H; Yoshimura, M; Ohkubo, J-I; Matsuura, T; Maruyama, T; Ishikura, T; Aritomi, T; Fujihara, H; Hashimoto, H; Suzuki, H; Murphy, D; Ueta, Y

    2014-05-01

    The up-regulation of c-fos gene expression is widely used as a marker of neuronal activation elicited by various stimuli. Anatomically precise observation of c-fos gene products can be achieved at the RNA level by in situ hybridisation or at the protein level by immunocytochemistry. Both of these methods are time and labour intensive. We have developed a novel transgenic rat system that enables the trivial visualisation of c-fos expression using an enhanced green fluorescent protein (eGFP) tag. These rats express a transgene consisting of c-fos gene regulatory sequences that drive the expression of a c-fos-eGFP fusion protein. In c-fos-eGFP transgenic rats, robust nuclear eGFP fluorescence was observed in osmosensitive brain regions 90 min after i.p. administration of hypertonic saline. Nuclear eGFP fluorescence was also observed in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) 90 min after i.p. administration of cholecystokinin (CCK)-8, which selectively activates oxytocin (OXT)-secreting neurones in the hypothalamus. In double transgenic rats that express c-fos-eGFP and an OXT-monomeric red fluorescent protein 1 (mRFP1) fusion gene, almost all mRFP1-positive neurones in the SON and PVN expressed nuclear eGFP fluorescence 90 min after i.p. administration of CCK-8. It is possible that not only a plane image, but also three-dimensional reconstruction image may identify cytoplasmic vesicles in an activated neurone at the same time.

  16. Enhancement of delay eyelid conditioning by microcurrent electrical stimulation of the medial prefrontal cortex is triggered by the expression of Fos protein in guinea pigs

    PubMed Central

    ZHENG, YA-JUAN; DONG, YU-CHEN; ZHU, CHAO; ZHAO, MEI-SHENG

    2016-01-01

    Eyelid conditioning, including delay eyelid conditioning and trace eyelid conditioning, has been used extensively to study neural structures and mechanisms of learning and memory as a form of associative learning. In the present study, microcurrent electrical stimulation was used to stimulate the medial prefrontal cortex (mPFC) to induce delay eyelid conditioning in guinea pigs. The acquisition rate and relative latency of the conditioned eyelid response (CR) and the startle eyelid response (SR) were analyzed. The mPFC sites in the guinea pigs were examined under a light microscope following Nissl staining. In addition, the expression of Fos protein in neurons was detected using immunohistochemistry and western blot analysis. The results indicated that the acquisition rates of CR and SR were increased significantly (P<0.05), whilst the relative latencies of CR and SR were decreased significantly (P<0.05). Lesions were observed in the mPFC regions in the training group when compared with the control group. In addition, immunohistochemistry and western blot analysis revealed that Fos expression was significantly increased in the training group when compared with the sham group for the control and resident-intruder test guinea pigs (P<0.05). Therefore, the enhancement of delay eyelid conditioning by microcurrent electrical stimulation of the mPFC in guinea pigs was triggered by the expression of Fos protein. The observations of the present study further expand the understanding of conditioned reflexes and may aid future investigations into the formation of eyelid conditioning and the mechanisms underlying the circuit in various conditions. PMID:26998030

  17. Light-induced c-Fos expression in the SCN and behavioural phase shifts of Djungarian hamsters with a delayed activity onset.

    PubMed

    Schöttner, Konrad; Vuillez, Patrick; Challet, Etienne; Pévet, Paul; Weinert, Dietmar

    2015-06-01

    C-Fos expression in the suprachiasmatic nucleus (SCN) and phase shifts of the activity rhythm following photic stimulation were investigated in Djungarian hamsters (Phodopus sungorus) of two different circadian phenotypes. Wild-type (WT) hamsters display robust daily patterns of locomotor activity according to the light/dark conditions. Hamsters of the DAO (delayed activity onset) phenotype, however, progressively delay the activity onset, whereas activity offset remains coupled to "light-on". Although the exact reason for the delayed activity onset is not yet clarified, it is connected with a disturbed interaction between the light/dark cycle and the circadian clock. The aim was to test the link between photoreception and the behavioral output of the circadian system in hamsters of both phenotypes, to get further insight in the underlying mechanism of the DAO phenomenon. Animals were exposed to short light pulses at different times during the dark period to analyze phase shifts of the activity rhythm and expression of Fos protein in the SCN. The results indicate that the photosensitive phase in DAO hamsters is shifted like the activity onset. Also, phase shifts were significantly smaller in DAO hamsters. At the same time, levels of Fos expression did not differ between phenotypes regarding the circadian phase. The results provide evidence that the shifted photosensitivity of the circadian system in DAO hamsters does not differ from that of WT animals, and lead us to conclude that processes within the SCN that enable light information to reset the circadian pacemaker might offer an explanation for the DAO phenomenon.

  18. Individual Variations in Maternal Care Early in Life Correlate with Later Life Decision-Making and c-Fos Expression in Prefrontal Subregions of Rats

    PubMed Central

    van Hasselt, Felisa N.; de Visser, Leonie; Tieskens, Jacintha M.; Cornelisse, Sandra; Baars, Annemarie M.; Lavrijsen, Marla; Krugers, Harm J.; van den Bos, Ruud; Joëls, Marian

    2012-01-01

    Early life adversity affects hypothalamus-pituitary-adrenal axis activity, alters cognitive functioning and in humans is thought to increase the vulnerability to psychopathology–e.g. depression, anxiety and schizophrenia- later in life. Here we investigated whether subtle natural variations among individual rat pups in the amount of maternal care received, i.e. differences in the amount of licking and grooming (LG), correlate with anxiety and prefrontal cortex-dependent behavior in young adulthood. Therefore, we examined the correlation between LG received during the first postnatal week and later behavior in the elevated plus maze and in decision-making processes using a rodent version of the Iowa Gambling Task (rIGT). In our cohort of male and female animals a high degree of LG correlated with less anxiety in the elevated plus maze and more advantageous choices during the last 10 trials of the rIGT. In tissue collected 2 hrs after completion of the task, the correlation between LG and c-fos expression (a marker of neuronal activity) was established in structures important for IGT performance. Negative correlations existed between rIGT performance and c-fos expression in the lateral orbitofrontal cortex, prelimbic cortex, infralimbic cortex and insular cortex. The insular cortex correlations between c-fos expression and decision-making performance depended on LG background; this was also true for the lateral orbitofrontal cortex in female rats. Dendritic complexity of insular or infralimbic pyramidal neurons did not or weakly correlate with LG background. We conclude that natural variations in maternal care received by pups may significantly contribute to later-life decision-making and activity of underlying brain structures. PMID:22693577

  19. Enhancement of delay eyelid conditioning by microcurrent electrical stimulation of the medial prefrontal cortex is triggered by the expression of Fos protein in guinea pigs.

    PubMed

    Zheng, Ya-Juan; Dong, Yu-Chen; Zhu, Chao; Zhao, Mei-Sheng

    2016-03-01

    Eyelid conditioning, including delay eyelid conditioning and trace eyelid conditioning, has been used extensively to study neural structures and mechanisms of learning and memory as a form of associative learning. In the present study, microcurrent electrical stimulation was used to stimulate the medial prefrontal cortex (mPFC) to induce delay eyelid conditioning in guinea pigs. The acquisition rate and relative latency of the conditioned eyelid response (CR) and the startle eyelid response (SR) were analyzed. The mPFC sites in the guinea pigs were examined under a light microscope following Nissl staining. In addition, the expression of Fos protein in neurons was detected using immunohistochemistry and western blot analysis. The results indicated that the acquisition rates of CR and SR were increased significantly (P<0.05), whilst the relative latencies of CR and SR were decreased significantly (P<0.05). Lesions were observed in the mPFC regions in the training group when compared with the control group. In addition, immunohistochemistry and western blot analysis revealed that Fos expression was significantly increased in the training group when compared with the sham group for the control and resident-intruder test guinea pigs (P<0.05). Therefore, the enhancement of delay eyelid conditioning by microcurrent electrical stimulation of the mPFC in guinea pigs was triggered by the expression of Fos protein. The observations of the present study further expand the understanding of conditioned reflexes and may aid future investigations into the formation of eyelid conditioning and the mechanisms underlying the circuit in various conditions.

  20. Regional Fos-expression induced by γ-hydroxybutyrate (GHB): comparison with γ-butyrolactone (GBL) and effects of co-administration of the GABAB antagonist SCH 50911 and putative GHB antagonist NCS-382.

    PubMed

    van Nieuwenhuijzen, P S; McGregor, I S; Chebib, M; Hunt, G E

    2014-09-26

    γ-Hydroxybutyrate (GHB) has a complex array of neural actions that include effects on its own high-affinity GHB receptor, the release of neuroactive steroids, and agonist actions at GABAA and GABAB receptors. We previously reported partial overlap in the c-Fos expression patterns produced by GHB and the GABAB agonist, baclofen in rats. The present study extends these earlier findings by examining the extent to which GHB Fos expression and behavioral sedation are prevented by (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), a GABAB antagonist, and NCS-382, a putative antagonist at the high-affinity GHB receptor. We also compare Fos expression caused by GHB and its precursor γ-butyrolactone (GBL), which is a pro-drug for GHB but lacks the high sodium content of the parent GHB molecule. Both GHB (1,000 mg/kg) and GBL (600 mg/kg) induced rapid sedation in rats that lasted over 90 min and caused similar Fos expression patterns, albeit with GBL causing greater activation of the nucleus accumbens (core and shell) and dentate gyrus (granular layer). Pretreatment with SCH 50911 (100mg/kg) partly reversed the sedative effects of GHB and significantly reduced GHB-induced Fos expression in only four regions: the tenia tecta, lateral habenula, dorsal raphe and laterodorsal tegmental nucleus. NCS-382 (50mg/kg) had no effect on GHB-induced sedation or Fos expression. When given alone, both NCS-382 and SCH 50911 increased Fos expression in the bed nucleus of the stria terminalis, central amygdala, parasubthalamic nucleus and nucleus of the solitary tract. SCH 50911 alone affected the Islands of Calleja and the medial, central and paraventricular thalamic nuclei. Overall, this study shows a surprising lack of reversal of GHB-induced Fos expression by two relevant antagonists, both of which have marked intrinsic actions. This may reflect the limited doses tested but also suggests that GHB Fos expression reflects mechanisms independent of GHB and GABAB receptors.

  1. Suckling and sucrose ingestion suppress persistent hyperalgesia and spinal Fos expression after forepaw inflammation in infant rats.

    PubMed

    Ren, K; Blass, E M; Zhou, Q; Dubner, R

    1997-02-18

    Sweet taste and nonnutritive suckling produce analgesia to transient noxious stimuli in infant rats and humans. The present study evaluated the pain-modulating effects of sucrose and suckling in a rat model of persistent pain and hyperalgesia that mimics the response to tissue injury in humans. Fore- and hindpaw withdrawal latencies from a 30 degrees or 48 degrees C brass stylus were determined in 10-day-old rats following paw inflammation induced by complete Freund's adjuvant (CFA; 1:1 injected s.c. in a 0.01 ml volume). CFA markedly decreased escape latencies to both 48 degrees and 30 degrees C stimulation, thereby demonstrating thermal hyperalgesia and mechanical allodynia. The combination of nonnutritive suckling and sucrose (7.5%, 0.01-0.06 ml/min) infusion markedly increased escape latencies to forepaw stimulation in both CFA-treated and control rats. In contrast, intraoral sucrose and suckling did not increase hindpaw withdrawal latencies in either control or CFA-inflamed rats. The effect was specific to sweet taste because neither water nor isotonic saline infusion affected forepaw escape latencies. Parallel findings were obtained for CFA-induced Fos-like immunoreactivity (Fos-LI), a marker of neuronal activation. Fos-LI was selectively induced in cervical and lumbar regions ipsilateral to forepaw and hindpaw inflammation, respectively. Suckling-sucrose treatment significantly reduced Fos-LI at the cervical but not at the lumbar regions. These findings demonstrate: (i) the development of persistent pain and hyperalgesia in 10-day-old rats that can be attenuated by endogenous pain-modulating systems activated by taste and nonnutritive suckling; (ii) the mediation of the sucrose-suckling analgesia and antihyperalgesia at the spinal level; and (iii) a differential rostrocaudal maturation of descending pain-modulating systems to the spinal cord of 10-day-old rats. These findings may provide new clinical approaches for engaging endogenous analgesic mechanisms in

  2. The non-peptide neurokinin-1 antagonist, RPR 100893, decreases c-fos expression in trigeminal nucleus caudalis following noxious chemical meningeal stimulation.

    PubMed

    Cutrer, F M; Moussaoui, S; Garret, C; Moskowitz, M A

    1995-02-01

    The effect of RPR 100893, a selective and specific neurokinin-1 antagonist, or its enantiomer RPR 103253 was examined on c-fos antigen expression in brain stem and upper cervical cord 2 h after intracisternal capsaicin injection (30.5 micrograms/ml) in pentobarbital-anesthetized Hartley guinea-pigs. Positive cells were counted at three levels corresponding to obex, -2.25 mm and -6.75 mm in 18 sections (50 microns). Immunoreactivity was strongly expressed within laminae I and IIo of trigeminal nucleus caudalis, area postrema and the leptomeninges. Moderate labeling was present in the nucleus of the solitary tract and the medullary lateral reticular nucleus, whereas few positive cells were found in the ventral portion of the medullary reticular nucleus and Rexed laminae III-V and X. The distribution of labeled cells was consistent with previously reported results following subarachnoid placement of the noxious agents, blood or carrageenin. Pretreatment with RPR 100893 (1, 10 and 100 micrograms/kg, i.v.) but not its enantiomer (100 micrograms/kg, i.v.) 30 min prior to capsaicin injection significantly reduced the number of positive cells in the trigeminal nucleus caudalis (P < 0.01) in a dose-dependent manner, but not within area postrema or nucleus of the solitary tract. These results indicate that (i) the instillation of capsaicin into the subarachnoid space is an effective stimulus for the induction of c-fos antigen within trigeminal nucleus caudalis, presumably through activation of trigeminovascular afferents, and (ii) the neurokinin-1 antagonist RPR 100893 reduces the number of positive cells selectively within this nucleus. The findings are significant because drugs which alleviate vascular headaches decrease the number of c-fos-positive cells within trigeminal nucleus caudalis following noxious meningeal stimulation. Hence, strategies aimed at blocking the neurokinin-1 receptor may be useful for treating migraine and cluster headache.

  3. Post-weaning social isolation attenuates c-Fos expression in GABAergic interneurons in the basolateral amygdala of adult female rats.

    PubMed

    Lukkes, Jodi L; Burke, Andrew R; Zelin, Naomi S; Hale, Matthew W; Lowry, Christopher A

    2012-12-05

    Previous studies have found that adolescent social isolation of rats can lead to an increased anxiety state during adulthood, while chronic anxiety states are associated with dysregulated local GABAergic inhibition within the basolateral amygdala (BL). Therefore, we investigated the effects of post-weaning social isolation of female rats, in combination with a challenge with the anxiogenic drug, N-methyl-beta-carboline-3-carboxamide (FG-7142), on a subset of GABAergic interneurons in the BL in adulthood using dual immunohistochemical staining for c-Fos and parvalbumin. Juvenile female rats were reared in isolation or in groups of three for a 3-week period from weaning to mid-adolescence, after which all rats were group-housed for an additional 2 weeks. Group-reared rats and isolation-reared rats injected with FG-7142 had increased c-Fos expression in GABAergic interneurons in the anterior part of the BL compared to group-reared rats and isolation-reared rats, respectively, injected with vehicle. Isolation rearing had a main effect to decrease c-Fos expression in GABAergic interneurons in the anterior part of the BL compared to group-reared rats. These data suggest that post-weaning social isolation of female rats leads to dysregulation of a parvalbumin-containing subset of local GABAergic interneurons in the anterior part of the BL, which have previously been implicated in the pathophysiology of chronic anxiety states. These cellular changes may lead to an increased vulnerability to stress- and anxiety-related responses in adulthood.

  4. Chronic stress disrupts fear extinction and enhances amygdala and hippocampal Fos expression in an animal model of post-traumatic stress disorder.

    PubMed

    Hoffman, Ann N; Lorson, Nickolaus G; Sanabria, Federico; Foster Olive, M; Conrad, Cheryl D

    2014-07-01

    Chronic stress may impose a vulnerability to develop maladaptive fear-related behaviors after a traumatic event. Whereas previous work found that chronic stress impairs the acquisition and recall of extinguished fear, it is unknown how chronic stress impacts nonassociative fear, such as in the absence of the conditioned stimulus (CS) or in a novel context. Male rats were subjected to chronic stress (STR; wire mesh restraint 6 h/d/21d) or undisturbed (CON), then tested on fear acquisition (3 tone-footshock pairings), and two extinction sessions (15 tones/session) within the same context. Then each group was tested (6 tones) in the same context (SAME) or a novel context (NOVEL), and brains were processed for functional activation using Fos immunohistochemistry. Compared to CON, STR showed facilitated fear acquisition, resistance to CS extinction on the first extinction day, and robust recovery of fear responses on the second extinction day. STR also showed robust freezing to the context alone during the first extinction day compared to CON. When tested in the same or a novel context, STR exhibited higher freezing to context than did CON, suggesting that STR-induced fear was independent of context. In support of this, STR showed increased Fos-like expression in the basolateral amygdala and CA1 region of the hippocampus in both the SAME and NOVEL contexts. Increased Fos-like expression was also observed in the central amygdala in STR-NOVEL vs. CON-NOVEL. These data demonstrate that chronic stress enhances fear learning and impairs extinction, and affects nonassociative processes as demonstrated by enhanced fear in a novel context.

  5. Autoregulation of fos: the dyad symmetry element as the major target of repression.

    PubMed Central

    König, H; Ponta, H; Rahmsdorf, U; Büscher, M; Schönthal, A; Rahmsdorf, H J; Herrlich, P

    1989-01-01

    Fos and Jun co-operatively repress the fos promoter. Removal of all putative Fos/Jun binding sites from the fos promoter neither obliterates the repression by Fos/Jun in transient cotransfection experiments in NIH3T3 cells nor the turn-off kinetics of serum-induced fos expression in stably transfected NIH3T3 cells. The dyad symmetry element (DSE) suffices to subject a promoter to this type of repression. However, one of the putative Fos/Jun binding sites (-292 to -299 and thus located immediately adjacent to the DSE), determines the very low level of basal expression. Images PMID:2511006

  6. Induction of interleukin 6 and interleukin 8 expression by Broncho-Vaxom (OM-85 BV) via C-Fos/serum responsive element.

    PubMed Central

    Keul, R.; Roth, M.; Papakonstantinou, E.; Nauck, M.; Perruchoud, A. P.; Block, L. H.

    1996-01-01

    BACKGROUND: Broncho-Vaxom (OM-85 BV) increases the resistance of the respiratory tract to bacterial infections by modulating host immune responses. The compound increases serum IgG levels but decreases IgE levels in patients suffering from chronic bronchitis or chronic obstructive pulmonary disease. It increases concentrations of gamma-interferon (IFN-gamma), IgA, and interleukin (IL)-2 in bronchoalveolar lavage fluid of patients with bronchitis. Treatment with OM-85 BV increases the number of T helper and natural killer cells. In this study the effects of OM-85 BV on transcription of cytokines is investigated in human lung fibroblasts. METHODS: Transcription and synthesis of IL-6 and IL-8 were assessed in cultured primary human lung fibroblasts using standard methods of Northern blot analysis for the level of mRNAs and enzyme linked immunosorbent assay for proteins. RESULTS: Broncho-Vaxom (OM-85 BV) at different concentrations induced transcription of IL-6 and IL-8. The effect of the drug on transcription of IL-6 and IL-8 genes correlated with secretion of the proteins into cell supernatants. OM-85 BV-dependent expression of the interleukin genes involved C-Fos/serum responsive element (C-Fos/SRE). CONCLUSIONS: The data suggest that the various immunopharmacological activities of OM-85 BV that have been described in clinical studies may be explained by its ability to induce expression of IL-6 and IL-8. Images PMID:8711646

  7. Inhibition of osteoclast differentiation and bone resorption by rotenone, through down-regulation of RANKL-induced c-Fos and NFATc1 expression.

    PubMed

    Kwak, Han Bok; Lee, Byeong Ki; Oh, Jaemin; Yeon, Jeong-Tae; Choi, Sik-Won; Cho, Hae Joong; Lee, Myeung Su; Kim, Jeong-Joong; Bae, Ji-Myung; Kim, Seong Hwan; Kim, Hun Soo

    2010-03-01

    Osteoclasts are responsible for bone erosion in diseases as diverse as osteoporosis, periodontitis, and rheumatoid arthritis. Natural plant-derived products have received recent attention as potential therapeutic and preventative drugs in human disease. The effect of rotenone in RANKL-induced osteoclast differentiation was examined in this study. Rotenone inhibited RANKL-mediated osteoclast differentiation in bone marrow macrophages (BMMs) in a dose-dependent manner without any evidence of cytotoxicity. The mRNA expression of c-Fos, NFATc1, TRAP, and OSCAR in RANKL-treated BMMs was inhibited by rotenone treatment. Rotenone strongly inhibited p38 and ERK phosphorylation and I-kappaB degradation in RANKL-stimulated BMMs, and did not inhibit JNK phosphorylation. Further, RANKL-induced c-Fos and NFATc1 protein expression was suppressed by rotenone. Rotenone additionally inhibited the bone resorptive activity of differentiated osteoclasts. A lipopolysaccharide (LPS)-induced bone erosion study was also performed to assess the effects of rotenone in vivo. Mice treated with rotenone demonstrated marked attenuation of bone erosion based on Micro CT and histologic analysis of femurs. These results collectively suggested that rotenone demonstrated inhibitory effects on osteoclast differentiation in vitro and suppressed inflammatory bone loss in vivo. Rotenone may therefore serve as a useful drug in the prevention of bone loss.

  8. Expression of c-fos mRNA in the Basal Ganglia Associated with Contingent Tolerance to Amphetamine-Induced Hypophagia

    PubMed Central

    Bachand, Kimberlee D.; Guthrie, Kathleen M.; Wolgin, David L.

    2009-01-01

    Tolerance to the hypophagic effect of psychostimulants is contingent on having access to food while intoxicated. Rats given chronic injections of such drugs with access to food learn to suppress stereotyped movements, which interfere with feeding. In contrast, controls given the drug after food access do not learn to suppress stereotypy and, therefore, do not become tolerant. To determine the role of the basal ganglia in this phenomenon, we used in situ hybridization to measure the expression of c-fos mRNA, a marker for neural activation, in the brains of tolerant and nontolerant rats. Rats given chronic amphetamine injections prior to food access learned to suppress stereotyped movements, whereas yoked controls given the drug after feeding did not. Following an acute injection of amphetamine, both of these groups had higher levels of c-fos mRNA than saline-treated controls throughout the striatum, in the nucleus accumbens core, the ventral pallidum and layers V–VI of the motor cortex. In contrast, tolerant rats, which had learned to suppress stereotypy, had higher levels of c-fos mRNA than both amphetamine- and saline-treated controls in the entopeduncular nucleus, globus pallidus, subthalamic nucleus, pedunculopontine nucleus, nucleus accumbens shell, olfactory tubercle, somatosensory cortex, and layers II–IV of motor cortex. These data suggest that the learned suppression of amphetamine-induced stereotypy involves the activation of dorsal striatal pathways previously implicated in response selection as well as the ventral striatum, long implicated in appetitive motivation and reinforcement. PMID:19084559

  9. Modulation of p53, c-fos, RARE, cyclin A, and cyclin D1 expression in human leukemia (HL-60) cells exposed to arsenic trioxide

    PubMed Central

    Yedjou, Clement G.; Tchounwou, Paul B.

    2010-01-01

    Arsenic trioxide (As2O3) has recently been successfully used to treat all-trans retinoic acid (ATRA) resistant relapsing acute promyelocytic leukemia. However, its molecular mechanisms of action are poorly understood. In the present study, we used the human leukemia (HL-60) cell line as a test model to study the cellular and molecular mechanisms of anti-cancer properties of As2O3. We hypothesized that As2O3-induced expression of stress genes and related proteins may play a role in the cellular and molecular events leading to cell cycle modulation in leukemic cells. To test this hypothesis, we performed Western blot analysis to assess the expression of specific cellular response proteins including p53, c-fos, RARE, Cyclin A, and Cyclin D1. Densitometric analysis was performed to determine the relative abundance of these proteins. Western Blot and densitometric analyses demonstrated a strong dose-response relationship with regard to p53 and RARE expression within the dose range of 0-8μg/mL. Expression of c-fos was slightly up-regulated at 2μg/mL, and down-regulated within the dose-range of 4-8 μg/mL. A statistically significant down-regulation of this protein was detected at the 6 and 8 μg/mL dose levels. No statistically significant differences (p>0.05) in Cyclin D1 expression was found between As2O3-treated cells and the control. Cyclin A expression in As2O3-treated HL-60 cells was up-regulated at 6μg/mL, suggesting that it is required for S phase and passage through G2 phase in cell cycle progression. Taken together, these results indicate that As2O3 has the potential to induce cell cycle arrest through activation of the 53-kDa tumor suppressor protein and repression of the c-fos transcription factor. Up-regulation of RARE by As2O3 indicates that its cytotoxicity may be mediated through interaction/binding with the retinoic acid receptor, and subsequent inhibition of growth and differentiation. PMID:19444595

  10. c-Fos immunoreactivity in the pig brain following deoxynivalenol intoxication: focus on NUCB2/nesfatin-1 expressing neurons.

    PubMed

    Gaigé, Stéphanie; Bonnet, Marion S; Tardivel, Catherine; Pinton, Philippe; Trouslard, Jérôme; Jean, André; Guzylack, Laurence; Troadec, Jean-Denis; Dallaporta, Michel

    2013-01-01

    Deoxynivalenol (DON), produced by the cereal-contaminating Fusarium fungi, is a major trichothecene responsible for mycotoxicoses in farm animals, including swine. The main effect of DON-intoxication is food intake reduction and the consequent body weight loss. The present study aimed to identify brain structures activated during DON intoxication in pigs. To this goal, we used c-Fos staining which constitutes a useful approach to identify activated neurons. We showed that per os administration of Fusarium graminearum extracts (containing the equivalent of 1mg DON per kg of body weight) induced an increase in c-Fos immunoreactivity in several central structures, including the ventrolateral medulla (VLM), dorsal vagal complex (DVC), paraventricular nucleus of the hypothalamus (PVN), arcuate nucleus (Arc), supraoptic nucleus (SON) and amygdala (CeA). Moreover, we coupled c-Fos staining with phenotypic markers detection in order to specify the neuronal populations activated during DON intoxication. This phenotypic characterization revealed the activation of catecholaminergic but not of serotoninergic neurons in response to the toxin. In this context, we also paid a particular attention to NUCB2/nesfatin-1 positive cells, since nesfatin-1 is known to exert a satiety effect. We report here, for the first time in the pig brain, the presence of NUCB2/nesfatin-1 neurons in the VLM, DVC, PVN, Arc and SON, and their activation during DON intoxication. Taken together, these data show that DON stimulates the main structures involved in food intake in pigs and suggest that catecholaminergic and NUCB2/nesfatin-1 neurons could contribute in the anorexigenic effects of the mycotoxin.

  11. Effects of alcohol exposure during development on play behavior and c-Fos expression in response to play behavior

    PubMed Central

    Lawrence, R. Charles; Bonner, H. Cale; Newsom, Ryan J.; Kelly, Sandra J.

    2008-01-01

    Developmental exposure to alcohol can produce characteristic physiological and cognitive deficits, often termed Fetal Alcohol Spectrum Disorder (FASD). More recently, social deficits have been shown to occur both in FASD and animal models of FASD; the behavioral and neural bases of these deficits remain to be determined. It was hypothesized that changes in sensory processing may in part underlie the social deficits seen in FASD. This study used a rat model of FASD and social play, a behavior critical to adult social functioning, to begin to examine this hypothesis. Somatosensory cues from dorsal contact to the nape of the neck, critical to the initiation of pinning, were systematically degraded by administration of different doses of xylocaine, a topical anesthetic. Neuronal activity after one hour of play was assessed by measurement of c-Fos immunoreactivity (IR) in different brain regions. Ethanol-exposed rats showed an increase frequency of pinning during social play and were more sensitive to the degradation of somatosensory cues compared to the control groups, suggesting difficulties in processing somatosensory cues. Neuronal activity in the somatosensory cortex induced by play was significantly decreased in the ethanol-exposed group compared to the non-treated group. The c-Fos IR in the nucleus accumbens was altered in a sexually dimorphic manner in the ethanol-exposed group. Thus, the behavioral and brain measures are consistent with the hypothesis that ethanol exposure during development induces alterations in social play via deficits in processing somatosensory cues that are important to social play. PMID:18160143

  12. Cyclodextrin-complexed Ocimum basilicum leaves essential oil increases Fos protein expression in the central nervous system and produce an antihyperalgesic effect in animal models for fibromyalgia.

    PubMed

    Nascimento, Simone S; Araújo, Adriano A S; Brito, Renan G; Serafini, Mairim R; Menezes, Paula P; DeSantana, Josimari M; Lucca, Waldecy; Alves, Pericles B; Blank, Arie F; Oliveira, Rita C M; Oliveira, Aldeidia P; Albuquerque, Ricardo L C; Almeida, Jackson R G S; Quintans, Lucindo J

    2014-12-29

    O. basilicum leaves produce essential oils (LEO) rich in monoterpenes. The short half-life and water insolubility are limitations for LEO medical uses. β-Cyclodextrin (β-CD) has been employed to improve the pharmacological properties of LEO. We assessed the antihyperalgesic profile of LEO, isolated or complexed in β-CD (LEO/β-CD), on an animal model for fibromyalgia. Behavioral tests: mice were treated every day with either LEO/β-CD (25, 50 or 100 mg/kg, p.o.), LEO (25 mg/kg, p.o.), tramadol (TRM 4 mg/kg, i.p.) or vehicle (saline), and 60 min after treatment behavioral parameters were assessed. Therefore, mice were evaluated for mechanical hyperalgesia (von Frey), motor coordination (Rota-rod) and muscle strength (Grip Strength Metter) in a mice fibromyalgia model. After 27 days, we evaluated the central nervous system (CNS) pathways involved in the effect induced by experimental drugs through immunofluorescence protocol to Fos protein. The differential scanning analysis (DSC), thermogravimetry/derivate thermogravimetry (TG/DTG) and infrared absorption spectroscopy (FTIR) curves indicated that the products prepared were able to incorporate the LEO efficiently. Oral treatment with LEO or LEO-βCD, at all doses tested, produced a significant reduction of mechanical hyperalgesia and we were able to significantly increase Fos protein expression. Together, our results provide evidence that LEO, isolated or complexed with β-CD, produces analgesic effects on chronic non-inflammatory pain as fibromyalgia.

  13. The effect of daily caffeine exposure on lever-pressing for sucrose and c-Fos expression in the nucleus accumbens in the rat.

    PubMed

    Retzbach, Edward P; Dholakia, Paulomi H; Duncan-Vaidya, Elizabeth A

    2014-08-01

    Recent reports suggest that caffeine exposure increases the motivation to consume drugs of abuse. As such, it may also enhance the motivation to consume palatable food. Because caffeine is a common constituent in over-the-counter weight-loss supplements, it is important to better understand the relationship between caffeine and food intake. The purpose of this study was to measure the effects of daily intermittent caffeine exposure on lever pressing for sucrose in rats and to assess the impact of caffeine on neuronal activation in the nucleus accumbens (NAc). Male Sprague-Dawley rats that received either saline or caffeine (1, 5, 20mg/kgi.p.) daily were tested on a fixed ratio 4 schedule for sucrose in operant chambers for 10days and then again following a 5-day treatment withdrawal period. After behavioral testing, a subset of the animals was sacrificed to measure the impact of caffeine on neuronal activation in the NAc using c-Fos as a marker. There was a significant increase in active lever presses for sucrose in the rats that had received 5mg/kg of caffeine when compared with the saline group. This treatment effect was no longer present after the withdrawal period. Acute, but not chronic, caffeine exposure elevated c-Fos expression in the NAc. These data suggest that intermittent daily caffeine exposure increases lever pressing for sucrose in rats, but leaves no lasting effect.

  14. The effect of electroacupuncture on extinction responding of heroin-seeking behavior and FosB expression in the nucleus accumbens core.

    PubMed

    Hu, Airong; Lai, Miaojun; Wei, Jianzi; Wang, Lina; Mao, Huijuan; Zhou, Wenhua; Liu, Sheng

    2013-02-08

    Augmentation of extinction with learning enhancing therapy may offer an effective strategy to combat heroin relapse. Our lab previously found that electroacupuncture (EA) not only significantly reduced cue-induced reinstatement of heroin seeking but also exhibited a promoting effect on the ability of learning and memory. In the present study, we further investigated the effects of EA on the extinction of heroin-seeking behavior in rats with a history of intravenous heroin self-administration. We trained Sprague-Dawley rats to nose-poke for i.v. heroin either daily for 4h or 25 infusions for 14 consecutive days; then the rats underwent 7 daily 3h extinction sessions in the operant chamber. To assess EA's effects on the extinction response of heroin-associated cues, 2Hz EA was administered 1h before each of the 7 extinction sessions. We also applied immunohistochemistry to detect FosB-positive nuclei in the nucleus accumbens core. We found that EA treatment facilitated the extinction response of heroin seeking but did not alter the locomotor activity in an open field testing environment. EA stimulation attenuated the FosB expression in the core of the nucleus accumbens, a brain region involved in the learning and execution of motor responses. Altogether, these results suggest that EA may provide a novel nonpharmacological approach to enhance extinction learning when combined with extinction therapy for the treatment of heroin addiction.

  15. Cyclodextrin-Complexed Ocimum basilicum Leaves Essential Oil Increases Fos Protein Expression in the Central Nervous System and Produce an Antihyperalgesic Effect in Animal Models for Fibromyalgia

    PubMed Central

    Nascimento, Simone S.; Araújo, Adriano A. S.; Brito, Renan G.; Serafini, Mairim R.; Menezes, Paula P.; DeSantana, Josimari M.; Lucca Júnior, Waldecy; Alves, Pericles B.; Blank, Arie F.; Oliveira, Rita C. M.; Oliveira, Aldeidia P.; Albuquerque-Júnior, Ricardo L. C.; Almeida, Jackson R. G. S.; Quintans-Júnior, Lucindo J.

    2014-01-01

    O. basilicum leaves produce essential oils (LEO) rich in monoterpenes. The short half-life and water insolubility are limitations for LEO medical uses. β-Cyclodextrin (β-CD) has been employed to improve the pharmacological properties of LEO. We assessed the antihyperalgesic profile of LEO, isolated or complexed in β-CD (LEO/β-CD), on an animal model for fibromyalgia. Behavioral tests: mice were treated every day with either LEO/β-CD (25, 50 or 100 mg/kg, p.o.), LEO (25 mg/kg, p.o.), tramadol (TRM 4 mg/kg, i.p.) or vehicle (saline), and 60 min after treatment behavioral parameters were assessed. Therefore, mice were evaluated for mechanical hyperalgesia (von Frey), motor coordination (Rota-rod) and muscle strength (Grip Strength Metter) in a mice fibromyalgia model. After 27 days, we evaluated the central nervous system (CNS) pathways involved in the effect induced by experimental drugs through immunofluorescence protocol to Fos protein. The differential scanning analysis (DSC), thermogravimetry/derivate thermogravimetry (TG/DTG) and infrared absorption spectroscopy (FTIR) curves indicated that the products prepared were able to incorporate the LEO efficiently. Oral treatment with LEO or LEO-βCD, at all doses tested, produced a significant reduction of mechanical hyperalgesia and we were able to significantly increase Fos protein expression. Together, our results provide evidence that LEO, isolated or complexed with β-CD, produces analgesic effects on chronic non-inflammatory pain as fibromyalgia. PMID:25551603

  16. Activations of c-fos/c-jun signaling are involved in the modulation of hypothalamic superoxide dismutase (SOD) and neuropeptide Y (NPY) gene expression in amphetamine-mediated appetite suppression

    SciTech Connect

    Hsieh, Y.-S.; Yang, S.-F.; Chiou, H.-L.; Kuo, D.-Y. . E-mail: dykuo@csmu.edu.tw

    2006-04-15

    Amphetamine (AMPH) is known as an anorectic agent. The mechanism underlying the anorectic action of AMPH has been attributed to its inhibitory action on hypothalamic neuropeptide Y (NPY), an appetite stimulant in the brain. This study was aimed to examine the molecular mechanisms behind the anorectic effect of AMPH. Results showed that AMPH treatment decreased food intake, which was correlated with changes of NPY mRNA level, but increased c-fos, c-jun and superoxide dismutase (SOD) mRNA levels in hypothalamus. To determine if c-fos or c-jun was involved in the anorectic response of AMPH, infusions of antisense oligonucleotide into the brain were performed at 1 h before daily AMPH treatment in freely moving rats, and the results showed that c-fos or c-jun knockdown could block this anorectic response and restore NPY mRNA level. Moreover, c-fos or c-jun knockdown could partially block SOD mRNA level that might involve in the modulation of NPY gene expression. It was suggested that c-fos/c-jun signaling might involve in the central regulation of AMPH-mediated feeding suppression via the modulation of NPY gene expression.

  17. Reactive Oxygen Species-Dependent c-Fos/Activator Protein 1 Induction Upregulates Heme Oxygenase-1 Expression by Bradykinin in Brain Astrocytes.

    PubMed

    Hsieh, Hsi-Lung; Wang, Hui-Hsin; Wu, Cheng-Ying; Yang, Chuen-Mao

    2010-12-15

    Heme oxygenase-1 (HO-1) plays a crucial role in tissue pathological changes such as brain injuries. Our previous studies have demonstrated that bradykinin (BK) induces the expression of several inflammatory proteins, including matrix metalloproteinase-9 and COX-2, via mitogen-activated protein kinases and nuclear factor-κB (NF-κB) in rat brain astrocytes (RBA-1). However, the molecular mechanisms underlying BK-induced HO-1 expression in RBA-1 cells remain poorly defined. Here we demonstrated that BK induced HO-1 expression and enzymatic activity via a B(2) BK receptor-activated reactive oxygen species (ROS)-dependent signaling pathway. NADPH oxidase (Nox)-dependent ROS generation led to activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun-N-terminal kinase (JNK) and then activated the downstream molecules NF-κB and c-Jun, respectively. The c-Fos, an activator protein 1 (AP-1) subunit, was upregulated by activation of NF-κB and c-Jun, which bound to HO-1 promoter and thereby turned on transcription of HO-1 gene. The rat HO-1 promoter containing a putative AP-1 cis-binding site was identified as a crucial domain linking to BK action. Taken together, these results suggested that in RBA-1 cells, activation of ERK/NF-κB and JNK/c-Jun cascades by a Nox/ROS-dependent event enhancing c-Fos/AP-1 activity is essential for HO-1 upregulation and activation induced by BK. Moreover, ROS-dependent NF-E2-related factor 2 activation also contributes to HO-1 induction by BK in astrocytes.

  18. Cell-type-specific expression and regulation of a c-fos-NGF fusion gene in neurons and astrocytes of transgenic mice.

    PubMed

    Onténiente, B; Horellou, P; Neveu, I; Makeh, I; Suzuki, F; Bourdet, C; Grimber, G; Colin, P; Brachet, P; Mallet, J

    1994-02-01

    A mouse line transgenic for nerve growth factor (NGF) was developed using the mouse prepro-NGF cDNA inserted within a plasmid containing the proximal region (-10 to -550 bp) of the c-fos promoter and the transcription termination and polyadenylation signals of the rabbit beta-globin gene. No significant modification of gross behavior or central nervous system anatomy was detected in adult animals as assessed by immunohistochemistry and in situ hybridization for NGF and choline acetyltransferase. The expression of the transgene and the possible regulation of its expression by agents acting on the promoter were investigated in vitro. Despite the presence of an additional pool of NGF mRNA specific to the transgene, basal levels of NGF in the supernatant of transgenic astrocytes were similar to normal ones. On the other hand, transgenic neurons spontaneously synthesized and released levels of NGF two to three times higher than normal neurons, while mRNA levels were barely detectable by conventional Northern blotting. The tissue-specificity of NGF expression was respected, with higher levels in hippocampal than neocortical neurons. Increases of NGF mRNA by agents acting on the promoter could be observed in normal and transgenic astrocytes only after inhibition of the protein synthesis by cycloheximide, suggesting a similar rapid turnover of normal and transgenic transcripts. Cyclic AMP agonists specifically increased the secretion of NGF protein by transgenic astrocytes and neurons, while activators of the protein kinase C had a similar effect on transgenic and normal cells. Differences between amounts of NGF secreted by neurons and astrocytes with regards to their respective content in mRNA suggest that transgenic transcripts are subject to normal cell- and tissue-specific post-transcriptional regulations. Agents acting on the c-fos promoter through the protein kinase C or cyclic AMP routes differentially increased the secretion of NGF by transgenic astrocytes or

  19. Endothelin stimulates phospholipase C, Na+/H+ exchange, c-fos expression, and mitogenesis in rat mesangial cells.

    PubMed Central

    Simonson, M S; Wann, S; Mené, P; Dubyak, G R; Kester, M; Nakazato, Y; Sedor, J R; Dunn, M J

    1989-01-01

    A recently described peptide hormone, endothelin, is a potent vasoconstrictor, but it is unclear whether endothelin has other biological actions. These experiments extend the range of biological actions of endothelin to stimulation of mitogenesis. Endothelin at low concentrations (0.1-10 nM) induced mitogenesis by quiescent rat glomerular mesangial cells in culture. Mitogenesis induced by endothelin was accompanied by activation of phospholipase C with increased inositol phosphate turnover and increments of intracellular [Ca2+]. Endothelin also activated Na+/H+ exchange, causing cytosolic alkalinization, and enhanced transcription of the c-fos protooncogene, additional biochemical signals closely linked to proliferation. In addition to being a vasoconstrictor, endothelin thus also functions as a mitogen, presumably through activation of phospholipase C. Images PMID:2536405

  20. The Expression of Fos, Jun and AP-1 DNA Binding Activity in Rat Supraoptic Nucleus Neurons Following Acute Versus Repeated Osmotic Stimulation

    DTIC Science & Technology

    1995-06-22

    stimulation. This pattern has been observed previously in the hippocampus after treatment with the seizure-inducing drug , metrazole (Sonnenberg et al... fosB , and fra-1 and -2. fra refers to ~OS­ ~elated ~ntigen. Western blot experiments and employment of less stringent nucleic acid hybridization...fos, fra-l and fosB , only form heterodimeric complexes with Jun-related proteins (Nakabeppu et al., 1988; Rauscher et al., 1988b) The AP-l site of many

  1. The nonpeptide oxytocin receptor agonist WAY 267,464: receptor-binding profile, prosocial effects and distribution of c-Fos expression in adolescent rats.

    PubMed

    Hicks, C; Jorgensen, W; Brown, C; Fardell, J; Koehbach, J; Gruber, C W; Kassiou, M; Hunt, G E; McGregor, I S

    2012-07-01

    Previous research suggests that the nonpeptide oxytocin receptor (OTR) agonist WAY 267,464 may only partly mimic the effects of oxytocin in rodents. The present study further explored these differences and related them to OTR and vasopressin 1a receptor (V(1a) R) pharmacology and regional patterns of c-Fos expression. Binding data for WAY 267,464 and oxytocin were obtained by displacement binding assays on cellular membranes, while functional receptor data were generated by luciferase reporter assays. For behavioural testing, adolescent rats were tested in a social preference paradigm, the elevated plus-maze (EPM) and for locomotor activity changes following WAY 267,464 (10 and 100 mg/kg, i.p.) or oxytocin (0.1 and 1 mg/kg, i.p.). The higher doses were also examined for their effects on regional c-Fos expression. Results showed that WAY 267,464 had higher affinity (K(i) ) at the V(1a) R than the OTR (113 versus 978 nm). However, it had no functional response at the V(1a) R and only a weak functional effect (EC(50) ) at the OTR (881 nm). This suggests WAY 267,464 is an OTR agonist with weak affinity and a possible V(1a) R antagonist. Oxytocin showed high binding at the OTR (1.0 nm) and V(1a) R (503 nm), with a functional EC(50) of 9.0 and 59.7 nm, respectively, indicating it is a potent OTR agonist and full V(1a) R agonist. WAY 267,464 (100 mg/kg), but not oxytocin, significantly increased the proportion of time spent with a live rat, over a dummy rat, in the social preference test. Neither compound affected EPM behaviour, whereas the higher doses of WAY 267,464 and oxytocin suppressed locomotor activity. WAY 267,464 and oxytocin produced similar c-Fos expression in the paraventricular hypothalamic nucleus, central amygdala, lateral parabrachial nucleus and nucleus of the solitary tract, suggesting a commonality of action at the OTR with the differential doses employed. However, WAY 267,464 caused greater c-Fos expression in the medial amygdala and the supraoptic

  2. Effect of rhynchophylline on the expression of p-CREB and sc-Fos in triatum and hippocampal CA1 area of methamphetamine-induced conditioned place preference rats.

    PubMed

    Liu, Wei; Peng, Qiu-Xian; Lin, Xiao-Liang; Luo, Chao-Hua; Jiang, Ming-Jin; Mo, Zhi-Xian; Yung, Ken Kin-Lam

    2014-01-01

    To explore the effect of rhynchophylline (Rhy) on the expression of p-CREB and c-Fos in the striatum and hippocampal CA1 area of methamphetamine-induced conditioned place preference (CPP) rat, methamphetamine (2 mg/kg) was injected to rats and the conditioned place preference was observed in these rats treated with or without Rhy. An immunohistochemistry assay was used to determine the expression of p-CREB and c-Fos in the striatum and hippocampal CA1 area. Methamphetamine induced significant behavior alteration in CPP, while after pretreatment with rhynchophylline or ketamine, the time of staying in methamphetamine-paired compartment of rats was significantly reduced. Methamphetamine also increased the number of p-CREB positive cells in the striatum and hippocampal CA1 zone, as well as p-Fos positive cells. However, the compound Rhy could attenuate the effect. These findings show that Rhy can suppress the acquisition of CPP in rats induced by methamphetamine and the action may be related with the reduced expression of p-CREB and p-Fos in the striatum and hippocampus.

  3. Effects of chemical stimulation of the lateral wings of the dorsal raphe nucleus on panic-like defensive behaviors and Fos protein expression in rats.

    PubMed

    Matthiesen, Melina; Spiacci, Ailton; Zangrossi, Hélio

    2017-03-06

    The lateral wings subnucleus of the dorsal raphe nucleus (lwDR) has been implicated in the modulation of panic-like behaviors, such as escape. Infusion of non- excitotoxic doses of the excitatory amino acid kainic acid into this subnucleus promptly evokes a vigorous escape response. In addition, rats exposed to panic-inducing situations show an increase in Fos protein expression in neurons within the lwDR. In the present study, we first investigated whether key structures associated with the mediation of escape behavior are recruited after chemical stimulation of the lwDR with kainic acid. We next investigated whether the infusion of the GABAA receptor antagonist bicuculline into the lwDR also evoked escape responses measured both in a circular arena and in the rat elevated T-maze. The effects of bicuculline in the circular arena were compared to those caused by the infusion of this antagonist into the ventrolateral periaqueductal gray (vlPAG), an area in close vicinity to the lwDR. The results showed that kainic acid infusion into the lwDR increased Fos protein immunostaining in brain structures deeply involved in panic-like defensive behaviors, such as the periaqueductal gray and hypothalamus, but not the amygdala. As observed with kainic acid, bicuculline evoked a pronounced escape response in the circular arena when microinjected in the lwDR, but not in the vlPAG. The escape-promoting effect of bicuculline in the lwDR was also evidenced in the elevated T-maze. These findings strength the view that dysfunction in mechanisms controlling escape in the lwDR is critically implicated in the pathophysiology of panic disorder.

  4. Resilience and reduced c-Fos expression in P2X7 receptor knockout mice exposed to repeated forced swim test.

    PubMed

    Boucher, A A; Arnold, J C; Hunt, G E; Spiro, A; Spencer, J; Brown, C; McGregor, I S; Bennett, M R; Kassiou, M

    2011-08-25

    There is considerable evidence suggesting genetic factors play an important role in the pathophysiology of depression, possibly by increasing susceptibility to repeated environmental stressors. Recent linkage studies have associated a polymorphism of the gene coding for the P2X7 receptor (P2X7R) with both major depressive disorder and bipolar disorder. Here we assessed whether P2X7 deletion affected the behavioural and neural response to repeated stress. P2X7R knockout (P2X7-/-) mice were subjected to the forced swim test for three consecutive days and neuronal activation in response to the third exposure was assessed using c-Fos immunohistochemistry. In addition, anxiety was evaluated in another group of P2X7-/- mice using the elevated plus maze (EPM) and light dark emergence (LDE) tests. Equivalent levels of immobility were observed in P2X7-/- mice and wild-type (WT) mice on the first exposure to forced swim, but much greater immobility was seen in WT mice on second and third exposures. This suggests that P2X7-/- mice exhibit an impaired adaptive coping response to repeated stress. Reinforcing this view, c-Fos expression in the dentate gyrus of the hippocampus and in the basolateral amygdala was seen in WT mice but not P2X7-/- mice following repeated forced swim. In addition, decreased locomotor activity was detected in P2X7-/- mice without any specific effects on anxiety in the LDE test. However, P2X7-/- mice showed greater anxiety-like behaviour in the EPM. These data suggest that the P2X7R may be involved in the adaptive mechanisms elicited by exposure to repeated environmental stressors that leads to the development of depression-like behaviours. This suggests that P2X7R antagonists may be useful therapeutics for the treatment of major depression, possibly by increasing resilience in the face of repeated stress.

  5. L-DOPA-induced dyskinesia in adult rats with a unilateral 6-OHDA lesion of dopamine neurons is paralleled by increased c-fos gene expression in the subthalamic nucleus.

    PubMed

    Soghomonian, Jean-Jacques

    2006-05-01

    Levodopa (L-DOPA), the metabolic precursor of dopamine, is widely used as a pharmacological agent for the symptomatic treatment of Parkinson's disease. However, long-term L-DOPA use results in abnormal involuntary movements such as dyskinesias. There is evidence that abnormal cell signaling in the basal ganglia is involved in L-DOPA-induced dyskinesia. The subthalamic nucleus (STN) plays a key role in the circuitry of the basal ganglia and in the pathophysiology of Parkinson's disease. However, the contribution of the STN to L-DOPA-induced dyskinesias remains unclear. The objective of this work was to study the effects of acute or chronic systemic administration of L-DOPA to adult rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of dopamine neurons on c-fos expression in the STN and test the hypothesis that these effects correlate with L-DOPA-induced dyskinesias. c-fos mRNA expression was measured in the STN by in situ hybridization histochemistry at the single cell level. Our results confirm earlier evidence that the chronic administration of L-DOPA to rats with a unilateral 6-OHDA lesion increases c-fos expression in the STN. We also report that c-fos expression can be increased following an acute injection of L-DOPA to 6-OHDA-lesioned rats but not following a chronic injection of L-DOPA to sham-operated, unlesioned rats. Finally, we provide evidence that the occurrence and severity of dyskinesia is correlated with c-fos mRNA levels in the ipsilateral STN. These results suggest that altered cell signaling in the STN is involved in some of the behavioral effects induced by systemic L-DOPA administration.

  6. Expression patterns of c-Fos early gene and phosphorylated ERK in the rat brain following 1-h immobilization stress: concomitant changes induced in association with stress-related sleep rebound.

    PubMed

    Keshavarzy, Fatemeh; Bonnet, Chantal; Behzadi, Gila; Bezhadi, Gila; Cespuglio, Raymond

    2015-01-01

    An immobilization stress (IS) of 1 h applied at the beginning of the dark phase is followed by a sleep rebound. During the restraint, serotonin released by the dorsal raphe nucleus within the arcuate area stimulates the availability of corticotropin-like intermediate lobe peptide (CLIP or ACTH18-39). Three hours after the restraint, CLIP, through its hypnogenic properties, contributes to the sleep rebound that follows the IS. Here, we immunohistochemically evaluated protein expression of the immediate early gene, c-Fos and phosphorylated extracellular signal-regulated kinase (p-ERK) in hypothalamic (preoptic area [POA], paraventricular nucleus [PVN], arcuate nucleus [ARC]) and brain stem (dorsal raphe [DR], locus coeruleus [LC]) nuclei involved in the acute response to stress and the subsequent stress-related sleep rebound (recovery period). Immediately after the 1-h restraint, c-Fos and p-ERK expression increased in all structures studied, particularly in PVN and LC. Three hours later, the number of p-ERK- and c-Fos-positive neurons was reduced in PVN and LC (p < 0.001) as well as in DR (p < 0.01) compared to control animals. In contrast, both c-Fos and p-ERK expression in POA neurons (p < 0.01) and c-Fos expression in ARC neurons (p < 0.001) were increased 3 h after the IS. The marked activation observed in PVN and LC nucleus immediately after the IS confirms that these structures are clearly reactive to stress. However, the high activity observed in POA and ARC neurons during the recovery period, not described to date, highlights the particular part played by these structures in the stress-related sleep rebound. An unbalance in the above processes may contribute to pathological outcomes, such as anxiety and depression.

  7. Activation of endogenous c-fos proto-oncogene expression by human T-cell leukemia virus type I-encoded p40 sup tax protein in the human T-cell line, Jurkat

    SciTech Connect

    Nagata, Kinya; Ohtani, Kiyoshi; Nakamura, Masataka; Sugamura, Kazuo )

    1989-08-01

    The authors examined the ability of the trans-acting factor p40{sup tax} of human T-cell leukemia virus type I (HTLV-I), which is thought to be a crucial molecule in T-cell transformation by HTLV-I, to activate expression of a set of endogenous cellular genes related to T-cell proliferation. For this purpose, they established a subclone (JPX-9) of Jurkat cells that was stably transfected with an expression plasmid containing the p40{sup tax} gene, whose expression is definitively dependent on heavy-metal ions. Expression of the interleukin-2 receptor {alpha} chain in JPX-9 cells was induced in response to the induction of p40{sup tax} expression, as has been demonstrated by others in transient transfection experiments with Jurkat cells. In addition, they found that significant enhancement of expression of the nuclear proto-oncogene c-fos was closely associated with expression of p40{sup tax}. Continuous enhancement in the level of c-fos mRNA was observed in the presence of p40{sup tax}. These results suggest that (i) in addition to the interleukin-2-interleukin-2 receptor system, cellular genes such as c-fos, which regulate normal T-cell growth, are also activated directly or indirectly by p40{sup tax} and (ii) p40{sup tax}-induced modulation of gene expression plays a crucial role in T-cell transformation by HTLV-I.

  8. Induction of c-fos mRNA expression in an in vitro hippocampal slice model of adult rats after kainate but not gamma-aminobutyric acid or bicuculline treatment.

    PubMed

    Massamiri, T; Khrestchatisky, M; Ben-Ari, Y

    1994-01-17

    Levels of gene expression following in vitro treatment of rat hippocampal slices with kainate, gamma-aminobutyric acid (GABA), or bicuculline were measured by the reverse transcription-coupled polymerase chain reaction method. Following a short-term exposure to kainate, c-fos gene expression was induced by 12-fold in the adult, but not the newborn, hippocampus. Under the same experimental conditions, zifl268 and brain-derived neurotrophic factor (BDNF) gene expression were unchanged. Our results also demonstrate a lack of induction of c-fos, zifl268 and BDNF after short-time treatment of either adult or newborn hippocampal slices with GABA or bicuculline. The relevance of the differential induction of gene expression in the adult and newborn in an in vitro hippocampal slice model as compared to previously described in vivo models is discussed.

  9. Chemical divisions in the medial geniculate body and surrounding paralaminar nuclei of the rat: quantitative comparison of cell density, NADPH diaphorase, acetyl cholin esterase and basal expression of c-fos.

    PubMed

    Olucha-Bordonau, Francisco E; Pérez-Villalba, Ana; Teruel-Martí, Vicent; Ruiz-Torner, Amparo

    2004-11-01

    Quantitative methods of cell density, the intensities of both acetyl cholinesterase (AChE) and NADPH diaphorase (NADPHd), as well as the basal expression of c-fos, have been carried out in order to study the anatomical divisions of the medial geniculate body (MGB) and the group of nuclei located ventromedially to the MGB called the paralaminar complex (PL). The MGB was composed of the dorsal (MGd), and the ventral (MGv) divisions. We included the medial, or the magnocellular division (MGm), in the PL complex. MGd was composed of a dorsolateral (DL) core and a belt. The belt was composed of the suprageniculate (SG), the deep dorsal (DD), the caudo-medial (CM) and the caudo-dorsal (CD) nuclei. In the MGv, the basal expression of c-fos was the only way to trace a clear boundary between the ovoid (Ov) and the ventrolateral (VL) divisions. However, the marginal zone (MZ) was clearly and contrastingly different. The PL was considered to be composed of: the MGm, the posterior intralaminar nucleus (PIN), the peripeduncular nucleus (PP) and the nucleus subparafascicularis lateralis (SPFL). The MGm and the PIN share most of the chemical features, meanwhile both SPFL and PP displayed different patterns of NADPHd reactivity. The study of cell density on Giemsa stained sections confirmed main divisions of the area. AChE and NADPHd methods allowed the main MGB divisions to be discriminated. The differences between subdivisions were emphasized when cell density and c-fos activity were quantified in each nucleus. Each MGB division displayed a different pattern of c-fos activity under basal conditions. Thus, c-fos basal expression was a particular feature in each MGB or PL nucleus.

  10. Prenatal ethanol exposure increases ethanol intake and reduces c-Fos expression in infralimbic cortex of adolescent rats.

    PubMed

    Fabio, Maria Carolina; March, Samanta M; Molina, Juan Carlos; Nizhnikov, Michael E; Spear, Norman E; Pautassi, Ricardo Marcos

    2013-02-01

    Prenatal ethanol exposure significantly increases later predisposition for alcohol intake, but the mechanisms associated with this phenomenon remain hypothetical. This study analyzed (Experiment 1) ethanol intake in adolescent inbred WKAH/Hok Wistar rats prenatally exposed to ethanol (2.0g/kg) or vehicle, on gestational days 17-20. Subsequent Experiments (2, 3 and 4) tested several variables likely to underlie the effect of gestational ethanol on adolescent ethanol preference, including ethanol-induced locomotor activation (LMA), ethanol-induced emission of ultrasonic vocalizations (USVs) after exposure to a rough exteroceptive stimulus, and induction of the immediate early gene C-fos in brain areas associated with processing of reward stimuli and with the retrieval and extinction of associative learning. Prenatal ethanol induced a two-fold increase in ethanol intake. Adolescents exhibited significant ethanol-induced LMA, emitted more aversive than appetitive USVs, and postnatal ethanol administration significantly exacerbated the emission of USVs. These effects, however, were not affected by prenatal ethanol. Adolescents prenatally exposed to ethanol as fetuses exhibited reduced neural activity in infralimbic cortex (but not in prelimbic cortex or nucleus accumbens core or shell), an area that has been implicated in the extinction of drug-mediated associative memories. Ethanol metabolism was not affected by prenatal ethanol. Late gestational exposure to ethanol significantly heightened drinking in the adolescent offspring of an inbred rat strain. Ethanol-induced LMA and USVs were not associated with differential ethanol intake due to prenatal ethanol exposure. Prenatal ethanol, however, altered basal neural activity in the infralimbic prefrontal cortex. Future studies should analyze the functionality of medial prefrontal cortex after prenatal ethanol and its potential association with predisposition for heightened ethanol intake.

  11. PRENATAL ETHANOL EXPOSURE INCREASES ETHANOL INTAKE AND REDUCES C-FOS EXPRESSION IN INFRALIMBIC CORTEX OF ADOLESCENT RATS

    PubMed Central

    Fabio, Maria Carolina; March, Samanta M.; Molina, Juan Carlos; Nizhnikov, Michael E; Spear, Norman E; Pautassi, Ricardo Marcos

    2013-01-01

    Prenatal ethanol exposure significantly increases later predisposition for alcohol intake, but the mechanisms associated with this phenomenon remain hypothetical. This study analyzed (Exp. 1) ethanol intake in adolescent inbred WKAH/Hok Wistar rats prenatally exposed to ethanol (2.0 g/kg) or vehicle, on gestational days 17–20. Subsequent Experiments (2, 3 and 4) tested several variables likely to underlie the effect of gestational ethanol on adolescent ethanol preference, including ethanol-induced locomotor activation (LMA), ethanol-induced emission of ultrasonic vocalizations (USVs) after exposure to a rough exteroceptive stimulus, and induction of the immediate early gene C-fos in brain areas associated with processing of reward stimuli and with the retrieval and extinction of associative learning. Prenatal ethanol induced a two-fold increase in ethanol intake. Adolescents exhibited significant ethanol-induced LMA, emitted more aversive than appetitive USVs, and postnatal ethanol administration significantly exacerbated the emission of USVs. These effects, however, were not affected by prenatal ethanol. Adolescents prenatally exposed to ethanol as fetuses exhibited reduced neural activity in infralimbic cortex (but not in prelimbic cortex or nucleus accumbens core or shell), an area that has been implicated in the extinction of drug-mediated associative memories. Ethanol metabolism was not affected by prenatal ethanol. Late gestational exposure to ethanol significantly heightened drinking in the adolescent offspring of an inbred rat strain. Ethanol-induced LMA and USVs were not associated with differential ethanol intake due to prenatal ethanol exposure. Prenatal ethanol, however, altered basal neural activity in the infralimbic prefrontal cortex. Future studies should analyze the functionality of medial prefrontal cortex after prenatal ethanol and its potential association with predisposition for heightened ethanol intake. PMID:23266368

  12. Peptide YY directly inhibits ghrelin-activated neurons of the arcuate nucleus and reverses fasting-induced c-Fos expression.

    PubMed

    Riediger, Thomas; Bothe, Christine; Becskei, Csilla; Lutz, Thomas A

    2004-01-01

    The hypothalamic arcuate nucleus (Arc) monitors and integrates hormonal and metabolic signals involved in the maintenance of energy homeostasis. The orexigenic peptide ghrelin is secreted from the stomach during negative status of energy intake and directly activates neurons of the medial arcuate nucleus (ArcM) in rats. In contrast to ghrelin, peptide YY (PYY) is released postprandially from the gut and reduces food intake when applied peripherally. Neurons in the ArcM express ghrelin receptors and neuropeptide Y receptors. Thus, PYY may inhibit feeding by acting on ghrelin-sensitive Arc neurons. Using extracellular recordings, we (1) characterized the effects of PYY on the electrical activity of ghrelin-sensitive neurons in the ArcM of rats. In order to correlate the effect of PYY on neuronal activity with the energy status, we (2) investigated the ability of PYY to reverse fasting-induced c-Fos expression in Arc neurons of mice. In addition, we (3) sought to confirm that PYY reduces food intake under our experimental conditions. Superfusion of PYY reversibly inhibited 94% of all ArcM neurons by a direct postsynaptic mechanism. The PYY-induced inhibition was dose-dependent and occurred at a threshold concentration of 10(-8)M. Consistent with the opposite effects of ghrelin and PYY on food intake, a high percentage (50%) of Arc neurons was activated by ghrelin and inhibited by PYY. In line with this inhibitory action, peripherally injected PYY partly reversed the fasting-induced c-Fos expression in Arc neurons of mice. Similarly, refeeding of food-deprived mice reversed the fasting-induced activation in the Arc. Furthermore, peripherally injected PYY reduced food intake in 12-hour fasted mice. Thus the activity of Arc neurons correlated with the feeding status and was not only reduced by feeding but also by administration of PYY in non-refed mice. In conclusion, our current observations suggest that PYY may contribute to signaling a positive status of energy intake

  13. Anxiogenic-like activity of 3,4-methylenedioxy-methamphetamine ("Ecstasy") in the social interaction test is accompanied by an increase of c-fos expression in mice amygdala.

    PubMed

    Navarro, José Francisco; Rivera, Alicia; Maldonado, Enrique; Cavas, María; de la Calle, Adelaida

    2004-03-01

    3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine popularly known as "Ecstasy." Animal studies examining acute effects of MDMA on anxiety are unclear because although an anxiolytic-like action of MDMA in different animal models of anxiety has been described, there is also substantial evidence supporting an anxiogenic-like effect of this drug. To date, several studies have examined c-fos expression following MDMA administration in rats. However, there is no information about the MDMA-induced c-fos expression in mice previously tested in an animal model of anxiety. In this study, male mice were injected with MDMA (1, 8 and 15 mg/kg ip) and assessed for changes on anxiety and for the expression of the immediate early gene c-fos in the amygdala (central, basolateral and basomedial). Anxiety was evaluated by the "social interaction test." Ten behavioral categories were recorded: body care, digging, nonsocial exploration, exploration from a distance, social investigation, threat, attack, avoidance/flee, defense/submission and immobility. As compared with the control group, mice treated with MDMA (all doses) showed a decrease in mean duration and total time spent in social investigation behaviors, whereas avoidance/flee behaviors were significantly increased after treatment with this compound (8 and 15 mg/kg). Likewise, a significant increase in c-fos expression was found in the basolateral (all doses) and central (15 mg/kg) amygdala after MDMA administration. Overall, these findings indicate that MDMA exhibits an anxiogenic-like profile in the social interaction test in mice, and that central and basolateral amygdala might be involved in these anxiogenic-like effects of the drug.

  14. Immunohistochemical analysis of the expression of cellular transcription NFκB (p65), AP-1 (c-Fos and c-Jun), and JAK/STAT in leprosy.

    PubMed

    Silva, Luciana Mota; Hirai, Kelly Emi; de Sousa, Jorge Rodrigues; de Souza, Juarez; Fuzii, Hellen Thais; Dias, Leonidas Braga; Carneiro, Francisca Regina Oliveira; de Souza Aarão, Tinara Leila; Quaresma, Juarez Antonio Simões

    2015-05-01

    Leprosy is a disease whose clinical spectrum depends on the cytokine patterns produced during the early stages of the immune response. The main objective of this study was to describe the activation pattern of cellular transcription factors and to correlate these factors with the clinical forms of leprosy. Skin samples were obtained from 16 patients with the tuberculoid (TT) form and 14 with the lepromatous (LL) form. The histologic sections were immunostained with anti-c-Fos and anti-c-Jun monoclonal antibodies for investigation of AP-1, anti-NFκB p65 for the study of NFκB, and anti-JAK2, STAT1, STAT3, and STAT4 for investigation of the JAK/STAT pathway. Cells expressing STAT1 were more frequent in the TT form than in LL lesions (P = .0096), in agreement with the protective immunity provided by IFN-γ. STAT4 was also more highly expressed in the TT form than in the LL form (P = .0098). This transcription factor is essential for the development of a Th1 response because it is associated with interleukin-12. NFκB (p65) and STAT4 expression in the TT form showed a strong and significant correlation (r = 0.7556 and P = .0007). A moderate and significant correlation was observed between JAK2 and STAT4 in the TT form (r = 0.6637 and P = .0051), with these factors responding to interleukin-12 in Th1 profiles. The results suggest that STAT1, JAK2, and NFκB, together with STAT4, contribute to the development of cell-mediated immunity, which is able to contain the proliferation of Mycobacterium leprae.

  15. Vesicular acetylcholine transporter knock down-mice are more susceptible to inflammation, c-Fos expression and sickness behavior induced by lipopolysaccharide.

    PubMed

    Leite, Hércules Ribeiro; Oliveira-Lima, Onésia Cristina de; Pereira, Luciana de Melo; Oliveira, Vinícius Elias de Moura; Prado, Vania Ferreira; Prado, Marco Antônio Máximo; Pereira, Grace Schenatto; Massensini, André Ricardo

    2016-10-01

    In addition to the well-known functions as a neurotransmitter, acetylcholine (ACh) can modulate of the immune system. Nonetheless, how endogenous ACh release inflammatory responses is still not clear. To address this question, we took advantage of an animal model with a decreased ACh release due a reduction (knockdown) in vesicular acetylcholine transporter (VAChT) expression (VAChT-KD(HOM)). These animals were challenged with lipopolysaccharide (LPS). Afterwards, we evaluated sickness behavior and quantified systemic and cerebral inflammation as well as neuronal activation in the dorsal vagal complex (DVC). VAChT-KD(HOM) mice that were injected with LPS (10mg/kg) showed increased mortality rate as compared to control mice. In line with this result, a low dose of LPS (0.1mg/kg) increased the levels of pro-inflammatory (TNF-α, IL-1β, and IL-6) and anti-inflammatory (IL-10) cytokines in the spleen and brain of VAChT-KD(HOM) mice in comparison with controls. Similarly, serum levels of TNF-α and IL-6 were increased in VAChT-KD(HOM) mice. This excessive cytokine production was completely prevented by administration of a nicotinic receptor agonist (0.4mg/kg) prior to the LPS injection. Three hours after the LPS injection, c-Fos expression increased in the DVC region of VAChT-KD(HOM) mice compared to controls. In addition, VAChT-KD(HOM) mice showed behavioral changes such as lowered locomotor and exploratory activity and reduced social interaction after the LPS challenge, when compared to control mice. Taken together, our results show that the decreased ability to release ACh exacerbates systemic and cerebral inflammation and promotes neural activation and behavioral changes induced by LPS. In conclusion, our findings support the notion that activity of cholinergic pathways, which can be modulated by VAChT expression, controls inflammatory and neural responses to LPS challenge.

  16. Ginsenosides Have a Suppressive Effect on c-Fos Expression in Brain and Reduce Cardiovascular Responses Increased by Noxious Stimulation to the Rat Tooth

    PubMed Central

    Jung, Ji-Yeon; Seong, Kyung-Joo; Moon, In-Ohk; Cho, Jin-Hyoung; Kim, Sun-Hun

    2013-01-01

    The purpose of this study is to investigate the antinociceptive effects of ginsenosides on toothache. c-Fos immunoreactive (IR) neurons were examined after noxious intrapulpal stimulation (NS) by intrapulpal injection of 2 M KCl into upper and lower incisor pulps exposed by bone cutter in Sprague Dawley rats. The number of Fos-IR neurons was increased in the trigeminal subnucleus caudalis (Vc) and the transitional region between Vc and subnucleus interpolaris (Vi) by NS to tooth. The intradental NS raised arterial blood pressure (BP) and heart rate (HR). The number of Fos-IR neurons was also enhanced in thalamic ventral posteromedial nucleus (VPMN) and centrolateral nucleus (CLN) by NS to tooth. The intradental NS increased the number of Fos-IR neurons in the nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM), hypothalamic supraoptic nucleus (SON) and paraventricular nucleus (PVN), central cardiovascular regulation centers. Ginsenosides reduced the number of c-Fos-IR increased by NS to tooth in the trigeminal Vc and thalamic VPMN and CLN. Naloxone, an opioid antagonist, did not block the effect of ginsenoside on the number of Fos-IR neurons enhanced by NS to tooth in the trigeminal Vc and thalamic VPMN and CLN. Ginsenosides ameliorated arterial BP and HR raised by NS to tooth and reduced the number of Fos-IR neurons increased by NS to tooth in the NTS, RVLM, hypothalamic SON, and PVN. These results suggest that ginsenosides have an antinociceptive effect on toothache through non-opioid system and attenuates BP and HR increased by NS to tooth. PMID:23626473

  17. Brain development is impaired in c-fos -/- mice.

    PubMed

    Velazquez, Fabiola N; Prucca, César G; Etienne, Olivier; D'Astolfo, Diego S; Silvestre, David C; Boussin, François D; Caputto, Beatriz L

    2015-07-10

    c-Fos is a proto-oncogene involved in diverse cellular functions. Its deregulation has been associated to abnormal development and oncogenic progression. c-fos-/- mice are viable but present a reduction in their body weight and brain size. We examined the importance of c-Fos during neocortex development at 13.5, 14.5 and 16.5 days of gestation. At E14.5, neocortex thickness, apoptosis, mitosis and expression of markers along the different stages of Neural Stem Progenitor Cells (NSPCs) differentiation in c-fos-/- and wild-type mice were analyzed. A ~15% reduction in the neocortex thickness of c-fos-/- embryos was observed which correlates with a decrease in the number of differentiated cells and an increase in apoptosis at the ventricular zone. No difference in mitosis rate was observed, although the mitotic angle was predominantly vertical in c-fos-/- embryos, suggesting a reduced trend of NSPCs to differentiate. At E13.5, changes in differentiation markers start to be apparent and are still clearly observed at E16.5. A tendency of more AP-1/DNA complexes present in nuclear extracts of cerebral cortex from c-fos-/- embryos with no differences in the lipid synthesis activity was found. These results suggest that c-Fos is involved in the normal development of NSPCs by means of its AP-1 activity.

  18. Osteoblasts are target cells for transformation in c-fos transgenic mice

    PubMed Central

    1993-01-01

    We have generated transgenic mice expressing the proto-oncogene c-fos from an H-2Kb class I MHC promoter as a tool to identify and isolate cell populations which are sensitive to altered levels of Fos protein. All homozygous H2-c-fosLTR mice develop osteosarcomas with a short latency period. This phenotype is specific for c-fos as transgenic mice expressing the fos- and jun-related genes, fosB and c-jun, from the same regulatory elements do not develop any pathology despite high expression in bone tissues. The c-fos transgene is not expressed during embryogenesis but is expressed after birth in bone tissues before the onset of tumor formation, specifically in putative preosteoblasts, bone- forming osteoblasts, osteocytes, as well as in osteoblastic cells present within the tumors. Primary and clonal cell lines established from c-fos-induced tumors expressed high levels of exogenous c-fos as well as the bone cell marker genes, type I collagen, alkaline phosphatase, and osteopontin/2ar. In contrast, osteocalcin/BGP expression was either low or absent. All cell lines were tumorigenic in vivo, some of which gave rise to osteosarcomas, expressing exogenous c- fos mRNA, and Fos protein in osteoblastic cells. Detailed analysis of one osteogenic cell line, P1, and several P1-derived clonal cell lines indicated that bone-forming osteoblastic cells were transformed by Fos. The regulation of osteocalcin/BGP and alkaline phosphatase gene expression by 1,25-dihydroxyvitamin D3 was abrogated in P1-derived clonal cells, whereas glucocorticoid responsiveness was unaltered. These results suggest that high levels of Fos perturb the normal growth control of osteoblastic cells and exert specific effects on the expression of the osteoblast phenotype. PMID:8335693

  19. Bi-directional effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on fear-related behavior and c-Fos expression after fear conditioning in rats

    PubMed Central

    Meloni, Edward G.; Venkataraman, Archana; Donahue, Rachel J.; Carlezon, William A.

    2015-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is implicated in stress regulation and learning and memory. PACAP has neuromodulatory actions on brain structures within the limbic system that could contribute to its acute and persistent effects in animal models of stress and anxiety-like behavior. Here, male Sprague-Dawley rats were implanted with intracerebroventricular (ICV) cannula for infusion of PACAP-38 (0.5, 1, or 1.5 ug) or vehicle followed 30 min later by fear conditioning. Freezing was measured early (1, 4, and 7days) or following a delay (7, 10, and 13 days)after conditioning. PACAP (1.5 μg) produced a bi-phasic response in freezing behavior across test days: relative to controls, PACAP-treated rats showed a reduction in freezing when tested 1 or 7 Days after fear conditioning that evolved into a significant elevation in freezing by the third test session in the early, but not delayed, group. Corticosterone (CORT) levels were significantly elevated in PACAP-treated rats following fear conditioning, but not at the time of testing (Day 1). Brain c-Fos expression revealed PACAP-dependent alterations within, as well as outside of, areas typically implicated in fear conditioning. Our findings raise the possibility that PACAP disrupts fear memory consolidation by altering synaptic plasticity within neurocircuits normally responsible for encoding fear-related cues, producing a type of dissociation or peritraumatic amnesia often seen in people early after exposure to a traumatic event. However, fear memories are retained such that repeated testing and memory reactivation (e.g. re-experiencing) causes the freezing response to emerge and persist at elevated levels. PACAP systems may represent an axis on which stress and exposure to trauma converge to promote maladaptive behavioral responses characteristic of psychiatric illnesses such as post-traumatic stress disorder (PTSD). PMID:26590791

  20. Fos Protein Expression in Olfactory-Related Brain Areas after Learning and after Reactivation of a Slowly Acquired Olfactory Discrimination Task in the Rat

    ERIC Educational Resources Information Center

    Roullet, Florence; Lienard, Fabienne; Datiche, Frederique; Cattarelli, Martine

    2005-01-01

    Fos protein immunodetection was used to investigate the neuronal activation elicited in some olfactory-related areas after either learning of an olfactory discrimination task or its reactivation 10 d later. Trained rats (T) progressively acquired the association between one odor of a pair and water-reward in a four-arm maze. Two groups of…

  1. Effects of acute heat exposure on prosencephalic c-Fos expression in normohydrated, water-deprived and salt-loaded rats.

    PubMed

    Santana, Rejane; de De Castro E Silva, Emilio; Reis de Oliveira, Irismar; Fregoneze, Josmara B

    2007-04-13

    In the present study, the distribution pattern of c-Fos protein immunoreactivity (Fos-IR) in prosencephalic areas of the brain involved in thermoregulatory and osmoregulatory responses was investigated, in rats exposed or not exposed to a hyperthermic environment, under three different conditions: normohydration, dehydration induced by water deprivation and hyperosmolarity induced by an acute intragastric salt load. Normohydrated, water-deprived or salt-loaded male Wistar rats (270+/-30 g) were submitted or not to acute heat exposure (33 degrees C for 45 min). A separate group of animals was submitted to the same experimental protocol and had blood samples collected before and after the heating period to measure serum osmolarity and sodium. The brains were processed for c-Fos immunohistochemistry using the avidin-biotin peroxidase method. After analyzing Fos-IR in the brains of animals in the present study, three different types of prosencephalic areas were identified: (1) those that respond to hydrational and to heat conditions, with an interaction between these two factors (PaMP and SON); (2) those that respond to hydrational and to heat conditions, but with no interaction between these factors (MnPO, LSV and OVLT); and (3) those that respond only to hydrational status (SFO and PaLM).

  2. Fos protein expression in olfactory-related brain areas after learning and after reactivation of a slowly acquired olfactory discrimination task in the rat.

    PubMed

    Roullet, Florence; Liénard, Fabienne; Datiche, Frédérique; Cattarelli, Martine

    2005-01-01

    Fos protein immunodetection was used to investigate the neuronal activation elicited in some olfactory-related areas after either learning of an olfactory discrimination task or its reactivation 10 d later. Trained rats (T) progressively acquired the association between one odor of a pair and water-reward in a four-arm maze. Two groups of pseudotrained rats were used: PO rats were not water restricted and were submitted to the olfactory stimuli in the maze without any reinforcement, whereas PW rats were water-deprived and systematically received water in the maze without any odorous stimulation. When the discrimination task was well mastered, a significantly lower Fos immunoreactivity was observed in T rats compared to PW and PO rats in most of the analyzed brain areas, which could reflect the post-acquisition consolidation process. Following memory reactivation, differences in Fos immunoreactivity between trained and some pseudotrained rats were found in the anterior part of piriform cortex, CA3, and orbitofrontal cortex. We also observed that Fos labeling was significantly higher in trained rats after memory reactivation than after acquisition of the olfactory task in most of the brain areas examined. Our results support the assumption of a differential involvement of neuronal networks after either learning or reactivation of an olfactory discrimination task.

  3. Reciprocal Patterns of c-Fos Expression in the Medial Prefrontal Cortex and Amygdala after Extinction and Renewal of Conditioned Fear

    ERIC Educational Resources Information Center

    Knapska, Ewelina; Maren, Stephen

    2009-01-01

    After extinction of conditioned fear, memory for the conditioning and extinction experiences becomes context dependent. Fear is suppressed in the extinction context, but renews in other contexts. This study characterizes the neural circuitry underlying the context-dependent retrieval of extinguished fear memories using c-Fos immunohistochemistry.…

  4. TMJ inflammation increases Fos expression in the nucleus raphe magnus induced by subsequent formalin injection of the masseter or hindpaw of rats.

    PubMed

    Oh, Sang-Hoon; Imbe, Hiroki; Iwai-Liao, Yasutomo

    2006-08-01

    The study was designed to examine the effect of persistent temporomandibular joint (TMJ) inflammation on neuronal activation in the descending pain modulatory system in response to noxious stimulus. Formalin was injected into the left masseter muscle or hindpaw of rats 10 days after injection of the left TMJ with saline or complete Freund's adjuvant (CFA). The results showed that 10-day persistent TMJ inflammation (induced by CFA) alone did not induce a significant increase in Fos-like immunoreactive (Fos-LI) neurons in the rostral ventromedial medulla (RVM) or locus coeruleus (LC), but that formalin injection of the masseter muscle or hindpaw induced a significant increase in Fos-LI neurons in the RVM and LC of rats with and without TMJ inflammation (P < 0.05). However, persistent TMJ inflammation significantly increased Fos-LI neurons in the nucleus raphe magnus (NRM) induced by subsequent formalin injection of the masseter muscle and hindpaw (70.2% increase and 53.8% increase, respectively, over the control TMJ-saline-injected rats; P < 0.05). The results suggest that persistent TMJ inflammation increases neuronal activity, in particularly in the NRM, by the plastic change of the descending pain modulatory system after ipsilateral application of a noxious stimulus to either orofacial area or a spatially remote body area.

  5. Ionic conditions modulate stimulus-induced capacitance changes in isolated neurohypophysial terminals of the rat.

    PubMed

    Marrero, Héctor G; Lemos, José R

    2010-01-15

    Peptidergic nerve terminals of the neurohypophysis (NH) secrete both oxytocin and vasopressin upon stimulation with peptide-specific bursts of action potentials from magnocellular neurons. These bursts vary in both frequency and action potential duration and also induce in situ ionic changes both inside and outside the terminals in the NH. These temporary effects include the increase of external potassium and decrease of external calcium, as well as the increase in internal sodium and chloride concentrations. In order to determine any mechanism of action that these ionic changes might have on secretion, stimulus-induced capacitance recordings were performed on isolated terminals of the NH using action potential burst patterns of varying frequency and action potential width. The results indicate that in NH terminals: (1) increased internal chloride concentration improves the efficiency of action potential-induced capacitance changes, (2) increasing external potassium increases stimulus-induced capacitance changes, (3) decreasing external calcium decreases the capacitance induced by low frequency broadened action potentials, while no capacitance change is observed with high frequency un-broadened action potentials, and (4) increasing internal sodium increases the capacitance change induced by low frequency bursts of broadened action potentials, more than for high frequency bursts of narrow action potentials. These results are consistent with previous models of stimulus-induced secretion, where optimal secretory efficacy is determined by particular characteristics of action potentials within a burst. Our results suggest that positive effects of increased internal sodium and external potassium during a burst may serve as a compensatory mechanism for secretion, counterbalancing the negative effects of reduced external calcium. In this view, high frequency un-broadened action potentials (initial burst phase) would condition the terminals by increasing internal sodium for

  6. Interleukin-1beta up-regulates the expression of thrombopoietin and transcription factors c-Jun, c-Fos, GATA-1, and NF-E2 in megakaryocytic cells.

    PubMed

    Chuen, Carmen Ka Yee; Li, Karen; Yang, Mo; Fok, Tai Fai; Li, Chi Kong; Chui, Cecilia Mei Yan; Yuen, Patrick Man Pan

    2004-02-01

    The multifunctional cytokine interleukin-1beta (IL-1beta) plays a central role in the body's immune and inflammatory responses. The mechanism of IL-1beta on thrombocytosis and megakaryocytopoiesis has remained controversial. In previous reports, we have demonstrated the expression of IL-1 receptors (IL-1RI and IL-1RII) and enhancing effects of IL-1beta on primary human megakaryocytic (MK) cells. In this study, we investigated the possible direct effects of IL-1beta on the expression of thrombopoietin (TPO) and transcription factors c-Jun, c-Fos, GATA-1, and p45 nuclear factor-E2 (NF-E2) in MK cell lines CHRF and Meg-01. Our results demonstrated that IL-1beta up-regulated messenger RNA (mRNA) and protein expressions of these transcription factors in a dose- and time-dependent manner. In CHRF cells, mRNA: c-Jun [3.4-fold, peaked at 15 minutes], c-Fos [4.2-fold, 15 minutes], GATA-1 [4.0-fold, 60 minutes], NF-E2 [3.2-fold, 120 minutes] and protein expression: c-Jun [3.0-fold, 30 minutes], c-Fos [1.7-fold, 30 minutes], GATA-1 [11.5-fold, 60 minutes], NF-E2 [12.5-fold, 120 minutes] were evidently enhanced after treatment with IL-1beta. The response to IL-1beta was consistent in the total cell and nuclear extracts and was significantly reduced by pretreatment with actinomycin D or cycloheximide. An IL-1-receptor antagonist (IL-1RA) inhibited the stimulatory effects of IL-1beta on these transcription factors by as much as 78%. TPO expression was increased by more than 9.9-fold on stimulation with IL-1beta. A TPO-neutralizing antibody did not significantly reduce the effects of IL-1beta. We conclude that IL-1beta up-regulates the expression of TPO, c-Jun, c-Fos, GATA-1, and NF-E2 in MK cells. The mechanism might be mediated by IL-1beta receptors and require transcription or protein synthesis. The direct involvement of IL-1beta in the MK lineage may provide an explanation for the phenomenon of thrombocytosis during inflammatory responses.

  7. Long-lasting c-fos and NGF mRNA expressions and loss of perikaryal parvalbumin immunoreactivity in the development of epileptogenesis after ethacrynic acid-induced seizure.

    PubMed

    Suzukawa, J; Omori, K; Okugawa, G; Fujiseki, Y; Heizmann, C W; Inagaki, C

    1999-07-10

    A single cerebroventricular injection of ethacrynic acid (EA), a Cl(-)-ATPase inhibitor, induces generalized tonic-clonic convulsions in mice. To clarify whether such convulsive stimulus triggers a long-lasting rearrangement of the neural circuitry culminating in seizure susceptibility, we examined molecular, cellular and behavioral changes following the EA-induced seizure. The expression of immediate early gene c-fos mRNA as an index for cellular activation increased biphasically, with an early transient increase at 60 min and a late prolonged increase on the 10th to 14th day post-EA administration, most remarkably in the hippocampus and pyriform cortex. On the 14th day post-EA seizure, subconvulsive dose of kainic acid (5-17.5 mg/kg) caused severe (stage 5) seizure in 77% of the mice, with 70% mortality. In addition, the expression of nerve growth factor (NGF) also showed biphasic increases with close spatiotemporal correlation with c-fos expression. Moreover, the number of cell somata and the density of axon fibers of parvalbumin (PARV)-positive cells, a subpopulation of GABAergic interneurons, decreased in area dentata, CA1 and CA3 on the 7th and 14th day post-EA seizure. In area dentata and CA1, the density of glutamic acid decarboxylase (GAD)-positive cells also decreased on the 14th day. Thus, the transient EA-induced seizures appear to develop seizure susceptibility by causing damage of a subpopulation of inhibitory interneurons along with increases in the expression of c-fos and NGF in limbic structures.

  8. FosB Null Mutant Mice Show Enhanced Methamphetamine Neurotoxicity: Potential Involvement of FosB in Intracellular Feedback Signaling and Astroglial Function

    PubMed Central

    Kuroda, Kumi O; Ornthanalai, Veravej G; Kato, Tadafumi; Murphy, Niall P

    2010-01-01

    Previous studies show that (1) two members of fos family transcription factors, c-Fos and FosB, are induced in frontal brain regions by methamphetamine; (2) null mutation of c-Fos exacerbates methamphetamine-induced neurotoxicity; and (3) null mutation of FosB enhances behavioral responses to cocaine. Here we sought a role of FosB in responses to methamphetamine by studying FosB null mutant (−/−) mice. After a 10 mg/kg methamphetamine injection, FosB(−/−) mice were more prone to self-injury. Concomitantly, the intracellular feedback regulators of Sprouty and Rad-Gem-Kir (RGK) family transcripts had lower expression profiles in the frontoparietal cortex and striatum of the FosB(−/−) mice. Three days after administration of four 10 mg/kg methamphetamine injections, the frontoparietal cortex and striatum of FosB(−/−) mice contained more degenerated neurons as determined by Fluoro-Jade B staining. The abundance of the small neutral amino acids, serine, alanine, and glycine, was lower and/or was poorly induced after methamphetamine administration in the frontoparietal cortex and striatum of FosB(−/−) mice. In addition, methamphetamine-treated FosB(−/−) frontoparietal and piriform cortices showed more extravasation of immunoglobulin, which is indicative of blood–brain barrier dysfunction. Methamphetamine-induced hyperthermia, brain dopamine content, and loss of tyrosine hydroxylase immunoreactivity in the striatum, however, were not different between genotypes. These data indicate that FosB is involved in thermoregulation-independent protective functions against methamphetamine neurotoxicity in postsynaptic neurons. Our findings suggest two possible mechanisms of FosB-mediated neuroprotection: one is induction of negative feedback regulation within postsynaptic neurons through Sprouty and RGK. Another is supporting astroglial function such as maintenance of the blood–brain barrier, and metabolism of serine and glycine, which are important

  9. FosB null mutant mice show enhanced methamphetamine neurotoxicity: potential involvement of FosB in intracellular feedback signaling and astroglial function.

    PubMed

    Kuroda, Kumi O; Ornthanalai, Veravej G; Kato, Tadafumi; Murphy, Niall P

    2010-02-01

    Previous studies show that (1) two members of fos family transcription factors, c-Fos and FosB, are induced in frontal brain regions by methamphetamine; (2) null mutation of c-Fos exacerbates methamphetamine-induced neurotoxicity; and (3) null mutation of FosB enhances behavioral responses to cocaine. Here we sought a role of FosB in responses to methamphetamine by studying FosB null mutant (-/-) mice. After a 10 mg/kg methamphetamine injection, FosB(-/-) mice were more prone to self-injury. Concomitantly, the intracellular feedback regulators of Sprouty and Rad-Gem-Kir (RGK) family transcripts had lower expression profiles in the frontoparietal cortex and striatum of the FosB(-/-) mice. Three days after administration of four 10 mg/kg methamphetamine injections, the frontoparietal cortex and striatum of FosB(-/-) mice contained more degenerated neurons as determined by Fluoro-Jade B staining. The abundance of the small neutral amino acids, serine, alanine, and glycine, was lower and/or was poorly induced after methamphetamine administration in the frontoparietal cortex and striatum of FosB(-/-) mice. In addition, methamphetamine-treated FosB(-/-) frontoparietal and piriform cortices showed more extravasation of immunoglobulin, which is indicative of blood-brain barrier dysfunction. Methamphetamine-induced hyperthermia, brain dopamine content, and loss of tyrosine hydroxylase immunoreactivity in the striatum, however, were not different between genotypes. These data indicate that FosB is involved in thermoregulation-independent protective functions against methamphetamine neurotoxicity in postsynaptic neurons. Our findings suggest two possible mechanisms of FosB-mediated neuroprotection: one is induction of negative feedback regulation within postsynaptic neurons through Sprouty and RGK. Another is supporting astroglial function such as maintenance of the blood-brain barrier, and metabolism of serine and glycine, which are important glial modulators of nerve cells.

  10. Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs): an intriguing EEG phenomenon.

    PubMed

    Silveira, Mariana Ribeiro Marcondes da; Andrade, Joaquina; Garzon, Eliana

    2013-12-01

    SIRPIDs, an acronym for stimulus-induced rhythmic, periodic, or ictal discharges, were first named in 2004. This is a pattern observed in continuous electroencephalogram (CEEG) consistently elicited by stimulation in comatose patients. The pathophysiology of SIRPIDs probably involves dysregulation of subcortico-cortical projections, particularly thalamocortical circuit, in a markedly abnormal brain with hyperexci-table cortex. This may explain some studies found an association of prolonged periodic epileptiform discharges (PEDs) activity and a higher incidence of concurrent electrographic seizures and SIRPIDs. An association of SIRPIDs and poor prognosis has already been described. However, it is not yet possible to assert whether these discharges can cause neuronal injury or if they are simply a marker of severe brain injury. Objective of this paper is to review clinical relevance and pathophysiology of SIRPIDs, as well as its role as a brain response in the critically ill patient.

  11. Stimulus-induced myoclonus treated effectively with clonazepam in genetically confirmed Coffin–Lowry syndrome☆

    PubMed Central

    Arslan, Elif Acar; Ceylaner, Serdar; Turanlı, Güzide

    2014-01-01

    Purpose Coffin–Lowry syndrome (CLS) is a rare X-linked semidominant syndromic genetic disorder that is characterized by typical facial and radiologic findings, psychomotor and growth retardation, and various skeletal anomalies. A distinctive paroxysmal disorder called stimulus-bound myoclonus is clinically heterogeneous and is generally characterized by a sudden loss of muscle tone that is regained within a few seconds and is induced by sudden auditory or tactile stimulus. As the pathophysiology of stimulus-induced drop episodes (SIDEs) is not well understood, there is no definite therapy for those episodes. Methods We report a 15-year-old female with stimulus-induced drop episodes occurring many times a day that resulted in failure to perform her daily activities. Because her SIDEs were misdiagnosed as atonic seizures, she was treated with several antiepileptic drugs, including valproic acid, levetiracetam, lamotrigine, primidone, carbamazepine, and clobazam. Results We realized that her clinical and radiological findings, together with SIDEs, are compatible with Coffin–Lowry syndrome. All of her medications were discontinued following the diagnosis of SIDE, and she was started on clonazepam. After treatment, she became more independent and was able to perform her daily activities. Subsequently, her episodes decreased from 3 times a day to 1–2 times a month. Sodium oxybate and fluoxetine were added to the treatment protocol without remarkable improvement. Her genetic analysis revealed a heterozygous variation of CLS. Conclusion We conclude that SIDE should be included in a differential diagnosis of epileptic seizures in patients with CLS and that clonazepam is an effective choice in the treatment of SIDEs. PMID:25667906

  12. C-Fos Regulation by the MAPK and PKC Pathways in Intervertebral Disc Cells

    PubMed Central

    Yokoyama, Katsuya; Hiyama, Akihiko; Arai, Fumiyuki; Nukaga, Tadashi; Sakai, Daisuke; Mochida, Joji

    2013-01-01

    Background The gene encoding c-fos is an important factor in the pathogenesis of joint disease in patients with osteoarthritis. However, it is unknown whether the signal mechanism of c-fos acts in intervertebral disc (IVD) cells. We investigated whether c-fos is activated in relation to mitogen-activated protein kinases (MAPKs) and the protein kinase C (PKC) pathway in nucleus pulposus (NP) cells. Methodology/Results Reverse transcription-polymerase chain reaction and western blotting analyses were used to measure the expression of c-fos in rat IVD cells. Transfections were performed to determine the effects of c-fos on target gene activity. The effect of c-fos protein expression was examined in transfection experiments and in a 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide cell viability assay. Phorbol 12-myristate 13-acetate (PMA), the most commonly used phorbol ester, binds to and activates protein kinase C (PKC), causing a wide range of effects in cells and tissues. PMA induced the expression of c-fos gene transcription and protein expression, and led to activation of the MAPK pathways in NP cells. The c-fos promoter was suppressed completely in the presence of the MAPK inhibitor PD98059, an inhibitor of the MEK/ERK kinase cascade, but not in the presence of SKF86002, SB202190, or SP600125. The effects of the PKC pathway on the transcriptional activity of the c-fos were evaluated. PKCγ and PKCδ suppressed the promoter activity of c-fos. Treatment with c-fos inhibited aggrecan and Col2 promoter activities and the expression of these genes in NP cells. Conclusions This study demonstrated, for the first time, that the MAPK and PKC pathways had opposing effects on the regulation of c-fos in NP cells. Thus, the expression of c-fos can be suppressed in the extracellular matrix of NP cells. PMID:24023832

  13. c-FOS suppresses ovarian cancer progression by changing adhesion

    PubMed Central

    Oliveira-Ferrer, L; Rößler, K; Haustein, V; Schröder, C; Wicklein, D; Maltseva, D; Khaustova, N; Samatov, T; Tonevitsky, A; Mahner, S; Jänicke, F; Schumacher, U; Milde-Langosch, K

    2014-01-01

    Background: C-Fos was initially described as oncogene, but was associated with favourable prognosis in ovarian cancer (OvCa) patients. The molecular and functional aspects underlying this effect are still unknown. Methods: Using stable transfectants of SKOV3 and OVCAR8 cells, proliferation, migration, invasion and apoptotic potential of c-FOS-overexpressing clones and controls were compared. Adherence to components of the extracellular matrix was analysed in static assays, and adhesion to E-selectin, endothelial and mesothelial cells in dynamic flow assays. The effect of c-FOS in vivo was studied after intraperitoneal injection of SKOV3 clones into SCID mice, and changes in gene expression were determined by microarray analysis. Results: Tumour growth after injection into SCID mice was strongly delayed by c-FOS overexpression, with reduction of lung metastases and circulating tumour cells. In vitro, c-FOS had only weak influence on proliferation and migration, but was strongly pro-apoptotic. Adhesion to components of the extracellular matrix (collagen I, IV) and to E-selectin, endothelial and mesothelial cells was significantly reduced in c-FOS-overexpressing OvCa cells. This corresponds to deregulation of adhesion proteins and glycosylation enzymes in microarray analysis. Conclusion: In addition to its known pro-apoptotic effect, c-FOS might influence OvCa progression by changing the adhesion of OvCa cells to peritoneal surfaces. PMID:24322891

  14. Medial prefrontal cortical injections of c-fos antisense oligonucleotides transiently lower c-Fos protein and mimic amphetamine withdrawal behaviours.

    PubMed

    Persico, A M; Schindler, C W; Davis, S C; Ambrosio, E; Uhl, G R

    1998-02-01

    Prefrontal cerebral cortical areas display decreased expression of several transcription factor/immediate-early genes, including c-fos, during amphetamine withdrawal. Antisense strategies can help to test possible roles for this prefrontal c-fos down-regulation in the behavioural correlates of amphetamine withdrawal. Medial prefrontal cortical injections delivering 1.7 nmoles of anti c-fos oligonucleotides revealed an approximately 3 h half-life for phosphothioate and a 15 min half-life for phosphodiester oligonucleotides. Antisense phosphothioates complementary to the c-fos translational start site reduced levels of c-Fos protein, while exerting modest and variable effects on c-fos messenger RNA levels. Neither missense phosphorothioate nor antisense phosphodiester oligonucleotides significantly reduced levels of either c-fos messenger RNA or protein. Animals injected with anti c-fos phosphothioate oligonucleotides into the medial prefrontal cortex displayed marked reductions in linear locomotor activity and repetitive movements measured in a novel environment, effects not seen when missense oligonucleotides were used or when animals were accustomed to the activity monitor prior to antisense oligonucleotide injection. Behavioural changes produced by prefrontal cortical injections of c-fos antisense oligonucleotides closely mimic alterations recorded during amphetamine withdrawal. Prefrontal c-fos could thus conceivably play roles in the neurobiological underpinnings of psychostimulant withdrawal and of responses to stressors such as exposure to novel environments.

  15. Brief pup exposure induces Fos expression in the lateral habenula and serotonergic caudal dorsal raphe nucleus of paternally experienced male California mice (Peromyscus californicus).

    PubMed

    de Jong, T R; Measor, K R; Chauke, M; Harris, B N; Saltzman, W

    2010-09-01

    Fathers play a substantial role in infant care in a small but significant number of mammalian species, including humans. However, the neural circuitry controlling paternal behavior is much less understood than its female counterpart. In order to characterize brain areas activated by paternal care, male California mice were separated from their female mate and litter for 3 h and then exposed to a pup or a control object (a glass pebble with the approximate size and oblong shape of a newborn pup) for 10 min. All males receiving a pup showed a strong paternal response towards it, whereas males receiving a pebble interacted with it only occasionally. Despite the clear behavioral differences, exposure to a pup did not increase Fos-like immunoreactivity (Fos-LIR) compared to a pebble in brain areas previously found to be associated with parental care, including the medial preoptic nucleus and medial bed nucleus of the stria terminalis. Pup exposure did, however, significantly increase Fos-LIR in the lateral habenula (LHb) and in predominantly serotonergic neurons in the caudal dorsal raphe nucleus (DRC), as compared to pebble exposure. Both the LHb and DRC are known to be involved in the behavioral responses to strong emotional stimuli; therefore, these areas might play a role in controlling parental behavior in male California mice.

  16. Structure, chromosome location, and expression of the mouse zinc finger gene Krox-20: multiple gene products and coregulation with the proto-oncogene c-fos.

    PubMed Central

    Chavrier, P; Janssen-Timmen, U; Mattéi, M G; Zerial, M; Bravo, R; Charnay, P

    1989-01-01

    We have analyzed the structure and the regulation of Krox-20, a mouse zinc finger-encoding gene which is transiently activated following serum stimulation of quiescent fibroblast cells in culture. The gene is localized on chromosome 10, band B5, in the mouse, and the homologous human gene also maps to chromosome 10 (region q21.1 to q22.1). Alternative splicing of the 5'-most intron of the Krox-20 gene gives rise to mRNAs encoding putative zinc finger proteins with different N termini. The first exon contains a sequence element with strong similarity to the c-fos proto-oncogene serum response element (SRE). This element can functionally substitute for the c-fos SRE, and it binds the same nuclear protein. It is probably responsible for the serum induction of Krox-20, possibly in combination with a weaker SRE located in the 5'-flanking region of the gene. Our findings suggest that c-fos, Krox-20, and a number of immediate-early serum response genes are coregulated and that the SRE and its cognate protein are essential components of this regulatory pathway. Images PMID:2496302

  17. Exposure to high- and low-light conditions in an open-field test of anxiety increases c-Fos expression in specific subdivisions of the rat basolateral amygdaloid complex.

    PubMed

    Hale, Matthew W; Bouwknecht, J Adriaan; Spiga, Francesca; Shekhar, Anantha; Lowry, Christopher A

    2006-12-11

    Anxiety states and anxiety-related behaviors appear to be regulated by a distributed and highly interconnected system of forebrain structures including the basolateral amygdaloid complex (basolateral amygdala). Despite a wealth of research examining the role of the basolateral amygdala in anxiety-related behaviors and anxiety states, the specific subdivisions of the basolateral amygdala that are involved in responses to anxiogenic stimuli have not been examined. In this study, we investigated the effects of exposure to a novel open-field environment, with either low- or high-levels of illumination, on expression of the protein product of the immediate-early gene c-Fos in subdivisions of the rat basolateral amygdala. The subdivisions studied included the lateral, ventrolateral and ventromedial parts of the lateral amygdaloid nucleus, the anterior, posterior and ventral parts of the basolateral amygdaloid nucleus and the anterior and posterior part of the basomedial amygdaloid nucleus. Small increases in the number of c-Fos-immunoreactive cells were observed in several, but not all, of the subdivisions of the basolateral amygdala studied following exposure of rats to either the high- or low-light conditions, compared to home cage or handled control groups. Open-field exposure in both the high- and low-light conditions resulted in a marked increase in c-Fos expression in the anterior part of the basolateral amygdaloid nucleus compared to either home cage or handled control groups. These findings point toward anatomical and functional heterogeneity within the basolateral amygdaloid complex and an important role of the anterior part of the basolateral amygdaloid nucleus in the neural mechanisms underlying physiological or behavioral responses to this anxiety-related stimulus.

  18. Using c-fos to study neuronal ensembles in corticostriatal circuitry of addiction

    PubMed Central

    Cruz, Fabio C.; Rubio, F. Javier; Hope, Bruce T.

    2014-01-01

    Learned associations between drugs and environment play an important role in addiction and are thought to be encoded within specific patterns of sparsely distributed neurons called neuronal ensembles. This hypothesis is supported by correlational data from in vivo electrophysiology and cellular imaging studies in relapse models in rodents. In particular, cellular imaging with the immediate early gene c-fos and its protein product Fos has been used to identify sparsely distributed neurons that were strongly activated during conditioned drug behaviors such as drug self-administration and context- and cue-induced reinstatement of drug seeking. Here we review how Fos and the c-fos promoter have been employed to demonstrate causal roles for Fos-expressing neuronal ensembles in prefrontal cortex and nucleus accumbens in conditioned drug behaviors. This work has allowed identification of unique molecular and electrophysiological alterations within Fos-expressing neuronal ensembles that may contribute to the development and expression of learned associations in addiction. PMID:25446457

  19. Accumbal FosB/DeltaFosB immunoreactivity and conditioned place preference in alcohol-preferring AA rats and alcohol-avoiding ANA rats treated repeatedly with cocaine.

    PubMed

    Marttila, Kristiina; Petteri Piepponen, T; Kiianmaa, Kalervo; Ahtee, Liisa

    2007-07-30

    Transcription factor DeltaFosB has been implicated in the psychomotor responses and rewarding effects of drugs of abuse. In the present study, we compared the effects of cocaine on the expression of DeltaFosB-like proteins by immunohistochemistry in striatal brain areas of alcohol-preferring (AA) and alcohol-avoiding (ANA) rats. Cocaine was administered using a previously verified treatment paradigm that sensitized the locomotor response to cocaine in AA but not in ANA rats. We also studied the rewarding effects of cocaine with a conditioned place preference (CPP) paradigm in both lines of rats. Cocaine treatment increased the FosB/DeltaFosB immunoreactivity (IR) in the nucleus accumbens of AA rats but not in ANA rats. In addition, after repeated saline injections the accumbal FosB/DeltaFosB IR was significantly greater in saline-injected AA rats than in ANA rats. In the caudate-putamen cocaine significantly increased FosB/DeltaFosB IR, but no differences were found between the rats of two lines. In the CPP experiment, AA rats treated with cocaine 2.5 mg/kg preferred the cocaine-associated compartment, in contrast to ANA rats, which did not show such a preference. In conclusion, our findings show that AA rats are more sensitive to cocaine than ANA rats, and suggest that one possible mediator for this increased sensitivity could be the increased expression of fosB-derived proteins in the nucleus accumbens of AA rats.

  20. Stimulus-induced transition of clustering firings in neuronal networks with information transmission delay

    NASA Astrophysics Data System (ADS)

    Wang, Qingyun; Zhang, Honghui; Chen, Guanrong

    2013-07-01

    We study the evolution of spatiotemporal dynamics and transition of clustering firing synchronization on spiking Hodgkin-Huxley neuronal networks as information transmission delay and the periodic stimulus are varied. In particular, it is shown that the tuned information transmission delay can induce a clustering anti-phase synchronization transition with the pacemaker, where two equal clusters can alternatively synchronize in anti-phase firing. More interestingly, we show that the periodic stimulus can drive the delay-induced clustering anti-phase firing synchronization bifurcate to the collective perfect synchronization, which is routed by the complex process including collective chaotic firings and clustering out-of-phase synchronization of the neuronal networks. In addition, the periodic stimulus induced clustering firings of the spiking neuronal networks are robust to the connectivity probability of small world networks. Furthermore, the different stimulus frequency induced complexity is also investigated. We hope that the results of this paper can provide insights that could facilitate the understanding of the joint impact of information transmission delays and periodic stimulus on controlling dynamical behaviors of realistic neuronal networks.

  1. Taste aversion learning induced c-fos expression in the nucleus of the solitary tract after spontaneous flavor intake: role of the inter-stimulus interval.

    PubMed

    Mediavilla, Cristina; Bernal, Antonio; Puerto, Amadeo

    2007-09-01

    Taste aversion learning (TAL) can be induced by associating a flavor intake with the immediate or delayed (30 min) intragastric administration of a noxious substance, e.g., hypertonic NaCl. The objective of this study was to analyze the induction of c-Fos immunoreactivity in the intermediate nucleus of the solitary nucleus (iNST) after acquisition of a contiguous or delayed TAL, offering the flavor for voluntary consumption in both cases. The behavioral results obtained indicate that, although the learning was established under both experimental conditions, an increase in c-Fos induction was only produced in the group that learned by means of a non-delayed TAL. Immunohistochemical analyses revealed the participation of different brain structures in these two TAL modalities. Thus, the nucleus of the solitary tract may be involved in the TAL procedure in which voluntary flavor intake and intragastric administration of the noxious visceral stimulus are contiguous but not in delayed TAL, which would depend on other anatomical circuits that do not include the iNST.

  2. Genome-wide analysis reveals PADI4 cooperates with Elk-1 to activate c-Fos expression in breast cancer cells.

    PubMed

    Zhang, Xuesen; Gamble, Matthew J; Stadler, Sonja; Cherrington, Brian D; Causey, Corey P; Thompson, Paul R; Roberson, Mark S; Kraus, W Lee; Coonrod, Scott A

    2011-06-01

    Peptidylarginine deiminase IV (PADI4) catalyzes the conversion of positively charged arginine and methylarginine residues to neutrally charged citrulline, and this activity has been linked to the repression of a limited number of target genes. To broaden our knowledge of the regulatory potential of PADI4, we utilized chromatin immunoprecipitation coupled with promoter tiling array (ChIP-chip) analysis to more comprehensively investigate the range of PADI4 target genes across the genome in MCF-7 breast cancer cells. Results showed that PADI4 is enriched in gene promoter regions near transcription start sites (TSSs); and, surprisingly, this pattern of binding is primarily associated with actively transcribed genes. Computational analysis found potential binding sites for Elk-1, a member of the ETS oncogene family, to be highly enriched around PADI4 binding sites; and coimmunoprecipitation analysis then confirmed that Elk-1 physically associates with PADI4. To better understand how PADI4 may facilitate gene transactivation, we then show that PADI4 interacts with Elk-1 at the c-Fos promoter and that, following Epidermal Growth Factor (EGF) stimulation, PADI4 catalytic activity facilitates Elk-1 phosphorylation, histone H4 acetylation, and c-Fos transcriptional activation. These results define a novel role for PADI4 as a transcription factor co-activator.

  3. Overexpression of c-fos increases recombination frequency in human osteosarcoma cells.

    PubMed

    van den Berg, S; Rahmsdorf, H J; Herrlich, P; Kaina, B

    1993-05-01

    We have shown previously that overexpression of c-Ha-ras, v-mos or c-fos increases the spontaneous level of chromosomal aberrations and gene mutations in NIH 3T3 cells, and that reduction of the Fos protein level inhibits aberration induction by c-Ha-ras and v-mos and also by irradiation with ultraviolet light (van den Berg et al., Mol. Carcinogenesis, 4, 460-466). In order to examine whether fos is also involved in DNA recombination, thymidine kinase (tk) deficient human osteosarcoma cells containing two versions of the herpes simplex virus tk gene inactivated by base insertion were either transiently or stably transfected with various fos expression plasmids. The frequency of tk+ revertants was significantly enhanced both upon transient transfection with RSV-promoter-fos gene constructs and by stimulation of Fos synthesis in stably transfected cells harbouring an inducible metallothionein promoter-fos construct. No such increases were observed in cells transfected with plasmids containing a truncated version of c-fos. The data indicate that c-fos is involved in generating various types of genetic changes including homologous recombination; a role of c-fos in genetic instability may contribute to its action in tumor promotion and progression.

  4. Hepatocyte growth factor-stimulated renal tubular mitogenesis: effects on expression of c-myc, c-fos, c-met, VEGF and the VHL tumour-suppressor and related genes.

    PubMed Central

    Clifford, S. C.; Czapla, K.; Richards, F. M.; O'Donoghue, D. J.; Maher, E. R.

    1998-01-01

    Hepatocyte growth factor (HGF/SF) is a potent renal proximal tubular cell (PTEC) mitogen involved in renal development. HGF/SF is the functional ligand for the c-met proto-oncogene, and germline c-met mutations are associated with familial papillary renal cell carcinoma. Somatic von Hippel-Lindau disease tumour-suppressor gene (VHL) mutations are frequently detected in sporadic clear cell renal cell carcinomas (RCC), and germline VHL mutations are the commonest cause of familial clear cell RCC. pVHL binds to the positive regulatory components of the trimeric elongin (SIII) complex (elongins B and C) and has been observed to deregulate expression of the vascular endothelial growth factor (VEGF) gene. HGF/SF has similarly been reported to up-regulate expression of the VEGF gene in non-renal experimental systems. To investigate the mechanism of HGF/SF action in PTECs and, specifically, to examine potential interactions between the HGF/c-met and the VHL-mediated pathways for renal tubular growth control, we have isolated untransformed PTECs from normal kidneys, developed conditions for their culture in vitro and used these cells to investigate changes in mRNA levels of the VHL, elongin A, B and C, VEGF, c-myc, c-fos and c-met genes after HGF/SF exposure. Significant elevations in the mRNA levels of VEGF, c-myc, c-fos, c-met and elongins A, B and C, but not VHL, were detected after HGF/SF stimulation of human PTECs (P < 0.02), with a consistent order of peak levels observed over successive replicates (c-fos at 1 h, VEGF at 2-4 h, c-myc, at 4 h, followed by c-met and all three elongin subunits at 8 h). This study highlights the spectrum of changes in gene expression observed in PTECs after HGF/SF stimulation and has identified possible candidate mediators of the HGF/SF-induced mitogenic response. Our evidence would suggest that the changes in PTEC VEGF expression induced by HGF/SF are mediated by a VHL-independent pathway. Images Figure 1 PMID:9652757

  5. DeltaFosB in the nucleus accumbens is critical for reinforcing effects of sexual reward

    PubMed Central

    Pitchers, Kyle K.; Frohmader, Karla S.; Vialou, Vincent; Mouzon, Ezekiell; Nestler, Eric J.; Lehman, Michael N.; Coolen, Lique M.

    2010-01-01

    Sexual behavior in male rats is rewarding and reinforcing. However, little is known about the specific cellular and molecular mechanisms mediating sexual reward or the reinforcing effects of reward on subsequent expression of sexual behavior. The current study tests the hypothesis that ΔFosB, the stably expressed truncated form of FosB, plays a critical role in the reinforcement of sexual behavior and experience-induced facilitation of sexual motivation and performance. Sexual experience was shown to cause ΔFosB accumulation in several limbic brain regions including the nucleus accumbens (NAc), medial prefrontal cortex, ventral tegmental area and caudate putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of ΔFosB, was measured in sexually experienced and naïve animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naïve controls. Finally, ΔFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with ΔFosB over-expression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of ΔJunD, a dominant-negative binding partner of ΔFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to GFP and ΔFosB over-expressing groups. Together, these findings support a critical role for ΔFosB expression in the NAc for the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. PMID:20618447

  6. c-fos-like immunoreactivity in the cat's neuraxis following moderate hypoxia or hypercapnia.

    PubMed

    Larnicol, N; Wallois, F; Berquin, P; Gros, F; Rose, D

    1994-01-01

    The overall pattern of c-fos immunoreactivity was studied in the brainstem and spinal cord of cats subjected to moderate hypoxia or hypercapnia. In control cats (normoxic, normocapnic), c-fos was expressed mainly in pontine and periaqueductal grey but not in brainstem structures engaged in respiratory control nor in the spinal cord. Both hypoxia and hypercapnia induced c-fos expression in the parabrachial area (pneumotaxic center). In the retrotrapezoid nucleus, a structure involved in respiratory rhythmogenesis and chemoreception, immunoreactivity was detected in hypoxic but not in hypercapnic cats. Neurons in the nucleus raphe pallidus preferentially expressed c-fos in response to hypercapnia. Labelled neurons were concentrated in the dorsal and gelatinosus subnuclei of the solitary tract following hypoxia and hypercapnia, respectively. Our data suggest that some neurons that express c-fos in hypoxic or hypercapnic cats may be involved in coordination of cardiovascular and respiratory function.

  7. TGF-β Effects on Prostate Cancer Cell Migration and Invasion Require FosB

    PubMed Central

    Barrett, Cachétne S.X.; Millena, Ana C.; Khan, Shafiq A.

    2017-01-01

    BACKGROUND Activator Protein-1 (AP-1) family (cJun, JunB, JunD, cFos, FosB, Fra1, and Fra2) plays a central role in the transcriptional regulation of many genes that are associated with cell proliferation, differentiation, migration, metastasis, and survival. Many oncogenic signaling pathways converge at the AP-1 transcription complex. Transforming growth factor beta (TGF-β) is a multifunctional regulatory cytokine that regulates many aspects of cellular function, including cellular proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival. METHODS This study investigated, the role of FOS proteins in TGF-β signaling in prostate cancer cell proliferation, migration, and invasion. Steady state expression levels of FOS mRNA and proteins were determined using RT-PCR and western blotting analyses. DU145 and PC3 prostate cancer cells were exposed to TGF-β1 at varying time and dosage, RT-PCR, western blot, and immunofluorescence analyses were used to determine TGF-β1 effect on FOS mRNA and protein expression levels as well as FosB subcellular localization. Transient silencing of FosB protein was used to determine its role in cell proliferation, migration, and invasion. RESULTS Our data show that FOS mRNA and proteins were differentially expressed in human prostate epithelial (RWPE-1) and prostate cancer cell lines (LNCaP, DU145, and PC3). TGF-β1 induced the expression of FosB at both the mRNA and protein levels in DU145 and PC3 cells, whereas cFos and Fra1 were unaffected. Immunofluorescence analysis showed an increase in the accumulation of FosB protein in the nucleus of PC3 cells after treatment with exogenous TGF-β1. Selective knockdown of endogenous FosB by specific siRNA did not have any effect on cell proliferation in PC3 and DU145 cells. However, basal and TGF-β1- and EGF-induced cell migration was significantly reduced in DU145 and PC3 cells lacking endogenous FosB. TGF-β1- and EGF-induced cell invasion

  8. Estrogen receptor alpha, fos-related antigen-2, and c-Jun coordinately regulate human UDP glucuronosyltransferase 2B15 and 2B17 expression in response to 17beta-estradiol in MCF-7 cells.

    PubMed

    Hu, Dong Gui; Mackenzie, Peter I

    2009-08-01

    UDP-glucuronosyltransferase 2B15 and 2B17 expression is up-regulated by 17beta-estradiol in MCF-7 breast cancer cells, as assessed by quantitative real-time polymerase chain reaction. Using 5'-deletion mapping and site-directed mutagenesis, we demonstrate that 17beta-estradiol activation of UGT2B15 gene transcription is mediated by a 282-base pair fragment positioned -454 to -172 nucleotides from the translation start site. This region contains two putative activator protein-1 (AP-1) elements, one imperfect estrogen response element (ERE), and two consensus ERE half-sites. We propose that these five sites act as an estrogen response unit (ERU), because mutation in any site reduces activation of the UGT2B15 promoter by 17beta-estradiol. Despite the presence of two AP-1 elements, the UGT2B15 promoter is not responsive to the AP-1 activator phorbol 12-myristate 13-acetate. Although electrophoretic mobility shift assays (EMSA) indicate that the AP-1 proteins c-Jun and Fos-related antigen 2 (Fra-2) bound to the distal AP-1 site, binding of Jun or Fos family members to the proximal AP-1 site was not detected by EMSA. Chromatin immunoprecipitation assays showed a 17beta-estradiol-induced recruitment of estrogen receptor (ER) alpha, c-Jun, and Fra-2 to the 282-bp ERU. The involvement of these three transcription factors in the stimulation of UGT2B15 gene expression by 17beta-estradiol was confirmed by siRNA silencing experiments. Mutagenesis and siRNA experiments indicate that UGT2B17 expression is also regulated by 17beta-estradiol via the ERU, which is fully conserved in both promoters. Because UGT2B15 and UGT2B17 inactivate steroid hormones by glucuronidation, the regulation of their genes by 17beta-estradiol may maintain steroid hormone homeostasis and prevent excessive estrogen signaling activity.

  9. A Signaling Network Controlling Androgenic Repression of c-Fos Protein in Prostate Adenocarcinoma Cells*

    PubMed Central

    Shankar, Eswar; Song, Kyung; Corum, Sarah L.; Bane, Kara L.; Wang, Hui; Kao, Hung-Ying; Danielpour, David

    2016-01-01

    The transcription factor c-Fos controls many important cellular processes, including cell growth and apoptosis. c-Fos expression is rapidly elevated in the prostate upon castration-mediated androgen withdrawal through an undefined mechanism. Here we show that androgens (5α-dihydrotestosterone and R1881) suppress c-Fos protein and mRNA expression induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) or EGF in human prostate cancer (PCa) cell lines. Such suppression transpires through a transcriptional mechanism, predominantly at the proximal serum response element of the c-fos promoter. We show that androgen signaling suppresses TPA-induced c-Fos expression through repressing a PKC/MEK/ERK/ELK-1 signaling pathway. Moreover, our results support the hypothesis that p38MAPK, PI3K, and PKCδ are involved in the androgenic regulation of c-Fos through controlling MEK/ERK. Stable silencing of c-Fos and PKCδ with shRNAs suggests that R1881 promotes cell death induced by low-dose TPA through a mechanism that is dependent on both PKCδ and loss of c-Fos expression. Reciprocally, loss of either PKCδ or c-Fos activates p38MAPK while suppressing the activation of ERK1/2. We also provide the first demonstration that R1881 permits cell death induced by low-dose TPA in the LNCaP androgen-dependent PCa cell line and that TPA-induced cell death is independent of exogenous androgen in the castration-resistant variants of LNCaP, C4-2 and C4-2B. Acquisition of androgen-independent killing by TPA correlates with activation of p38MAPK, suppression of ERK1/2, and loss of c-Fos. These results provide new insights into androgenic control of c-Fos and use of PKC inhibitors in PCa therapy. PMID:26786102

  10. Functional role of the N-terminal domain of ΔFosB in response to stress and drugs of abuse.

    PubMed

    Ohnishi, Y N; Ohnishi, Y H; Vialou, V; Mouzon, E; LaPlant, Q; Nishi, A; Nestler, E J

    2015-01-22

    Previous work has implicated the transcription factor, ΔFosB, acting in the nucleus accumbens, in mediating the pro-rewarding effects of drugs of abuse such as cocaine as well as in mediating resilience to chronic social stress. However, the transgenic and viral gene transfer models used to establish these ΔFosB phenotypes express, in addition to ΔFosB, an alternative translation product of ΔFosB mRNA, termed Δ2ΔFosB, which lacks the N-terminal 78 aa present in ΔFosB. To study the possible contribution of Δ2ΔFosB to these drug and stress phenotypes, we prepared a viral vector that overexpresses a point mutant form of ΔFosB mRNA which cannot undergo alternative translation as well as a vector that overexpresses Δ2ΔFosB alone. Our results show that the mutant form of ΔFosB, when overexpressed in the nucleus accumbens, reproduces the enhancement of reward and of resilience seen with our earlier models, with no effects seen for Δ2ΔFosB. Overexpression of full length FosB, the other major product of the FosB gene, also has no effect. These findings confirm the unique role of ΔFosB in the nucleus accumbens in controlling responses to drugs of abuse and stress.

  11. Age-associated changes in basal c-fos transcription factor binding activity in rat hearts.

    PubMed

    Tsou, H; Azhar, G; Lu, X G; Kovacs, S; Peacocke, M; Wei, J Y

    1996-12-15

    The early response proto-oncogene c-fos is expressed at very low levels in the mammalian heart at baseline. To further investigate the mechanism of altered c-fos expression with age, we studied in the basal state the binding of five transcription proteins to their cognate sites in the c-fos promoter/enhancer region, in adult and old F344 rats. Our results show a reduced binding of E2F and AP1 proteins to the c-fos promoter in aging hearts. The major calcium/cyclic AMP response element (CRE) and SP1 binding was unchanged. The only increase seen with age was in the serum response element (SRE) binding proteins. SRE is the point of convergence of different signal transduction pathways (via MAP kinases and the Rho family of GTPases) at the c-fos promoter. Increased SRE binding may reflect a compensation for a decreased binding of other transcription proteins to the c-fos promoter, alteration in the phosphorylation status of SRF, or a change in the ternary complex factors Elk 1 or SAP 1. Other possibilities include defects in the signal transduction pathways with aging, which combine to produce an overall negative balance in the function of the c-fos promoter despite the increased SRE binding activity. Both in vitro and in vivo experiments have shown decreased c-fos expression with age. This may be due partly to alterations in the basal levels of transcription factor binding.

  12. Serotonin2C receptor stimulation inhibits cocaine-induced Fos expression and DARPP-32 phosphorylation in the rat striatum independently of dopamine outflow.

    PubMed

    Devroye, Céline; Cathala, Adeline; Maitre, Marlène; Piazza, Pier Vincenzo; Abrous, Djoher Nora; Revest, Jean-Michel; Spampinato, Umberto

    2015-02-01

    The serotonin(2C) receptor (5-HT(2C)R) is known to control dopamine (DA) neuron function by modulating DA neuronal firing and DA exocytosis at terminals. Recent studies assessing the influence of 5-HT(2C)Rs on cocaine-induced neurochemical and behavioral responses have shown that 5-HT2CRs can also modulate mesoaccumbens DA pathway activity at post-synaptic level, by controlling DA transmission in the nucleus accumbens (NAc), independently of DA release itself. A similar mechanism has been proposed to occur at the level of the nigrostriatal DA system. Here, using in vivo microdialysis in freely moving rats and molecular approaches, we assessed this hypothesis by studying the influence of the 5-HT(2C)R agonist Ro 60-0175 on cocaine-induced responses in the striatum. The intraperitoneal (i.p.) administration of 1 mg/kg Ro 60-0175 had no effect on the increase in striatal DA outflow induced by cocaine (15 mg/kg, i.p.). Conversely, Ro 60-0175 inhibited cocaine-induced Fos immunoreactivity and phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine 75 residue in the striatum. Finally, the suppressant effect of Ro 60-0175 on cocaine-induced DARPP-32 phosphorylation was reversed by the selective 5-HT(2C)R antagonist SB 242084 (0.5 mg/kg, i.p.). In keeping with the key role of DARPP-32 in DA neurotransmission, our results demonstrate that 5-HT(2C)Rs are capable of modulating nigrostriatal DA pathway activity at post-synaptic level, by specifically controlling DA signaling in the striatum.

  13. Expression of c-Fos protein in medial septum/diagonal band of Broca and CA3 region, associated with the temporary inactivation of the supramammillary area.

    PubMed

    Aranda, Lourdes

    2016-07-01

    The supramammillary (SuM) area is part of the diencephalic nuclei comprising the mammillary bodies, and is a key structure in the memory and spatial learning processes. It is a critical region in the modulation/generation of hippocampal theta rhythm. In addition, many papers have recently shown a clear involvement of this structure in the processes of spatial learning and memory in animal models, although it is still not known how it modulates spatial navigation and response emotional. The aim of the present research was to study the effect of the temporary inactivation of the SuM area on synaptic plasticity of crucial structures in the formation of spatial memory and emotional response. Sprague-Dawley rats were asigned in three groups: a control group where the animals were not subjected to any treatment, and two groups where the rats received microinjections of tetrodotoxin (TTX) in the SuM area (5ng diluted in 0.5μl of saline) or saline (0.5μl). The microinjections were administered 90min before the perfusion. Later, cellular activity in medial septum/diagonal band of Broca (MS/DBB) and CA3 region of the dorsal hippocampus was assessed, by measuring the immediate early gene c-fos. The results show a clear hiperactivity cellular in medial septum/diagonal band of Broca and a clear hypoactivity cellular in the CA3 region of the hippocampus when there was a functional inactivation of the SuM area. It suggests that the SuM area seems to be part of the connection and information input pathways to CA3 region of the hippocampal formation, key for proper functioning in spatial memory and emotional response.

  14. fra-1: a serum-inducible, cellular immediate-early gene that encodes a fos-related antigen.

    PubMed Central

    Cohen, D R; Curran, T

    1988-01-01

    A set of proteins antigenically related to the c-fos protein (Fos) are induced by serum in fibroblasts. To isolate cDNA clones of genes encoding such proteins, a lambda gt11 expression cDNA library constructed from serum-stimulated rat fibroblasts was screened with antibodies raised against a hydrophilic region (amino acids 127 to 152) of Fos. One of the positive clones identified, termed fra-1 (Fos-related antigen) was characterized. It encoded a protein that shared several regions of extensive amino acid homology with Fos (including the region that showed similarity to both the yeast GCN4 regulatory protein and the protein encoded by the jun oncogene), although its nucleotide sequence was considerably diverged from that of the c-fos gene. Only a subset of the agents and conditions that activated c-fos also induced fra-1. Induction of fra-1 expression following serum stimulation was delayed compared with that of c-fos. However, like c-fos, fra-1 was induced rapidly by serum in the presence of protein synthesis inhibitors. Thus, a family of Fos-related, inducible genes are involved in the cellular immediate-early transcriptional response to extracellular stimuli. Images PMID:3133553

  15. TGF alpha and v-fos cooperation in transgenic mouse epidermis induces aberrant keratinocyte differentiation and stable, autonomous papillomas.

    PubMed

    Wang, X J; Greenhalgh, D A; Lu, X R; Bickenbach, J R; Roop, D R

    1995-01-19

    To assess the synergistic effect of growth and transcription factor deregulation on carcinogenesis in vivo, mating experiments were performed between transgenic mice expressing human TGF alpha or v-fos exclusively in the epidermis by means of a human keratin K1-based targeting vector (HK1.fos, HK1.TGF alpha and HK1.fos/alpha). While HK1.TGF alpha mice exhibited mild epidermal hyperplasia resulting in a wrinkled appearance, this hyperplasia was significantly increased in HK1.fos/alpha mice which also exhibited a novel opalescent and peeling skin phenotype. HK1.fos/alpha keratinocyte differentiation was considerably deregulated with cornified cells appearing in the granular layer, granular cells in the spinous layer and a sixfold increase in BrdU labeling over normal. In addition, hyperplastic HK1.fos/alpha epidermis exhibited aberrant loricrin, filaggrin and novel K13 expression associated with v-fos expression. Unlike adult HK1.TGF alpha controls, hyperplasia persisted in HK1.fos/alpha adults which also rapidly developed autonomous squamous cell papillomas. These results demonstrate that v-fos and TGF alpha over-expression can cooperate to reprogram keratinocyte differentiation and elicit the early stages of neoplasia. Moreover, TGF alpha over-expression appeared to play an early, initiating role in HK1.fos/alpha papilloma etiology, and a promotion role in the accelerated appearance of v-fos wound-associated preneoplastic phenotypes. However, the stable persistence of HK1.fos/alpha papillomas for up to 12 months, suggests that additional events are required for malignant conversion.

  16. cAMP and in vivo hypoxia induce tob, ifr1, and fos expression in erythroid cells of the chick embryo.

    PubMed

    Dragon, Stefanie; Offenhäuser, Nina; Baumann, Rosemarie

    2002-04-01

    During avian embryonic development, terminal erythroid differentiation occurs in the circulation. Some of the key events, such as the induction of erythroid 2,3-bisphosphoglycerate (2,3-BPG), carbonic anhydrase (CAII), and pyrimidine 5'-nucleotidase (P5N) synthesis are oxygen dependent (Baumann R, Haller EA, Schöning U, and Weber M, Dev Biol 116: 548-551, 1986; Dragon S and Baumann R, Am J Physiol Regulatory Integrative Comp Physiol 280: R870-R878, 2001; Dragon S, Carey C, Martin K, and Baumann R, J Exp Biol 202: 2787-2795, 1999; Dragon S, Glombitza S, Götz R, and Baumann R, Am J Physiol Regulatory Integrative Comp Physiol 271: R982-R989, 1996; Dragon S, Hille R, Götz R, and Baumann R, Blood 91: 3052-3058, 1998; Million D, Zillner P, and Baumann R, Am J Physiol Regulatory Integrative Comp Physiol 261: R1188-R1196, 1991) in an indirect way: hypoxia stimulates the release of norepinephrine (NE)/adenosine into the circulation (Dragon et al., J Exp Biol 202: 2787-2795, 1999; Dragon et al., Am J Physiol Regulatory Integrative Comp Physiol 271: R982-R989, 1996). This leads via erythroid beta-adrenergic/adenosine A(2) receptor activation to a cAMP signal inducing several proteins in a transcription-dependent manner (Dragon et al., Am J Physiol Regulatory Integrative Comp Physiol 271: R982-R989, 1996; Dragon et al., Blood 91: 3052-3058, 1998; Glombitza S, Dragon S, Berghammer M, Pannermayr M, and Baumann R, Am J Physiol Regulatory Integrative Comp Physiol 271: R973-R981, 1996). To understand how the cAMP-dependent processes are initiated, we screened an erythroid cDNA library for cAMP-regulated genes. We detected three genes that were strongly upregulated (>5-fold) by cAMP in definitive and primitive red blood cells. They are homologous to the mammalian Tob, Ifr1, and Fos proteins. In addition, the genes are induced in the intact embryo during short-term hypoxia. Because the genes are regulators of proliferation and differentiation in other cell types, we suggest that c

  17. Differential activation of c-Fos in the paraventricular nuclei of the hypothalamus and thalamus following myocardial infarction in rats

    PubMed Central

    Tae, Hyun-Jin; Park, Seung Min; Cho, Jeong Hwi; Kim, In Hye; Ahn, Ji Hyeon; Park, Joon Ha; Won, Moo-Ho; Chen, Bai Hui; Shin, Bich-Na; Shin, Myoung Cheol; Lee, Choong Hyun; Hong, Seongkweon; Lee, Jae-Chul; Cho, Jun Hwi

    2016-01-01

    Proto-oncogene c-Fos (c-Fos) is frequently used to detect a pathogenesis in central nervous system disorders. The present study examined changes in the immunoreactivity of c-Fos in the paraventricular nucleus of the hypothalamus (PVNH) and paraventricular nucleus of the thalamus (PVNT) following myocardial infarction (MI) in rats. Infarction in the left ventricle was examined by Masson's trichrome staining. Neuronal degeneration was monitored for 56 days after MI using crystal violet and Fluoro-Jade B histofluorescence staining. Changes in the immunoreactivity of c-Fos were determined using immunohistochemistry for c-Fos. The average infarct size of the left ventricle circumference was ~44% subsequent to MI. Neuronal degeneration was not detected in PVNH and PVNT following MI. c-Fos immunoreactive (+) cells were infrequently observed in the nuclei of the sham-group. However, the number of c-Fos+ cells was increased in the nuclei following MI and peaked in the PVNH and PVNT at 3 and 14 days, respectively. The number of c-Fos+ cells were comparable with the sham group at 56 days after MI. Therefore, MI may induce c-Fos immunoreactivity in PVNH and PVNT, this increase of c-Fos expression levels may be associated with the stress that occurs in the brain following MI. PMID:27601012

  18. Fos family protein degradation by the proteasome.

    PubMed

    Gomard, Tiphanie; Jariel-Encontre, Isabelle; Basbous, Jihane; Bossis, Guillaume; Moquet-Torcy, Gabriel; Mocquet-Torcy, Gabriel; Piechaczyk, Marc

    2008-10-01

    c-Fos proto-oncoprotein defines a family of closely related transcription factors (Fos proteins) also comprising Fra-1, Fra-2, FosB and DeltaFosB, the latter two proteins being generated by alternative splicing. Through the regulation of many genes, most of them still unidentified, they regulate major functions from the cell level up to the whole organism. Thus they are involved in the control of proliferation, differentiation and apoptosis, as well as in the control of responses to stresses, and they play important roles in organogenesis, immune responses and control of cognitive functions, among others. Fos proteins are intrinsically unstable. We have studied how two of them, c-Fos and Fra-1, are degraded. Departing from the classical scenario where unstable key cell regulators are hydrolysed by the proteasome after polyubiquitination, we showed that the bulk of c-Fos and Fra-1 can be broken down independently of any prior ubiquitination. Certain conserved structural domains suggest that similar mechanisms may also apply to Fra-2 and FosB. Computer search indicates that certain motifs shared by the Fos proteins and putatively responsible for instability are found in no other protein, suggesting the existence of degradation mechanisms specific for this protein family. Under particular signalling conditions, others have shown that a part of cytoplasmic c-Fos requires ubiquitination for fast turnover. This poses the question of the multiplicity of degradation pathways that apply to proteins depending on their intracellular localization.

  19. Evaluate the Antigenotoxicity and Anticancer Role of β-Sitosterol by Determining Oxidative DNA Damage and the Expression of Phosphorylated Mitogen-activated Protein Kinases’, C-fos, C-jun, and Endothelial Growth Factor Receptor

    PubMed Central

    Sharmila, Ramalingam; Sindhu, Ganapathy

    2017-01-01

    reduced the elevated expression of p-p38 MAPK, p-JNK, p-ERK, c-fos and c-jun in carcinogen induced rats, which suggest that β-sitosterol might protect renal tissue from neoplastic transformation. The interaction of β-sitosterol with the ATP binding site of ERK-2 by molecular docking studies also validates the inhibitory effect of β-sitosterol on ERK-2. The results of the present study reveal that β-sitosterol inhibit oncogenic MAPK signaling, to abrogate hyper cell proliferation, angiogenesis, and to induce apoptosis thereby prevent DEN and Fe-NTA induced renal carcinogenesis. Thus,β-sitosterol that modulates signal transduction pathways and their downstream events may serve as a potential cancer chemopreventive and therapeutic agent. Abbreviation used: AP-1: Activator protein-1,DEPC: Diethyl pyrocarbonate,EDTA: Ethylenediaminetetraacetic acid,EGFR: Endothelial growth factor receptor,ERK: Extracellular-signal regulating kinase,Fe-NTA: Ferric nitrilotriacetate,GAPDH: Glyceraldehyde-3-phosphate dehydrogenase,HBSS: Hank's balanced salt solution,JNK: c-Jun N-terminal kinase,MAPK: Mitogen-activated protein kinase,DEN: N-diethylnitrosamine,RCC: Renal cell carcinoma,SDS-PAGE: Sodium dodecyl sulfate polyacrylamide gel electrophoresis PMID:28216890

  20. Soft Coral-Derived Lemnalol Alleviates Monosodium Urate-Induced Gouty Arthritis in Rats by Inhibiting Leukocyte Infiltration and iNOS, COX-2 and c-Fos Protein Expression

    PubMed Central

    Lee, Hsin-Pai; Huang, Shi-Ying; Lin, Yen-You; Wang, Hui-Min; Jean, Yen-Hsuan; Wu, Shu-Fen; Duh, Chang-Yih; Wen, Zhi-Hong

    2013-01-01

    An acute gout attack manifests in the joint as dramatic inflammation. To date, the clinical use of medicinal agents has typically led to undesirable side effects. Numerous efforts have failed to create an effective and safe agent for the treatment of gout. Lemnalol—an extract from Formosan soft coral—has documented anti-inflammatory and anti-nociceptive properties. In the present study, we attempt to examine the therapeutic effects of lemnalol on intra-articular monosodium urate (MSU)-induced gouty arthritis in rats. In the present study, we found that treatment with lemnalol (intramuscular [im]), but not colchicine (oral [po]), significantly attenuated MUS-induced mechanical allodynia, paw edema and knee swelling. Histomorphometric and immunohistochemistry analysis revealed that MSU-induced inflammatory cell infiltration, as well as the elevated expression of c-Fos and pro-inflammatory proteins (inducible nitric oxide synthase and cyclooxygenase-2) observed in synovial tissue, were significantly inhibited by treatment with lemnalol. We conclude that lemnalol may be a promising candidate for the development of a new treatment for gout and other acute neutrophil-driven inflammatory diseases. PMID:23306170

  1. Soft coral-derived lemnalol alleviates monosodium urate-induced gouty arthritis in rats by inhibiting leukocyte infiltration and iNOS, COX-2 and c-Fos protein expression.

    PubMed

    Lee, Hsin-Pai; Huang, Shi-Ying; Lin, Yen-You; Wang, Hui-Min; Jean, Yen-Hsuan; Wu, Shu-Fen; Duh, Chang-Yih; Wen, Zhi-Hong

    2013-01-10

    An acute gout attack manifests in the joint as dramatic inflammation. To date, the clinical use of medicinal agents has typically led to undesirable side effects. Numerous efforts have failed to create an effective and safe agent for the treatment of gout. Lemnalol-an extract from Formosan soft coral-has documented anti-inflammatory and anti-nociceptive properties. In the present study, we attempt to examine the therapeutic effects of lemnalol on intra-articular monosodium urate (MSU)-induced gouty arthritis in rats. In the present study, we found that treatment with lemnalol (intramuscular [im]), but not colchicine (oral [po]), significantly attenuated MUS-induced mechanical allodynia, paw edema and knee swelling. Histomorphometric and immunohistochemistry analysis revealed that MSU-induced inflammatory cell infiltration, as well as the elevated expression of c-Fos and pro-inflammatory proteins (inducible nitric oxide synthase and cyclooxygenase-2) observed in synovial tissue, were significantly inhibited by treatment with lemnalol. We conclude that lemnalol may be a promising candidate for the development of a new treatment for gout and other acute neutrophil-driven inflammatory diseases.

  2. Fos immunohistochemical determination of brainstem neuronal activation in the muskrat after nasal stimulation.

    PubMed

    McCulloch, P F; Panneton, W M

    1997-06-01

    Stimulation of the nasal passages of muskrats with either ammonia vapours or retrogradely-flowing water produced cardiorespiratory responses (an immediate 62% decrease in heart rate, 29% increase in mean arterial blood pressure, and sustained expiratory apnoea). We used the immunohistological detection of Fos, the protein product of the c-fos gene, as a marker of neuronal activation to help elucidate the brainstem circuitry of this cardiorespiratory response. After repeated ammonia stimulation of the nasal passages, increased Fos expression was detected within the spinal trigeminal nucleus (ventral laminae I and II of the medullary dorsal horn, ventral paratrigeminal nucleus, and spinal trigeminal nucleus interpolaris), an area just ventromedial to the medullary dorsal horn, the caudal dorsal reticular formation and the area of the A5 catecholamine group compared to control animals. Repeated water stimulation of the nasal passages produced increased Fos expression only in the A5 catecholamine group. There was an increase in the number of Fos-positive cells in the ammonia group in the ventral laminae I and II of the medullary dorsal horn and the ventral paratrigeminal nuclei compared with the water group. We conclude that ammonia stimulation of the nasal passages produces a different pattern of neuronal activation within the brainstem compared with water stimulation. We also conclude that Fos immunohistochemistry is a good technique to determine functional afferent somatotopy, but that immunohistochemical detection of Fos is not a good technique to identify the medullary neurons responsible for the efferent aspects of an intermittently produced cardiorespiratory reflex.

  3. An Indirect Action Contributes to C-Fos Induction in Paraventricular Hypothalamic Nucleus by Neuropeptide Y

    PubMed Central

    Fan, Shengjie; Dakshinamoorthy, Janani; Kim, Eun Ran; Xu, Yong; Huang, Cheng; Tong, Qingchun

    2016-01-01

    Neuropeptide Y (NPY) is a well-established orexigenic peptide and hypothalamic paraventricular nucleus (PVH) is one major brain site that mediates the orexigenic action of NPY. NPY induces abundant expression of C-Fos, an indicator for neuronal activation, in the PVH, which has been used extensively to examine the underlying NPY orexigenic neural pathways. However, PVH C-Fos induction is in discordance with the abundant expression of NPY receptors, a group of inhibitory Gi protein coupled receptors in the PVH, and with the overall role of PVH neurons in feeding inhibition, suggesting a mechanism of indirect action. Here we showed that the ability of NPY on C-Fos induction in the PVH was blunted in conditions of insulin deficiency and fasting, a condition associated with a high level of NPY and a low level of insulin. Moreover, insulin insufficiency blunted C-Fos induction in the PVH by fasting-induced re-feeding, and insulin and NPY induced c-Fos induction in the same group of PVH neurons. Finally, NPY produced normal C-Fos induction in the PVH with disruption of GABA-A receptors. Thus, our results revealed that PVH C-Fos induction by NPY is mediated by an indirect action, which is at least partially mediated by insulin action, but not GABA-A receptors. PMID:26813148

  4. Differential induction of FosB isoforms throughout the brain by fluoxetine and chronic stress.

    PubMed

    Vialou, Vincent; Thibault, Mackenzie; Kaska, Sophia; Cooper, Sarah; Gajewski, Paula; Eagle, Andrew; Mazei-Robison, Michelle; Nestler, Eric J; Robison, A J

    2015-12-01

    Major depressive disorder is thought to arise in part from dysfunction of the brain's "reward circuitry", consisting of the mesolimbic dopamine system and the glutamatergic and neuromodulatory inputs onto this system. Both chronic stress and antidepressant treatment regulate gene transcription in many of the brain regions that make up these circuits, but the exact nature of the transcription factors and target genes involved in these processes remain unclear. Here, we demonstrate induction of the FosB family of transcription factors in ∼25 distinct regions of adult mouse brain, including many parts of the reward circuitry, by chronic exposure to the antidepressant fluoxetine. We further uncover specific patterns of FosB gene product expression (i.e., differential expression of full-length FosB, ΔFosB, and Δ2ΔFosB) in brain regions associated with depression--the nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus--in response to chronic fluoxetine treatment, and contrast these patterns with differential induction of FosB isoforms in the chronic social defeat stress model of depression with and without fluoxetine treatment. We find that chronic fluoxetine, in contrast to stress, causes induction of the unstable full-length FosB isoform in the NAc, PFC, and hippocampus even 24 h following the final injection, indicating that these brain regions may undergo chronic activation when fluoxetine is on board, even in the absence of stress. We also find that only the stable ΔFosB isoform correlates with behavioral responses to stress. These data suggest that NAc, PFC, and hippocampus may present useful targets for directed intervention in mood disorders (ie, brain stimulation or gene therapy), and that determining the gene targets of FosB-mediated transcription in these brain regions in response to fluoxetine may yield novel inroads for pharmaceutical intervention in depressive disorders.

  5. Differential induction of FosB isoforms throughout the brain by fluoxetine and chronic stress

    PubMed Central

    Vialou, Vincent; Thibault, Mackenzie; Kaska, Sophia; Gajewski, Paula; Eagle, Andrew; Mazei-Robison, Michelle; Nestler, Eric J.; Robison, A.J.

    2015-01-01

    Major depressive disorder is thought to arise in part from dysfunction of the brain's “reward circuitry,” consisting of the mesolimbic dopamine system and the glutamatergic and neuromodulatory inputs onto this system. Both chronic stress and antidepressant treatment regulate gene transcription in many of the brain regions that make up these circuits, but the exact nature of the transcription factors and target genes involved in these processes remain unclear. Here, we demonstrate induction of the FosB family of transcription factors in ∼25 distinct regions of adult mouse brain, including many parts of the reward circuitry, by chronic exposure to the antidepressant fluoxetine. We further uncover specific patterns of FosB gene product expression (i.e., differential expression of full-length FosB, ΔFosB, and Δ2ΔFosB) in brain regions associated with depression – the nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus – in response to chronic fluoxetine treatment, and contrast these patterns with differential induction of FosB isoforms in the chronic social defeat stress model of depression with and without fluoxetine treatment. We find that chronic fluoxetine, in contrast to stress, causes induction of the unstable full-length FosB isoform in the NAc, PFC, and hippocampus even 24 hours following the final injection, indicating that these brain regions may undergo chronic activation when fluoxetine is on board, even in the absence of stress. We also find that only the stable ΔFosB isoform correlates with behavioral responses to stress. These data suggest that NAc, PFC, and hippocampus may present useful targets for directed intervention in mood disorders (ie, brain stimulation or gene therapy), and that determining the gene targets of FosB-mediated transcription in these brain regions in response to fluoxetine may yield novel inroads for pharmaceutical intervention in depressive disorders. PMID:26164345

  6. A mechanism of AP-1 suppression through interaction of c-Fos with lamin A/C

    PubMed Central

    Ivorra, Carmen; Kubicek, Markus; González, José M.; Sanz-González, Silvia M.; Álvarez-Barrientos, Alberto; O'Connor, José-Enrique; Burke, Brian; Andrés, Vicente

    2006-01-01

    AP-1 (Activating Protein 1) transcription factor activity is tightly regulated at multiple levels, including dimer formation (i.e., Fos/Jun). Here we show that the intermediate filament protein lamin A/C suppresses AP-1 function through direct interaction with c-Fos, and that both proteins can interact and colocalize at the nuclear envelope (NE) in mammalian cells. Perinuclear localization of c-Fos is absent in Lmna-null cells but can be restored by lamin A overexpression. In vitro, preincubation of c-Fos with lamin A prior to the addition of c-Jun inhibits AP-1 DNA-binding activity. In vivo, overexpression of lamin A reduces the formation of c-Fos/c-Jun heterodimers, and suppresses AP-1 DNA-binding and transcriptional activity. Notably, c-Fos colocalizes with lamin A/C at the NE in starvation-synchronized quiescent cells lacking detectable AP-1 DNA binding. In contrast, serum-induced AP-1 DNA-binding activity coincides with abundant nucleoplasmic c-Fos expression without changes in lamin A/C localization. We also found that Lmna-null cells display enhanced proliferation. In contrast, lamin A overexpression causes growth arrest, and ectopic c-Fos partially overcomes lamin A/C-induced cell cycle alterations. We propose lamin A/C-mediated c-Fos sequestration at the NE as a novel mechanism of transcriptional and cell cycle control. PMID:16452503

  7. Involvement of FOS-mediated miR-181b/miR-21 signalling in the progression of malignant gliomas.

    PubMed

    Tao, Tao; Wang, Yingyi; Luo, Hui; Yao, Lei; Wang, Lin; Wang, Jiajia; Yan, Wei; Zhang, Junxia; Wang, Huibo; Shi, Yan; Yin, Yu; Jiang, Tao; Kang, Chunsheng; Liu, Ning; You, Yongping

    2013-09-01

    Recently, a group of microRNAs (miRNAs) were shown to be dysregulated in gliomas, and involved in glioma development. However, the effect of miRNA-miRNA functional networks on gliomas is poorly understood. In this study, we identified that FBJ murine osteosarcoma viral oncogene homolog (FOS)-mediated miR-181b/miR-21 signalling was critical for glioma progression. Using microarrays and quantitative RT-PCR (qRT-PCR), we found increased FOS in high grade gliomas. FOS depletion (via FOS-shRNA), inhibited invasion and promoted apoptosis in glioma cells. Using microarrays, combined with Pearson correlation analysis, we found FOS positively correlated with miR-21 expression. Reduction of FOS inhibited miR-21 expression by binding to the miR-21 promoter using luciferase reporter assays. Introduction of miR-21 abrogated FOS knockdown-induced cell invasion and apoptosis. Moreover, bioinformatics and luciferase reporter assays showed that miR-181b modulated FOS expression by directly targeting the binding site within the 3'UTR. Expression of FOS with a FOS cDNA lacking 3'UTR overrided miR-181b-induced miR-21 expression and cell function. Finally, immunohistochemistry (IHC) and in situ hybridisation (ISH) analysis revealed a significant correlation in miR-181b, FOS and miR-21 expression in nude mouse tumour xenograft and human glioma tissues. To our knowledge, it is the first time to demonstrate that miR-181b/FOS/miR-21 signalling plays a critical role in the progression of gliomas, providing important clues for understanding the key roles of transcription factor mediated miRNA-miRNA functional network in the regulation of gliomas.

  8. Centralization of noxious stimulus-induced analgesia (NSIA) is related to activity at inhibitory synapses in the spinal cord.

    PubMed

    Tambeli, Claudia H; Levine, Jon D; Gear, Robert W

    2009-06-01

    The duration of noxious stimulus-induced antinociception (NSIA) has been shown to outlast the pain stimulus that elicited it, however, the mechanism that determines the duration of analgesia is unknown. We evaluated the role of spinal excitatory and inhibitory receptors (NMDA, mGluR(5), mu-opioid, GABA(A), and GABA(B)), previously implicated in NSIA initiation, in its maintenance. As in our previous studies, the supraspinal trigeminal jaw-opening reflex (JOR) in the rat was used for nociceptive testing because of its remoteness from the region of drug application, the lumbar spinal cord. NSIA was reversed by antagonists for two inhibitory receptors (GABA(B) and mu-opioid) but not by antagonists for either of the two excitatory receptors (NMDA and mGluR(5)), indicating that NSIA is maintained by ongoing activity at inhibitory synapses in the spinal cord. Furthermore, spinal administration of the GABA(B) agonist baclofen mimicked NSIA in that it could be blocked by prior injection of the mu-opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) in nucleus accumbens. CTAP also blocked baclofen antinociception when administered in the spinal cord. We conclude that analgesia induced by noxious stimulation is maintained by activity in spinal inhibitory receptors.

  9. Effect of acute and chronic bilateral visual deafferentation on c-Fos immunoreactivity in the visual system of adult rats.

    PubMed

    Wiedmann, Rhea; Rosahl, Steffen K; Brinker, Thomas; Samii, Madjid; Nakamura, Makoto

    2013-09-01

    In our study we examined acute and chronic changes in c-Fos expression patterns in the visual system of the rat after complete visual deafferentation. In 20 male Lewis rats, the retro-bulbar part of the optic nerve was sectioned bilaterally. Ten animals underwent c-Fos immunohistochemistry after 3 days and 10 animals after 3 weeks examining time-dependent changes. The control group consisted of 10 animals, which did not undergo any surgical manipulation. c-Fos expression in the rat visual system experienced significant changes after acute and chronic bilateral complete visual deafferentation. Acute decrease in c-Fos level was observed in the ventral lateral geniculate nucleus, intergeniculate leaflet, superficial gray layer of the superior colliculus and layers IV and V of the primary visual cortex. After chronic deafferentation, c-Fos expression was also found to be decreased in the optic and deep layers of the superior colliculus and layer VI of the primary visual cortex. No change in c-Fos expression was observed in the dorsal lateral geniculate nucleus and layers I, II and III of the primary visual cortex. This work shows that secondary complete blindness does not lead to uniform decrease in c-Fos levels in all subcortical and cortical brain regions related to vision. These findings provide important information concerning expression of the immediate-early gene product c-Fos in secondary blind rodent models. It may further serve as a relevant baseline finding when electrical stimulation of the visual system is performed, aiding the assessment of visual neuroprosthesis using c-Fos as a functional mapping tool when evaluating different stimulus parameters in blind rodent models.

  10. Selective uptake and degradation of c-Fos and v-Fos by rat liver lysosomes.

    PubMed

    Aniento, F; Papavassiliou, A G; Knecht, E; Roche, E

    1996-07-15

    The transcription factor c-Fos is a short-lived protein and calpains and ubiquitin-dependent systems have been proposed to be involved in its degradation. In this report, we consider a lysosomal degradation pathway for c-Fos. Using a cell-free assay, we have found that freshly isolated lysosomes can take up and degrade c-Fos with high efficiency. v-Fos, the oncogenic counterpart of c-Fos, can also be taken up by lysosomes, yet the amount of incorporated protein is much lower. c-Fos uptake is independent of its phosphorylation state but it appears to be regulated by dimerization with differentially phosphorylated forms of c-Jun, while v-Fos escapes this regulation. Moreover, we show that c-Fos is immunologically detected in lysosomes isolated from the liver of rats treated with the protease inhibitor leupeptin. Altogether, these results suggest that lysosomes can also participate in the selective degradation of c-Fos in rat liver.

  11. Effects of chronic treatment with corticosterone and imipramine on fos immunoreactivity and adult hippocampal neurogenesis.

    PubMed

    Diniz, L; dos Santos, T B; Britto, L R G; Céspedes, I C; Garcia, M C; Spadari-Bratfisch, R C; Medalha, C C; de Castro, G M; Montesano, F T; Viana, M B

    2013-02-01

    In a previous study we showed that rats chronically treated with corticosterone (CORT) display anxiogenic behavior, evidenced by facilitation of avoidance responses in the elevated T-maze (ETM) model of anxiety. Treatment with the tricyclic antidepressant imipramine significantly reversed the anxiogenic effects of CORT, while inhibiting ETM escape, a response related to panic disorder. To better understand the neurobiological mechanisms underlying these behavioral effects, analysis of c-fos protein immunoreactivity (fos-ir) was used here to map areas activated by chronic CORT (200 mg pellets, 21-day release) and imipramine (15 mg/kg, IP) administration. We also evaluated the number of cells expressing the neurogenesis marker doublecortin (DCX) in the hippocampus and measured plasma CORT levels on the 21st day of treatment. Results showed that CORT increased fos-ir in the ventrolateral septum, medial amygdala and paraventricular hypothalamic nucleus and decreased fos-ir in the lateral periaqueductal gray. Imipramine, on the other hand, increased fos-ir in the medial amygdala and decreased fos-ir in the anterior hypothalamus. CORT also decreased the number of DCX-positive cells in the ventral and dorsal hippocampus, an effect antagonized by imipramine. CORT levels were significantly higher after treatment. These data suggest that the behavioral effects of CORT and imipramine are mediated through specific, at times overlapping, neuronal circuits, which might be of relevance to a better understanding of the physiopathology of generalized anxiety and panic disorder.

  12. Characterization of E-cadherin-dependent and -independent events in a new model of c-Fos-mediated epithelial-mesenchymal transition

    SciTech Connect

    Mejlvang, Jakob; Kriajevska, Marina; Berditchevski, Fedor; Bronstein, Igor; Lukanidin, Eugene M.; Pringle, J. Howard; Mellon, J. Kilian; Tulchinsky, Eugene M. . E-mail: et32@le.ac.uk

    2007-01-15

    Fos proteins have been implicated in control of tumorigenesis-related genetic programs including invasion, angiogenesis, cell proliferation and apoptosis. In this study, we demonstrate that c-Fos is able to induce mesenchymal transition in murine tumorigenic epithelial cell lines. Expression of c-Fos in MT1TC1 cells led to prominent alterations in cell morphology, increased expression of mesenchymal markers, vimentin and S100A4, DNA methylation-dependent down-regulation of E-cadherin and abrogation of cell-cell adhesion. In addition, c-Fos induced a strong {beta}-catenin-independent proliferative response in MT1TC1 cells and stimulated cell motility, invasion and adhesion to different extracellular matrix proteins. To explore whether loss of E-cadherin plays a role in c-Fos-mediated mesenchymal transition, we expressed wild-type E-cadherin and two different E-cadherin mutants in MT1TC1/c-fos cells. Expression of wild-type E-cadherin restored epithelioid morphology and enhanced cellular levels of catenins. However, exogenous E-cadherin did not influence expression of c-Fos-dependent genes, only partly suppressed growth of MT1TC1/c-fos cells and produced no effect on c-Fos-stimulated cell motility and invasion in matrigel. On the other hand, re-expression of E-cadherin specifically negated c-Fos-induced adhesion to collagen type I, but not to laminin or fibronectin. Of interest, mutant E-cadherin which lacks the ability to form functional adhesive complexes had an opposite, potentiating effect on cell adhesion to collagen I. These data suggest that cell adhesion to collagen I is regulated by the functional state of E-cadherin. Overall, our data demonstrate that, with the exception of adhesion to collagen I, c-Fos is dominant over E-cadherin in relation to the aspects of mesenchymal transition assayed in this study.

  13. NMDA preconditioning and neuroprotection in vivo: delayed onset of kainic acid-induced neurodegeneration and c-Fos attenuation in CA3a neurons.

    PubMed

    Mohammadi, Shirin; Pavlik, Alfred; Krajci, Dimitrolos; Al-Sarraf, Hameed

    2009-02-23

    Intraventricular (i.c.v.) kainic acid (KA) causes an acute excitotoxic lesion to the CA3 region of rodent hippocampus. Recent evidence implicated c-fos gene in regulating neuron survival and death following an excitotoxic insult. In this study we attempted to prevent KA-induced damage in CA3 neurons with NMDA preconditioning, which produced a marked expression of c-fos in the hippocampus. NMDA (0.6-6 microg, i.c.v.) was injected to anesthetized rats alone or 1 h before KA (0.15 microg, i.c.v.). Following KA injection, vibratome sections were processed for immunohistochemistry/electron microscopy. c-Fos and Nissl staining were used to estimate the extent of neuronal excitation and damage, respectively. Quantitative evaluation of c-Fos-labeled cells showed significantly less c-Fos in CA3a than in neighboring CA3b and CA2 from 1 to 4 h after KA alone. Attenuation of expressed c-Fos in CA3a was accompanied by damage of neurons with more apoptotic than necrotic signs. NMDA preconditioning elevated CA3a c-Fos expression and at 1 and 2 h exceeded markedly that after KA alone. However, at 4 h after KA, NMDA-preconditioned c-Fos induction in CA3a diminished to the same level as that seen after KA alone. The onset of neuronal degeneration was delayed in similar way. While NMDA-induced c-Fos expression in CA3a could be blocked by MK-801 completely, MK-801 and CNQX were both without significant effect on KA-induced c-Fos expression and neuronal damage. In conclusion, inhibition of c-Fos expression and onset of neuronal damage in CA3a following icv KA injection might be transiently delayed by i.c.v. NMDA preconditioning.

  14. Differences in basal and morphine-induced FosB/DeltaFosB and pCREB immunoreactivities in dopaminergic brain regions of alcohol-preferring AA and alcohol-avoiding ANA rats.

    PubMed

    Kaste, Kristiina; Kivinummi, Tanja; Piepponen, T Petteri; Kiianmaa, Kalervo; Ahtee, Liisa

    2009-06-01

    Besides alcohol, alcohol-preferring AA and alcohol-avoiding ANA rats differ also with respect to other abused drugs. To study the molecular basis of these differences, we examined the expression of two transcription factors implicated in addiction, DeltaFosB and pCREB, in brain dopaminergic regions of AA and ANA rats. The effects of morphine and nicotine were studied to relate the behavioral and molecular changes induced by these drugs. Baseline FosB/DeltaFosB immunoreactivity (IR) in the nucleus accumbens core and pCREB IR in the prefrontal cortex (PFC) were elevated in AA rats. Morphine increased DeltaFosB-like IR more readily in the caudate-putamen of AA rats than in ANA rats. In the PFC morphine decreased pCREB IR in AA rats, but increased it in ANA rats. In addition to enhanced locomotor response, the development of place preference to morphine was enhanced in AA rats. The enhanced nicotine-induced locomotor sensitization found in AA compared with ANA rats seems to depend in addition to dopamine and DeltaFosB on other mechanisms. These findings suggest that enhanced sensitivity of AA rats to morphine is related to augmented morphine-induced expression of FosB/DeltaFosB and morphine-induced reduction of pCREB levels. Moreover, altered innate expression of FosB/DeltaFosB and pCREB in AA rats is likely to affect the sensitivity of these rats to abused drugs.

  15. Forebrain patterns of c-Fos and FosB induction during cancer-associated anorexia-cachexia in rat.

    PubMed

    Konsman, Jan Pieter; Blomqvist, Anders

    2005-05-01

    Forebrain structures are necessary for the initiation of food intake and its coupling to energy expenditure. The cancer-related anorexia-cachexia syndrome is typified by a prolonged increase in metabolic rate resulting in body weight loss which, paradoxically, is accompanied by reduced food intake. The aim of the present work was to study the forebrain expression of Fos proteins as activation markers and thus to identify potential neurobiological mechanisms favouring catabolic processes or modulating food intake in rats suffering from cancer-related anorexia-cachexia. Neurons in forebrain structures showing most pronounced induction of Fos proteins were further identified neurochemically. To provoke anorexia-cachexia, cultured Morris hepatoma 7777 cells were injected subcutaneously in Buffalo rats. This resulted in a slowly growing tumour inducing approximately 7% body weight loss and a 20% reduction in food intake when the tumour represented 1-2% of body mass. Anorexia-cachexia in these animals was found to be accompanied by Fos induction in several hypothalamic nuclei including the paraventricular and ventromedial hypothalamus, in the parastrial nucleus, the amygdala, the bed nucleus of the stria terminalis, ventral striatal structures and the piriform and somatosensory cortices. Neurochemical identification revealed that the vast majority of FosB-positive neurons in the nucleus accumbens, ventral caudate-putamen and other ventral striatal structures contained prodynorphin or proenkephalin mRNA. These findings indicate that forebrain structures that are part of neuronal networks modulating catabolic pathways and food ingestion are activated during tumour-associated anorexia-cachexia and may contribute to the lack of compensatory eating in response to weight loss characterizing this syndrome.

  16. Parathyroid hormone induces c-fos and c-jun messenger RNA in rat osteoblastic cells

    NASA Technical Reports Server (NTRS)

    Clohisy, J. C.; Scott, D. K.; Brakenhoff, K. D.; Quinn, C. O.; Partridge, N. C.

    1992-01-01

    PTH is a potent regulator of osteoblast gene expression, yet the nuclear events that mediate PTH action are poorly understood. We were interested in identifying immediate early genes which may regulate PTH-altered gene expression in the osteoblast. Therefore, we examined the effects of PTH on c-fos and c-jun gene expression in a rat osteoblastic cell line (UMR 106-01). Under control conditions, c-fos and c-jun mRNAs were present at low basal levels. After PTH treatment, c-fos mRNA abundance dramatically increased, with a maximal and transient response at 30 min. PTH also stimulated an increase in c-jun mRNA, but in a biphasic manner, with maximal levels at 30 min and 2 h. These responses were dose dependent, not altered by cotreatment with the protein synthesis inhibitor cycloheximide, and preceded PTH-induced expression of matrix metallo-proteinase-1 mRNA. Nuclear run-on assays demonstrated an increased rate of c-fos and c-jun transcription after PTH exposure. To determine the signal transduction pathways involved, second messenger analogs were tested for their ability to mimic the effects of PTH. 8-Bromo-cAMP and phorbol 12-myristate 13-acetate (PMA) caused increases in the abundance of c-fos and c-jun transcripts. Ionomycin had no effect on the expression of these genes. Pretreatment of the cells with PMA resulted in a decrease in basal c-jun expression, but did not alter the PTH-mediated increase in c-fos, c-jun, or matrix metalloproteinase-1 mRNAs.(ABSTRACT TRUNCATED AT 250 WORDS).

  17. Diacylglycerol kinase ζ (DGKζ) is a critical regulator of bone homeostasis via modulation of c-Fos levels in osteoclasts†

    PubMed Central

    Zamani, Ali; Decker, Corinne; Cremasco, Viviana; Hughes, Lindsey; Novack, Deborah V.; Faccio, Roberta

    2015-01-01

    Increased diacylglycerol (DAG) levels are observed in numerous pathologies, including conditions associated with bone loss. However, the effects of DAG accumulation on the skeleton have never been directly examined. Because DAG is strictly controlled by tissue specific diacylglycerol kinases (DGKs), we sought to examine the biological consequences of DAG accumulation on bone homeostasis by genetic deletion of DGKζ, a highly expressed DGK isoform in osteoclasts (OCs). Strikingly, DGKζ−/− mice are osteoporotic due to a marked increase in OC numbers. In vitro, DGKζ−/− bone marrow macrophages (BMMs) form more numerous, larger and highly resorptive OCs. Surprisingly, while increased DAG levels do not alter RANK/RANKL osteoclastogenic pathway, DGKζ deficiency increases responsiveness to the proliferative and pro-survival cytokine M-CSF. We find that M-CSF is responsible for increased DGKζ−/− OC differentiation by promoting higher expression of the transcription factor c-Fos, and c-Fos knockdown in DGKζ−/− cultures dose-dependently reduces OC differentiation. Using a c-Fos luciferase reporter assay lacking the TRE responsive element, we also demonstrate that M-CSF induces optimal c-Fos expression through DAG production. Finally, to demonstrate the importance of the M-CSF/DGKζ/DAG axis on regulation of c-Fos during osteoclastogenesis, we turned to PLCγ2+/− BMMs, which have reduced DAG levels and form fewer OCs due to impaired expression of the master regulator of osteoclastogenesis NFATc1 and c-Fos. Strikingly, genetic deletion of DGKζ in PLCγ2+/− mice rescues OC formation and normalizes c-Fos levels without altering NFATc1 expression. To our knowledge, this is the first report implicating M-CSF/DGKζ/DAG axis as a critical regulator of bone homeostasis via its actions on OC differentiation and c-Fos expression. PMID:25891971

  18. Long-Term Exercise Is a Potent Trigger for ΔFosB Induction in the Hippocampus along the dorso–ventral Axis

    PubMed Central

    Nishijima, Takeshi; Kawakami, Masashi; Kita, Ichiro

    2013-01-01

    Physical exercise improves multiple aspects of hippocampal function. In line with the notion that neuronal activity is key to promoting neuronal functions, previous literature has consistently demonstrated that acute bouts of exercise evoke neuronal activation in the hippocampus. Repeated activating stimuli lead to an accumulation of the transcription factor ΔFosB, which mediates long-term neural plasticity. In this study, we tested the hypothesis that long-term voluntary wheel running induces ΔFosB expression in the hippocampus, and examined any potential region-specific effects within the hippocampal subfields along the dorso–ventral axis. Male C57BL/6 mice were housed with or without a running wheel for 4 weeks. Long-term wheel running significantly increased FosB/ΔFosB immunoreactivity in all hippocampal regions measured (i.e., in the DG, CA1, and CA3 subfields of both the dorsal and ventral hippocampus). Results confirmed that wheel running induced region-specific expression of FosB/ΔFosB immunoreactivity in the cortex, suggesting that the uniform increase in FosB/ΔFosB within the hippocampus is not a non-specific consequence of running. Western blot data indicated that the increased hippocampal FosB/ΔFosB immunoreactivity was primarily due to increased ΔFosB. These results suggest that long-term physical exercise is a potent trigger for ΔFosB induction throughout the entire hippocampus, which would explain why exercise can improve both dorsal and ventral hippocampus-dependent functions. Interestingly, we found that FosB/ΔFosB expression in the DG was positively correlated with the number of doublecortin-immunoreactive (i.e., immature) neurons. Although the mechanisms by which ΔFosB mediates exercise-induced neurogenesis are still uncertain, these data imply that exercise-induced neurogenesis is at least activity dependent. Taken together, our current results suggest that ΔFosB is a new molecular target involved in regulating exercise

  19. Expression of the nuclear factor-kappaB and proto-oncogenes c-fos and c-jun are induced by low extracellular Mg2+ in aortic and cerebral vascular smooth muscle cells: possible links to hypertension, atherogenesis, and stroke.

    PubMed

    Altura, Burton M; Kostellow, Adele B; Zhang, Aimin; Li, Wenyan; Morrill, Gene A; Gupta, Raj K; Altura, Bella T

    2003-09-01

    Proto-oncogene (c-fos, c-jun) and nuclear factor-kappa B (NF-kappaB) expression, as well as DNA synthesis, in aortic and cerebral vascular smooth muscle cells (VSMCs) were upregulated by a decrease in extracellular magnesium ions ([Mg2+]o). Upregulation of these transcriptional factors was inversely proportional to the [Mg2+]o and occurred over the pathophysiologic range of serum Mg2+ found in patients presenting with hypertension, ischemic heart disease, and stroke. Removal of extracellular Ca2+ ([Ca2+]o), use of nifedipine or protein kinase C (PKC) inhibitors prevented the upregulation of the proto-oncogenes and DNA synthesis in VSMCs. These data show that [Mg2+]o may be an important, heretofore, overlooked natural modulator of proto-oncogene and NF-kappaB expression in VSMCs and that Ca2+ and PKC may play critical roles in induction of c-fos and c-jun in VSMCs induced by a decrease in [Mg2+]o. These results point to a role for low serum Mg2+ in potential development of hypertension, atherogenesis, vascular disease, and stroke.

  20. Microgravity decreases c-fos induction and serum response element activity.

    PubMed

    de Groot, R P; Rijken, P J; den Hertog, J; Boonstra, J; Verkleij, A J; de Laat, S W; Kruijer, W

    1990-09-01

    Several studies have shown that altered gravity conditions influence mammalian cell growth and differentiation. The molecular mechanisms underlying these effects, however, remain relatively obscure. In this paper we show that microgravity reached in a sounding rocket strongly decreases epidermal growth factor (EGF)-induced expression of the proto-oncogenes c-fos and c-jun, which are both implicated in the regulation of proliferation and differentiation. Decreased activity of the serum response element (SRE), present in the c-fos promoter-enhancer region, is probably responsible for the decrease in EGF-induced c-fos expression. In addition, we show that gravity alterations differentially modulate distinctive signal transduction pathways, indicating that gravity-dependent modulations of mammalian cell proliferation are unlikely to be caused by a nonspecific stress response of the cell.

  1. Chronic morphine treatment enhances sciatic nerve stimulation-induced immediate early gene expression in the rat dorsal horn.

    PubMed

    Bojovic, Ognjen; Bramham, Clive R; Tjølsen, Arne

    2015-01-01

    Synaptic plasticity is a property of neurons that can be induced by conditioning electrical stimulation (CS) of afferent fibers in the spinal cord. This is a widely studied property of spinal cord and hippocampal neurons. CS has been shown to trigger enhanced expression of immediate early gene proteins (IEGPs), with peak increases observed 2 hour post stimulation. Chronic morphine treatment has been shown to promoteinduce opioid-induced hyperalgesia, and also to increase CS-induced central sensitization in the dorsal horn. As IEGP expression may contribute to development of chronic pain states, we aimed to determine whether chronic morphine treatment affects the expression of IEGPs following sciatic nerve CS. Changes in expression of the IEGPs Arc, c-Fos or Zif268 were determined in cells of the lumbar dorsal horn of the spinal cord. Chronic Morphine pretreatment over 7 days led to a significant increase in the number of IEGP positive cells observed at both 2 h and 6 h after CS. The same pattern of immunoreactivity was obtained for all IEGPs, with peak increases occurring at 2 h post CS. In contrast, morphine treatment alone in sham operated animals had no effect on IEGP expression. We conclude that chronic morphine treatment enhances stimulus-induced expression of IEGPs in the lumbar dorsal horn. These data support the notion that morphine alters gene expression responses linked to nociceptive stimulation and plasticity.

  2. Suppression of prostaglandin E(2)-mediated c-fos mRNA induction by interleukin-4 in murine macrophages.

    PubMed

    Zhuang, D; Kawajiri, H; Takahashi, Y; Yoshimoto, T

    2000-03-01

    When murine peritoneal macrophages were stimulated for 30 min with arachidonic acid, the growth-associated immediate early gene c-fos was induced in a concentration-dependent manner as assessed by Northern blot analysis. The arachidonic acid-induced c-fos mRNA expression was inhibited by a cyclooxygenase inhibitor, indomethacin, but not by a lipoxygenase inhibitor, nordihydroguaiaretic acid. Macrophages produced prostaglandin (PG) E(2) from arachidonic acid as determined by an enzyme immunoassay. Northern blot analysis revealed the expression of PGE receptor EP2 and EP4 subtypes, but not EP1 and EP3 in murine macrophages. PGE(2) brought about a marked elevation of cAMP, and c-fos mRNA expression was increased by PGE(2) and dibutyryl cAMP in these cells. These results suggest that arachidonic acid is transformed to PGE(2), which then binds to EP2 and EP4 receptors to increase intracellular cAMP and c-fos mRNA expression. Furthermore, the induction of c-fos by arachidonic acid, PGE(2), and cAMP was suppressed by pretreatment with interleukin (IL)-4. We also showed that the tyrosine phosphorylation of a Janus kinase, JAK3, is enhanced by IL-4 treatment, suggesting that the PGE(2)-mediated c-fos mRNA induction is inhibited by IL-4 through the tyrosine phosphorylation of JAK3.

  3. Prostaglandin E2 and the protein kinase A pathway mediate arachidonic acid induction of c-fos in human prostate cancer cells

    NASA Technical Reports Server (NTRS)

    Chen, Y.; Hughes-Fulford, M.

    2000-01-01

    Arachidonic acid (AA) is the precursor for prostaglandin E2 (PGE2) synthesis and increases growth of prostate cancer cells. To further elucidate the mechanisms involved in AA-induced prostate cell growth, induction of c-fos expression by AA was investigated in a human prostate cancer cell line, PC-3. c-fos mRNA was induced shortly after addition of AA, along with a remarkable increase in PGE2 production. c-fos expression and PGE2 production induced by AA was blocked by a cyclo-oxygenase inhibitor, flurbiprofen, suggesting that PGE2 mediated c-fos induction. Protein kinase A (PKA) inhibitor H-89 abolished induction of c-fos expression by AA, and partially inhibited PGE2 production. Protein kinase C (PKC) inhibitor GF109203X had no significant effect on c-fos expression or PGE2 production. Expression of prostaglandin (EP) receptors, which mediate signal transduction from PGE2 to the cells, was examined by reverse transcription polymerase chain reaction in several human prostate cell lines. EP4 and EP2, which are coupled to the PKA signalling pathway, were expressed in all cells tested. Expression of EP1, which activates the PKC pathway, was not detected. The current study showed that induction of the immediate early gene c-fos by AA is mediated by PGE2, which activates the PKA pathway via the EP2/4 receptor in the PC-3 cells.

  4. Continuous administration of antisense oligonucleotides to c-fos reduced the development of seizure susceptibility after ethacrynic acid-induced seizure in mice.

    PubMed

    Suzukawa, Junko; Omori, Kyoko; Yang, Li; Inagaki, Chiyoko

    2003-09-25

    We previously demonstrated that seizure susceptibility developed by the 14th day post-ethacrynic acid (EA)-induced seizure in mice, with a prolonged increase in the expression of c-fos mRNA in the brain during days 10-14. To examine whether such c-fos increase contributes to the development of seizure susceptibility, we administered antisense oligodeoxynucleotide to c-fos by continuous infusion into the lateral ventricle of mice that had shown a moderate stage of EA seizure, and evaluated the seizure susceptibility to kainic acid (10 mg/kg) on the 14th day. Antisense-infused mice displayed significant reduction of the c-Fos level in the hippocampus and cerebral cortex on the 7th and 14th days, and a significant decrease in seizure severity. These findings suggest that the prolonged increase in c-fos expression after EA seizure may lead to the development of seizure susceptibility.

  5. The c-Fos and c-Jun from Litopenaeus vannamei play opposite roles in Vibrio parahaemolyticus and white spot syndrome virus infection.

    PubMed

    Li, Chaozheng; Li, Haoyang; Wang, Sheng; Song, Xuan; Zhang, Zijian; Qian, Zhe; Zuo, Hongliang; Xu, Xiaopeng; Weng, Shaoping; He, Jianguo

    2015-09-01

    Growing evidence indicates that activator protein-1 (AP-1) plays a major role in stimulating the transcription of immune effector molecules in cellular response to an incredible array of stimuli, including growth factors, cytokines, cellular stresses and bacterial and viral infection. Here, we reported the isolation and characterization of a cDNA from Litopenaeus vannamei encoding the full-length c-Fos protein (named as Lvc-Fos). The predicted amino acid sequences of Lvc-Fos contained a basic-leucine zipper (bZIP) domain, which was characteristic of members of the AP-1 family. Immunoprecipitation and native-PAGE assays determined that Lvc-Fos could interact with the Lvc-Jun, a homolog of c-Jun family in L. vannamei, in a heterodimer manner. Further investigation demonstrated that Lvc-Fos and Lvc-Jun were expressed in all tested tissues and located in the nucleus. Real-time RT-PCR analysis showed both Lvc-Fos and Lvc-Jun in gills were up-regulated during Vibrio parahaemolyticus and white spot syndrome virus (WSSV) challenges. In addition, reporter gene assays indicated Lvc-Fos and Lvc-Jun could activate the expression of antimicrobial peptides (AMPs) of Drosophila and shrimp, as well as WSSV immediate early (IE) genes wsv069 and wsv249, in a different manner. Knockdown of Lvc-Fos or Lvc-Jun by RNA interference (RNAi) resulted in higher mortalities of L. vannamei after infection with V. parahaemolyticus, suggesting that Lvc-Fos and Lvc-Jun might play protective roles in bacterial infection. However, silencing of Lvc-Fos or Lvc-Jun in shrimp caused lower mortalities and virus loads under WSSV infection, suggesting that Lvc-Fos and Lvc-Jun could be engaged for WSSV replication and pathogenesis. In conclusion, our results provided experimental evidence and novel insight into the roles of L. vannamei AP-1 in bacterial and viral infection.

  6. Modification of fos proteins: phosphorylation of c-fos, but not v-fos, is stimulated by 12-tetradecanoyl-phorbol-13-acetate and serum.

    PubMed Central

    Barber, J R; Verma, I M

    1987-01-01

    We have investigated the covalent modification of the proteins encoded by the murine fos proto-oncogene (c-fos) and that of the corresponding gene product of FBJ murine osteosarcoma virus (v-fos). Both proteins are posttranslationally processed in the cell, resulting in forms with lower electrophoretic mobilities than that of the initial translation product on sodium dodecyl sulfate-polyacrylamide gels. Treatment with alkaline phosphatase indicates that most, if not all, of this electrophoretic shift is due to phosphoesterification of both proteins. These phosphoryl groups stoichiometrically modify the v-fos and c-fos proteins on serine residues and turn over rapidly in vivo in the presence of protein kinase inhibitors (half-life, less than 15 min). Direct quantitative comparison of steady-state labeling studies with L-[35S]methionine and [32P]phosphate reveals that the c-fos protein is four- to fivefold more highly phosphorylated than the v-fos protein is. Comparison of tryptic fragments from [32P]phosphate-labeled proteins indicates that although the two proteins have several tryptic phosphopeptides in common, the c-fos protein contains unique major tryptic phosphopeptides that the v-fos protein lacks. These unique sites of c-fos phosphorylation have been tentatively localized to the carboxy-terminal 20 amino acid residues of the protein. Phosphorylation of the c-fos protein, but not the v-fos protein, can be stimulated at least fivefold in vivo by the addition of either 12-tetradecanoyl-phorbol-13-acetate or serum. This increase in the steady-state degree of phosphorylation of c-fos appears to be independent of protein kinase C since phosphorylation is Ca2+ and diacylglycerol independent. The possible role of phosphorylation of these proteins in cellular transformation is discussed. Images PMID:3110603

  7. Unique gene alterations are induced in FACS-purified Fos-positive neurons activated during cue-induced relapse to heroin seeking.

    PubMed

    Fanous, Sanya; Guez-Barber, Danielle H; Goldart, Evan M; Schrama, Regina; Theberge, Florence R M; Shaham, Yavin; Hope, Bruce T

    2013-01-01

    Cue-induced heroin seeking after prolonged withdrawal is associated with neuronal activation and altered gene expression in prefrontal cortex (PFC). However, these previous studies assessed gene expression in all neurons regardless of their activity state during heroin seeking. Using Fos as a marker of neural activity, we describe distinct molecular alterations induced in activated versus non-activated neurons during cue-induced heroin seeking after prolonged withdrawal. We trained rats to self-administer heroin for 10 days (6 h/day) and assessed cue-induced heroin seeking in extinction tests after 14 or 30 days. We used fluorescent-activated cell sorting (FACS) to purify Fos-positive and Fos-negative neurons from PFC 90 min after extinction testing. Flow cytometry showed that Fos-immunoreactivity was increased in less than 10% of sparsely distributed PFC neurons. mRNA levels of the immediate early genes fosB, arc, egr1, and egr2, as well as npy and map2k6, were increased in Fos-positive, but not Fos-negative, neurons. In support of these findings, double-label immunohistochemistry indicated substantial coexpression of neuropeptide Y (NPY)- and Arc-immunoreactivity in Fos-positive neurons. Our data indicate that cue-induced relapse to heroin seeking after prolonged withdrawal induces unique molecular alterations within activated PFC neurons that are distinct from those observed in the surrounding majority of non-activated neurons.

  8. An indirect action contributes to c-fos induction in paraventricular hypothalamic nucleus by neuropeptide Y

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Neuropeptide Y (NPY) is a well-established orexigenic peptide and hypothalamic paraventricular nucleus (PVH) is one major brain site that mediates the orexigenic action of NPY. NPY induces abundant expression of C-Fos, an indicator for neuronal activation, in the PVH, which has been used extensively...

  9. ΔFosB in the supraoptic nucleus contributes to hyponatremia in rats with cirrhosis.

    PubMed

    Cunningham, J Thomas; Nedungadi, Thekkethil Prashant; Walch, Joseph D; Nestler, Eric J; Gottlieb, Helmut B

    2012-07-15

    Bile duct ligation (BDL), a model of hepatic cirrhosis, is associated with dilutional hyponatremia and inappropriate vasopressin release. ΔFosB staining was significantly increased in vasopressin and oxytocin magnocellular neurosecretory cells in the supraoptic nucleus (SON) of BDL rats. We tested the role of SON ΔFosB in fluid retention following BDL by injecting the SON (n = 10) with 400 nl of an adeno-associated virus (AAV) vector expressing ΔJunD (a dominant negative construct for ΔFosB) plus green fluorescent protein (GFP) (AAV-GFP-ΔJunD). Controls were either noninjected or injected with an AAV vector expressing only GFP. Three weeks after BDL or sham ligation surgery, rats were individually housed in metabolism cages for 1 wk. Average daily water intake was significantly elevated in all BDL rats compared with sham ligated controls. Average daily urine output was significantly greater in AAV-GFP-ΔJunD-treated BDL rats compared with all other groups. Daily average urine sodium concentration was significantly lower in AAV-GFP-ΔJunD-treated BDL rats than the other groups, although average daily sodium excretion was not different among the groups. SON expression of ΔJunD produced a diuresis in BDL rats that may be related to decreased circulating levels of vasopressin or oxytocin. These findings support the view that ΔFosB expression in SON magnocellular secretory cells contribute to dilutional hyponatremia in BDL rats.

  10. Cryptotanshinone Regulates Androgen Synthesis through the ERK/c-Fos/CYP17 Pathway in Porcine Granulosa Cells

    PubMed Central

    Ye, Danfeng; Li, Meifang; Zhang, Yuehui; Wang, Xinhua; Liu, Hua; Wu, Wanting; Ma, Wanying; Quan, Kewei; Ng, Ernest H. Y.

    2017-01-01

    The aim of the study is to investigate the molecular mechanism behind androgen reduction in porcine granulosa cells (pGCs) with Salvia miltiorrhiza Bunge extract cryptotanshinone. PGCs were isolated from porcine ovaries and identified. Androgen excess model of the pGCs was induced with the MAPK inhibitor PD98059 and then treated with cryptotanshinone. The testosterone level was measured by radioimmunoassay in the culture media. The protein levels of P-ERK1/2, c-Fos, and CYP17 in the cells were measured by western blot. Cryptotanshinone decreased the concentration of testosterone and the protein level of CYP17 and increased the protein levels of P-ERK1/2 and c-Fos in the androgen excess mode. After the c-Fos gene was silenced by infection with c-Fos shRNA lentivirus, we measured the mRNA expression by quantitative RT-PCR and protein level by western blot of P-ERK1/2, c-Fos, and CYP17. This showed that the mRNA expression and protein level of P-ERK1/2 and c-Fos were significantly reduced in the shRNA–c-Fos group compared to the scrambled group, while those of CYP17 were significantly increased. So we concluded that cryptotanshinone can significantly reduce the androgen excess induced by PD98059 in pGCs. The possible molecular mechanism for this activity is regulating the ERK/c-Fos/CYP17 pathway. PMID:28167972

  11. Stimulation of Fos- and Jun-related genes during distraction osteogenesis.

    PubMed

    Lewinson, Dina; Rachmiel, Adi; Rihani-Bisharat, Souhir; Kraiem, Zaki; Schenzer, Pesia; Korem, Sigal; Rabinovich, Yaron

    2003-09-01

    Bone cells respond to mechanical stimulation by gene expression. The molecular events involved in the translation of mechanical stimulation into cell proliferation and bone formation are not yet well understood. We looked for the expression of early-response genes of the AP-1 transcription factor complex in an in vivo bone regeneration system subjected to mechanical forces because these genes were found to be related to mechanotransduction and important for bone development. Sheep maxillary bone was distracted daily for 15 days. c-Jun and c-Fos were evaluated by Northern blotting analysis and immunohistochemistry in biopsy specimens removed at 8 and 15 days and were compared with post-osteotomy but not distracted repair tissue. Elevated levels of c-Jun and c-Fos mRNA were found after 8 days of distraction. Likewise, mesenchyme-like and fibroblast-like cells composing the 8-day distracted regeneration tissue showed increases in the intensity of immunostaining compared to cells in the corresponding non-distracted fracture repair tissue. After 15 days of distraction, when bone trabeculae start to form distally and proximally in the distracted regeneration tissue, mostly preosteoblasts and osteoblasts retained c-Fos and c-Jun immunoreactivity, similar to bone-associated cells in control non-distracted fracture repair tissue. We propose that the elevated expression of c-Jun and c-Fos is related to mechanical stimulation in this in vivo bone regeneration system.

  12. Prostaglandin E2-induced up-regulation of c-fos messenger ribonucleic acid is primarily mediated by 3',5'-cyclic adenosine monophosphate in MC3T3-E1 osteoblasts

    NASA Technical Reports Server (NTRS)

    Fitzgerald, J.; Dietz, T. J.; Hughes-Fulford, M.

    2000-01-01

    The mechanism by which the proto-oncogene, c-fos, is up-regulated in response to PGE2 in the mouse osteoblastic (MC3T3-E1) cell line was investigated using RT-PCR. c-fos messenger RNA up-regulation by dmPGE2 is rapid, starting 10 min post stimulation, and transient. The specific protein kinase A (PKA) inhibitor, H89, inhibited c-fos induction. Moreover, down-regulation of protein kinase C (PKC) activity by chronic TPA treatment had no effect on the induction of c-fos by dmPGE2. We conclude that up-regulation of c-fos by dmPGE2 is primarily dependent on PKA in MC3T3-E1 osteoblasts. In S49 lymphoma wild-type but not S49 cyc- cells, which are deficient in cAMP signaling, dmPGE2 up-regulates c-fos and increases cell growth compared with unstimulated cells. Thus in S49 lymphoma cells, c-fos induction by PGE2 is also dependent on cAMP signaling. The minimal c-fos promoter region required for dmPGE2-induced expression was identified by transfecting c-fos promoter deletion constructs coupled to the chloramphenicol acetyltransferase (CAT) reporter gene into Vero cells. Transfection of a plasmid containing 99 bp c-fos proximal promoter was sufficient to direct c-fos/CAT expression following stimulation with dmPGE2. Because induction of c-fos is mediated by cAMP, these data are consistent with activation of c-fos via the CRE/ATF cis element.

  13. Classic phenotype of Coffin-Lowry syndrome in a female with stimulus-induced drop episodes and a genotype with preserved N-terminal kinase domain.

    PubMed

    Rojnueangnit, Kitiwan; Jones, Julie R; Basehore, Monica J; Robin, Nathaniel H

    2014-02-01

    An adolescent female presented with intellectual disability, stimulus-induced drop episodes (SIDEs), facial characteristics that include wide set eyes, short nose with wide columella, full and everted lips with wide mouth and progressive skeletal changes: scoliosis, spondylolisthesis and pectus excavatum. These findings were suggestive of Coffin-Lowry syndrome (CLS), and this was confirmed by the identification of a novel mutation in RPS6KA3, a heterozygous one basepair duplication at nucleotide 1570 (c.1570dupA). This mutation occurs within the C-terminal kinase domain of the protein, and, therefore contradicts the previous report that SIDEs is only associated with premature truncation of the protein in the N-terminal kinase domain or upstream of this domain. As CLS is X-linked, it is unusual for a female to have such a classic phenotype.

  14. Fluctuations and Stimulus-Induced Changes in Blood Flow Observed in Individual Capillaries in Layers 2 through 4 of Rat Neocortex

    NASA Astrophysics Data System (ADS)

    Kleinfeld, David; Mitra, Partha P.; Helmchen, Fritjof; Denk, Winfried

    1998-12-01

    Cortical blood flow at the level of individual capillaries and the coupling of neuronal activity to flow in capillaries are fundamental aspects of homeostasis in the normal and the diseased brain. To probe the dynamics of blood flow at this level, we used two-photon laser scanning microscopy to image the motion of red blood cells (RBCs) in individual capillaries that lie as far as 600 μ m below the pia mater of primary somatosensory cortex in rat; this depth encompassed the cortical layers with the highest density of neurons and capillaries. We observed that the flow was quite variable and exhibited temporal fluctuations around 0.1 Hz, as well as prolonged stalls and occasional reversals of direction. On average, the speed and flux (cells per unit time) of RBCs covaried linearly at low values of flux, with a linear density of ≈ 70 cells per mm, followed by a tendency for the speed to plateau at high values of flux. Thus, both the average velocity and density of RBCs are greater at high values of flux than at low values. Time-locked changes in flow, localized to the appropriate anatomical region of somatosensory cortex, were observed in response to stimulation of either multiple vibrissae or the hindlimb. Although we were able to detect stimulus-induced changes in the flux and speed of RBCs in some single trials, the amplitude of the stimulus-evoked changes in flow were largely masked by basal fluctuations. On average, the flux and the speed of RBCs increased transiently on stimulation, although the linear density of RBCs decreased slightly. These findings are consistent with a stimulus-induced decrease in capillary resistance to flow.

  15. The designed protein M(II)-Gly-Lys-His-Fos(138-211) specifically cleaves the AP-1 binding site containing DNA.

    PubMed

    Harford, C; Narindrasorasak, S; Sarkar, B

    1996-04-09

    A new specific DNA cleavage protein, Gly-Lys-His-Fos(138-211), was designed, expressed, and characterized. The DNA-binding component of the design uses the basic and leucine zipper regions of the leucine zipper Fos, which are represented by Fos(138-211). The DNA cleavage moiety was provided by the design of the amino-terminal Cu(II)-, Ni(II)-binding site GKH at the amino terminus of Fos(138-211). Binding of Cu(II) or Ni(II) by the protein activates its cleavage ability. The GKH motif was predicted to form a specific amino-terminal Cu(II)-, Ni(II)-binding motif as previously defined [Predki, P. F., Harford, C., Brar, P., & Sarkar, B. (1992) Biochem. J. 287, 211 -215]. This prediction was verified as the tripeptide, GKH, and the expressed protein, GKH-Fos(138-211), were both shown to be capable of binding Cu(II) and Ni(II). The designed protein upon heterodimerization with Jun(248-334) was shown to bind to and cleave several forms of DNA which contained an AP-1 binding site. The cleavage was shown to be specific. This design demonstrates the versatility of the amino-terminal Cu(II)-, Ni(II)-binding motif and the variety of motifs which can be generated. The site of cleavage by GKH-Fos(138-211) on DNA provides further information regarding the bending of DNA upon binding to Fos-Jun heterodimers.

  16. Fos immunoreactivity in the rat forebrain induced by electrical stimulation of the dorsolateral periaqueductal gray matter.

    PubMed

    Lim, Lee Wei; Temel, Yasin; Visser-Vandewalle, Veerle; Blokland, Arjan; Steinbusch, Harry

    2009-10-01

    Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) matter induces panic- or fear-like responses with intense emotional distress and severe anxiety. In this study, we evoked panic-like behaviour by dlPAG stimulation and evaluated the effect on neuronal activation in different brain regions. The number of c-Fos immunoreactive (c-Fos-ir) cells was measured semi-quantitatively through series of stained rat brain sections. Our results demonstrate strong neural activation in the medial prefrontal cortex, orbital cortex, anterior olfactory nuclei, secondary motor cortex, and the somatosensory cortex. Moderate increases in the number of c-Fos-ir cells were detected in various regions, including the hypothalamus, amygdala, and striatum. Additionally, there was mild expression of c-Fos-ir cells in the hippocampus, thalamus, and habenula regions. In conclusion, we have shown that deep brain stimulation of the dlPAG produced a distinctive pattern of neuronal activation across forebrain regions as compared to the sham and control animals.

  17. Sequence-specific photoinduced c-fos gene damage mediated by triple stranded-forming oligonucleotide conjugated to psoralen

    NASA Astrophysics Data System (ADS)

    Cao, En-Hua; Wang, Ju-jun; Ma, Wenjian; Qin, Jingfen

    1999-09-01

    A psoralen-oligonucleotide conjugate was designed to photoinduce a cross-link at a specific sequence of c-fos oncogene. Psoralen was attached to its C-3 position of a 20-base mer oligonucleotide, which binds to a synthetic 49 bp duplex containing the c-fos gene polypurine site, where it forms a triple stranded DNA. Upon near-UV-irradiation, the two strand of DNA are crosslinked at the TpA step present at the triple-duplex junction. Results show that the yield of the photoinduce cross- linking reaction is quite high. We treated HeLa cells with above 2-mer oligonucleotide conjugated to psoralen. The expression of c-fos oncogene was significant reduced, no significant effect on the level of c-myc mRNA. These data indicate that such psoralen- oligonucleotide conjugates could be used to selectively control gene expression or to induce sequence-specific damages.

  18. CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum

    PubMed Central

    Levine, Amir A.; Guan, Zhonghui; Barco, Angel; Xu, Shiqin; Kandel, Eric R.; Schwartz, James H.

    2005-01-01

    Remodeling chromatin is essential for cAMP-regulated gene expression, necessary not only for development but also for memory storage and other enduring mental states. Histone acetylation and deacetylation mediate long-lasting forms of synaptic plasticity in Aplysia as well as cognition in mice. Here, we show that histone acetylation by the cAMP-response element binding protein (CREB)-binding protein (CBP) mediates sensitivity to cocaine by regulating expression of the fosB gene and its splice variant, ΔfosB, a transcription factor previously implicated in addiction. Using the chromatin immunoprecipitation assay with antibodies against histone H4 or CBP, we find that CBP is recruited to the fosB promoter to acetylate histone H4 in response to acute exposure to cocaine. We show that mutant mice that lack one allele of the CBP gene and have normal levels of fosB expression are less sensitive to chronic (10-day) administration of cocaine than are wild-type mice. This decreased sensitivity is correlated with decreased histone acetylation and results in decreased fosB expression and diminished accumulation of ΔfosB. Thus, CBP, which forms part of the promoter complex with CREB, mediates sensitivity to cocaine by acetylating histones. PMID:16380431

  19. ΔFosB induction in orbitofrontal cortex potentiates locomotor sensitization despite attenuating the cognitive dysfunction caused by cocaine

    PubMed Central

    Winstanley, Catharine A.; Green, Thomas A.; Theobald, David E.H.; Renthal, William; LaPlant, Quincey; DiLeone, Ralph J.; Chakravarty, Sumana; Nestler, Eric J.

    2010-01-01

    The effects of addictive drugs change with repeated use: many individuals become tolerant of their pleasurable effects but also more sensitive to negative sequelae (e.g., anxiety, paranoia, and drug craving). Understanding the mechanisms underlying such tolerance and sensitization may provide valuable insight into the basis of drug dependency and addiction. We have recently shown that chronic cocaine administration reduces the ability of an acute injection of cocaine to affect impulsivity in rats. However, animals become more impulsive during withdrawal from cocaine self-administration. We have also shown that chronic administration of cocaine increases expression of the transcription factor ΔFosB in the orbitofrontal cortex (OFC). Mimicking this drug-induced elevation in OFC ΔFosB through viral-mediated gene transfer mimics these behavioural changes: ΔFosB over-expression in OFC induces tolerance to the effects of an acute cocaine challenge but sensitizes rats to the cognitive sequelae of withdrawal. Here we report novel data demonstrating that increasing ΔFosB in the OFC also sensitizes animals to the locomotor-stimulant properties of cocaine. Analysis of nucleus accumbens tissue taken from rats over-expressing ΔFosB in the OFC and treated chronically with saline or cocaine does not provide support for the hypothesis that increasing OFC ΔFosB potentiates sensitization via the nucleus accumbens. These data suggest that both tolerance and sensitization to cocaine’s many effects, although seemingly opposing processes, can be induced in parallel via the same biological mechanism within the same brain region, and that drug-induced changes in gene expression within the OFC play an important role in multiple aspects of addiction. PMID:19135469

  20. Compression Induces Ephrin-A2 in PDL Fibroblasts via c-fos

    PubMed Central

    Sen, S.; Diercke, K.; Zingler, S.; Lux, C. J.

    2015-01-01

    Ephrin-A2–EphA2 and ephrin-B2–EphB4 interactions have been implicated in the regulation of bone remodeling. We previously demonstrated a potential role for members of the Eph-ephrin family of receptor tyrosine kinases for bone remodeling during orthodontic tooth movement: compression-dependent upregulation of ephrin-A2 in fibroblasts of the periodontal ligament (PDL) attenuated osteogenesis in osteoblasts of the alveolar bone. However, factors affecting the regulation of ephrin-A2 expression upon the application of compressive forces remained unclear. Here, we report a mechano-dependent pathway of ephrin-A2 induction in PDL fibroblasts (PDLFs) involving extracellular signal–regulated kinases (ERK) 1/2 and c-fos. PDLF subjected to compressive forces (30.3 g/cm2) upregulated c-fos and ephrin-A2 mRNA and protein expression and displayed increased ERK1/2 phosphorylation. Inhibition of the MAP kinase kinase (MEK)/ERK1/2 pathway using the specific MEK inhibitor U0126 significantly reduced ephrin-A2 messenger RNA upregulation upon compression. Silencing of c-fos using a small interfering RNA approach led to a significant inhibition of ephrin-A2 induction upon the application of compressive forces. Interestingly, ephrin-A2 stimulation of PDLF induced c-fos expression and led also to the induction of ephrin-A2 expression. Using a reporter gene construct in murine 3T3 cells, we found that ephrin-A2 was able to stimulate serum response element (SRE)–dependent luciferase activity. As the regulation of c-fos is SRE dependent, ephrin-A2 might induce c-fos via SRE activation. Taken together, we provide evidence for an ERK1/2- and c-fos–dependent regulation of ephrin-A2 in compressed PDLF and suggest a novel pathway for ephrin-A2 induction emanating from ephrin-A2 itself. We showed previously that ephrin-A2 at compression sites might contribute to tooth movement by inhibiting osteogenic differentiation. The regulatory pathway of ephrin-A2 induction during tooth movement

  1. Fos and pERK immunoreactivity in spinal cord slices: Comparative analysis of in vitro models for testing putative antinociceptive molecules.

    PubMed

    Ferrini, Francesco; Russo, Arianna; Salio, Chiara

    2014-07-01

    To detect central neuron activation, expression of the transcription factor Fos and phosphorylation of the protein kinase ERK (pERK) can be visualized by immunocytochemistry. These approaches have been extensively used to quantify the activation of nociceptive neurons in the spinal dorsal horn (DH) following peripheral stimulation in vivo. Here we propose an alternative and simplified in vitro model to investigate Fos and pERK expression based on the stimulation of acutely dissected spinal cord slices to mimic acute inflammatory changes in DH. Transverse slices were obtained from postnatal (P8-P12) CD1 mice and were treated for 5 min with capsaicin (CAP, 2 μM). CAP induces a strong release of glutamate from primary afferent terminals which, in turn, excites spinal DH neurons. Since ERK phosphorylation and Fos expression occur following different time frames, two distinct protocols were used to detect their activation. Thus, for studying Fos immunoreactivity CAP-treated slices were left for 3h in Krebs solution after stimulation. Instead, for studying pERK immunoreactivity slices were maintained in Krebs solution for only 15 min after stimulation. Both Fos and pERK were significantly up-regulated following CAP challenge. To validate our model we tested the efficacy of octreotide (OCT, 1 μM) in preventing the CAP effect on Fos and pERK expression. OCT is a synthetic antinociceptive analog of somatostatin, one of the neuropeptides involved in the negative modulation of pain signals in DH. After CAP, OCT reduced the response to both Fos and pERK. Our data validate the use of Fos and pERK immunoreactivity in vitro to investigate the activation of spinal nociceptive pathways and testing potentially antinociceptive molecules.

  2. Fos induction in lamina I projection neurons in response to noxious thermal stimuli.

    PubMed

    Todd, A J; Spike, R C; Young, S; Puskár, Z

    2005-01-01

    Lamina I of the spinal cord contains many projection neurons: the majority of these are activated by noxious stimulation, although some respond to other stimuli, such as innocuous cooling. In the rat, approximately 80% of lamina I projection neurons express the neurokinin 1 (NK1) receptor, on which substance P acts. Lamina I neurons can be classified into three main morphological classes: pyramidal, fusiform and multipolar cells. It has been reported that in the cat, pyramidal cells respond to innocuous cooling, and whilst both fusiform and multipolar cells are activated by noxious mechanical and heat stimuli, only cells in the latter group respond to noxious cold [Nat Neurosci 1 (1998) 218]. However, we have previously shown that NK1 receptor-immunoreactive projection neurons belonging to each morphological class are equally likely to up-regulate the transcription factor Fos after noxious chemical stimulation, and that the density of innervation by substance P-containing (nociceptive) afferents is similar for cells of each type [J Neurosci 22 (2002) 4103]. This suggests that the morphological-physiological correlation that has been reported in the cat may not apply in the rat. We have tested this further by examining Fos expression in lamina I spinoparabrachial neurons in the rat after application of noxious heat or noxious cold stimuli under general anesthesia. Following noxious heat, 57-69% of NK1 receptor-immunoreactive spinoparabrachial neurons expressed Fos, and the proportion did not differ significantly between morphological groups. However, after noxious cold stimulation Fos was present in 63% of multipolar neurons, but only 19-26% of fusiform or pyramidal cells. These results suggest that although most NK1 receptor-expressing spinoparabrachial neurons are activated by noxious stimuli, responsiveness to noxious cold is significantly more common in those of the multipolar type. There therefore appears to be a correlation between morphology and function for

  3. D1 and D2 dopamine receptors differentially increase Fos-like immunoreactivity in accumbal projections to the ventral pallidum and midbrain.

    PubMed

    Robertson, G S; Jian, M

    1995-02-01

    Alterations in dopaminergic neurotransmission have profound effects on neuronal expression of the putative activity marker, Fos, in both the dorsal and ventral striatum. Stimulants such as D-amphetamine and cocaine increase Fos-like immunoreactivity by enhancing the activation of D1 dopamine receptors. In contrast, neuroleptics such as haloperidol and raclopride increase Fos-like immunoreactivity by blocking striatal D2 dopamine receptors. In the dorsal striatum, D1 receptor stimulation elevates Fos-like immunoreactivity predominantly in neurons projecting to the midbrain (substantia nigra), whereas D2 receptor antagonism enhances Fos-like immunoreactivity principally in neurons projecting to the pallidum (globus pallidus). These findings are consistent with the proposal that D1 receptors are located chiefly on striatonigral neurons, whereas D2 receptors reside mainly on striatopallidal neurons. Since the nucleus accumbens (largest component of the ventral striatum) also sends projections to the midbrain (ventral tegmental area and substantia nigra) and pallidum (ventral pallidum), the present study utilized retrograde tract-tracing techniques to determine if there was a similar segregation of D1 agonist- and D2 antagonist-induced Fos-like immunoreactivity in these accumbal projections. In addition, we examined whether these relationships were the same in the core and shell regions of the nucleus accumbens. Like the dorsal striatum, D1 agonists (D-amphetamine and CY 208-243), but not D2 antagonists (haloperidol and clozapine), increased Fos-like immunoreactivity in accumbal neurons projecting to the midbrain (ventral tegmental area and substantia nigra). Also like the dorsal striatum, D2 antagonist-induced Fos-like immunoreactivity was located preferentially in accumbal neurons projecting to the pallidum (ventral pallidum). However, unlike the dorsal striatum, where the vast majority of neurons which display D1 agonist-induced Fos-like immunoreactivity project to

  4. Regional induction of c-fos and heat shock protein-72 mRNA following fluid-percussion brain injury in the rat

    SciTech Connect

    Raghupathi, R.; Welsh, F.A.; Gennarelli, T.A.

    1995-05-01

    To evaluate the cellular response to traumatic brain injury, the expression of mRNA for c-fos and the 72-kDa heat shock protein (hsp72) was determined using in situ hybridization following lateral fluid-percussion injury (2.2-2.4 atm) in rat brain. At 2 h after injury, induction of c-fos mRNA was restricted to regions of the cortex surrounding the contusion area. An increase in c-fos mRNA, but not hsp72 mRNA, was observed bilaterally in the CA{sub 3} subfield of the hippocampus and the granule cells of the dentate gyrus and in the thalamus ipsilateral to the impact site. By 6 h, increased expression of c-fos mRNA was observed only in the corpus callosum on the impact side; hsp72 mRNA persisted in the deep cortical layers and upper layers of the subcortical white matter below the site of maximal injury. By 24 h, both c-fos and hsp72 mRNA had returned to control levels in all regions of the brain. These results demonstrate that lateral fluid-percussion brain injury triggers regionally and temporally specific expression of c-fos and hsp72 mRNA, which may be suggestive of differential neurochemical alterations in neurons and glia following experimental brain injury. 33 refs., 3 figs., 1 tab.

  5. Silymarin suppresses basal and stimulus-induced activation, exhaustion, differentiation, and inflammatory markers in primary human immune cells.

    PubMed

    Lovelace, Erica S; Maurice, Nicholas J; Miller, Hannah W; Slichter, Chloe K; Harrington, Robert; Magaret, Amalia; Prlic, Martin; De Rosa, Stephen; Polyak, Stephen J

    2017-01-01

    Silymarin (SM), and its flavonolignan components, alter cellular metabolism and inhibit inflammatory status in human liver and T cell lines. In this study, we hypothesized that SM suppresses both acute and chronic immune activation (CIA), including in the context of HIV infection. SM treatment suppressed the expression of T cell activation and exhaustion markers on CD4+ and CD8+ T cells from chronically-infected, HIV-positive subjects. SM also showed a trend towards modifying CD4+ T cell memory subsets from HIV+ subjects. In the HIV-negative setting, SM treatment showed trends towards suppressing pro-inflammatory cytokines from non-activated and pathogen-associated molecular pattern (PAMP)-activated primary human monocytes, and non-activated and cytokine- and T cell receptor (TCR)-activated mucosal-associated invariant T (MAIT) cells. The data suggest that SM elicits broad anti-inflammatory and immunoregulatory activity in primary human immune cells. By using novel compounds to alter cellular inflammatory status, it may be possible to regulate inflammation in both non-disease and disease states.

  6. Silymarin suppresses basal and stimulus-induced activation, exhaustion, differentiation, and inflammatory markers in primary human immune cells

    PubMed Central

    Lovelace, Erica S.; Maurice, Nicholas J.; Miller, Hannah W.; Slichter, Chloe K.; Harrington, Robert; Magaret, Amalia; Prlic, Martin; De Rosa, Stephen; Polyak, Stephen J.

    2017-01-01

    Silymarin (SM), and its flavonolignan components, alter cellular metabolism and inhibit inflammatory status in human liver and T cell lines. In this study, we hypothesized that SM suppresses both acute and chronic immune activation (CIA), including in the context of HIV infection. SM treatment suppressed the expression of T cell activation and exhaustion markers on CD4+ and CD8+ T cells from chronically-infected, HIV-positive subjects. SM also showed a trend towards modifying CD4+ T cell memory subsets from HIV+ subjects. In the HIV-negative setting, SM treatment showed trends towards suppressing pro-inflammatory cytokines from non-activated and pathogen-associated molecular pattern (PAMP)-activated primary human monocytes, and non-activated and cytokine- and T cell receptor (TCR)-activated mucosal-associated invariant T (MAIT) cells. The data suggest that SM elicits broad anti-inflammatory and immunoregulatory activity in primary human immune cells. By using novel compounds to alter cellular inflammatory status, it may be possible to regulate inflammation in both non-disease and disease states. PMID:28158203

  7. Changes in NGF/c-Fos colocalization in specific limbic structures of juvenile and aged rats after open field stimulation.

    PubMed

    Badowska-Szalewska, E; Klejbor, I; Cecot, T; Domaradzka-Pytel, B; Ludkiewicz, B; Moryś, J

    2009-08-01

    Changes in NGF release during stressful events have been associated with the activation of neurons expressing NGF receptors. This study examined the influence of acute stress-induced stimulation on NGF/c-Fos colocalization in the following limbic regions: the paraventricular (PV) nucleus of the hypothalamus, medial (MeA) nucleus of the amygdala, and CA3 hippocampus. Juvenile (P21) and aged rats (P360) were exposed to a 15-minute acute open field (OF) test. Double immunofluorescence staining, used to detect NGF-ir and c-Fos-ir cells, revealed a higher percentage of NGF/c-Fos-ir neurons in the P21 control group than in the P360 control group. Under OF acute stimulation, a statistically significant (p < 0.05) increase of NGF/c-Fos level in CA3 of juvenile animals and in PV and CA3 of the aged rats was observed. These observations indicate that the investigated structures in both age groups show a different response to acute OF stimulation. Acute OF affects the levels of NGF/c-Fos more significantly in aged rats.

  8. MicroRNA-490-5p inhibits proliferation of bladder cancer by targeting c-Fos

    SciTech Connect

    Li, Shiqi; Xu, Xianglai; Xu, Xin; Hu, Zhenghui; Wu, Jian; Zhu, Yi; Chen, Hong; Mao, Yeqing; Lin, Yiwei; Luo, Jindan; Zheng, Xiangyi; Xie, Liping

    2013-11-29

    Highlights: •We examined the level of miR-490-5p in bladder cancer tissues and three cancer cell lines. •We are the first to show the function of miR-490-5p in bladder cancer. •We demonstrate c-Fos may be a target of miR-490-5p. -- Abstract: MicroRNAs (miRNAs) are non-protein-coding sequences that play a crucial role in tumorigenesis by negatively regulating gene expression. Here, we found that miR-490-5p is down-regulated in human bladder cancer tissue and cell lines compared to normal adjacent tissue and a non-malignant cell line. To better characterize the function of miR-490-5p in bladder cancer, we over-expressed miR-490-5p in bladder cancer cell lines with chemically synthesized mimics. Enforced expression of miR-490-5p in bladder cancer cells significantly inhibited the cell proliferation via G1-phase arrest. Further studies found the decreased c-Fos expression at both mRNA and protein levels and Luciferase reporter assays demonstrated that c-Fos is a direct target of miR-490-5p in bladder cancer. These findings indicate miR-490-5p to be a novel tumor suppressor of bladder cancer cell proliferation through targeting c-Fos.

  9. Pregnancy affects FOS rhythms in brain regions regulating sleep/wake state and body temperature in rats.

    PubMed

    Schrader, Jessica A; Smale, Laura; Nunez, Antonio A

    2012-10-22

    Circadian rhythms in behavior and physiology change substantially as female mammals undergo the transition from a non-pregnant to a pregnant state. Here, we examined the possibility that site-specific changes in brain regions known to regulate the sleep/wake cycle and body temperature might reflect altered rhythms in these overt functions. Specifically, we compared daily patterns of immunoreactive FOS in early pregnant and diestrous rats in the medial septum (MS), vertical and horizontal diagonal bands of Broca (VDB and HDB), perifornical lateral hypothalamus (LH), and ventrolateral, medial, and median preoptic areas (VLPO, MPA, and MnPO, respectively). In the pregnant animals, FOS expression was reduced and the daily rhythms of expression were lost or attenuated in the MS, VDB, and LH, areas known to support wakefulness, and in the MPA, a brain region that may coordinate sleep/wake patterns with temperature changes. However, despite the well-documented differences in sleep patterns between diestrous and pregnant rats, reproductive state did not affect FOS expression in the VLPO or MnPO, two brain regions in which FOS expression usually correlates with sleep. These data indicate that plasticity in sleep/wake patterns during early pregnancy may be driven by a reduction in wakefulness-promotion by the brain, rather than by an increase in sleep drive.

  10. Mechanical Stimulus-Induced Wthdrawal Behavior Increases Subsequent Pre-Stimulus Local Field Potential Power in the Rostral Anterior Cingulate Cortex in Unanesthetized Rats.

    PubMed

    Shen, Zui; Sun, Jing; Liu, Boyi; Jiang, Yongliang; Wu, Yuanyuan; Wang, Jialing; Shao, Xiaomei; Fang, Jianqiao

    2017-03-02

    BACKGROUND The rostral anterior cingulate cortex (rACC) is important in pain expectation. Previous studies demonstrated that mechanical stimulus-induced withdrawal behaviors are spinally-mediated nocifensive reflexes in rats, but it is not known whether pain expectation is influenced by withdrawal behaviors. MATERIAL AND METHODS We reanalyzed previous mechanosensitivity measurements of 244 rats measured 5 times in succession. To study neural oscillation in the rACC, 1 recording microwire array was surgically implanted. Then, we simultaneously recorded the local field potential (LFP) of the rACC over the course of multiple withdrawal behaviors in unanesthetized rats. RESULTS From our previous withdrawal behavioral data in 244 rats, we observed that the distributions of paw withdrawal thresholds (PWTs) were denser and more concentrated after the first withdrawal behavior. Compared to the first mechanical stimulus, increased neuronal synchrony and a stronger delta band component existed in each pre-stimulus LFP in the rACC during subsequent stimuli. CONCLUSIONS Pain expectation could be involved in withdrawal behaviors, which is related to increased total power and delta band power of the subsequent pre-stimulus LFPs in the rACC.

  11. Background and stimulus-induced patterns of high metabolic activity in the visual cortex (area 17) of the squirrel and macaque monkey

    SciTech Connect

    Humphrey, A.L.; Hendrickson, A.E.

    1983-02-01

    The authors have used 2-deoxy-D-(/sup 14/C)glucose (2-DG) autoradiography and cytochrome oxidase histochemistry to examine background and stimulus-induced patterns of metabolic activity in monkey striate cortex. In squirrel monkeys (Saimiri sciureus) that binocularly or monocularly viewed diffuse white light or binocularly viewed bars of many orientations and spatial frequencies, 2-DG consumption was not uniform across the cortex but consisted of regularly spaced radial zones of high uptake. The cytochrome oxidase stain in these animals also revealed patches of high metabolism which coincided with the 2-DG patches. Squirrel monkeys binocularly viewing vertical stripes showed parallel bands of increased 2-DG uptake in the cortex, while the cytochrome label in these animals remained patchy. In macaque (Macaca nemestrina) monkeys, binocular stimulation with many orientations and spatial frequencies produced radial zones of high 2-DG uptake. When viewed tangentially, these zones formed a dots-in-rows pattern with a spacing of 350 X 500 microns; cytochrome oxidase staining produced an identical pattern. Macaca differed from Saimiri in that monocular stimulation labeled alternate rows. These results indicate that there are radial zones of high background metabolism across squirrel and macaque monkey striate cortex. In Saimiri these zones do not appear to be related to an eye dominance system, while in Macaca they do. The presence of these zones of high metabolism may complicate the interpretation of 2-DG autoradiographs that result from specific visual stimuli.

  12. Mechanical Stimulus-Induced Withdrawal Behavior Increases Subsequent Pre-Stimulus Local Field Potential Power in the Rostral Anterior Cingulate Cortex in Unanesthetized Rats

    PubMed Central

    Shen, Zui; Sun, Jing; Liu, Boyi; Jiang, Yongliang; Wu, Yuanyuan; Wang, Jialing; Shao, Xiaomei; Fang, Jianqiao

    2017-01-01

    Background The rostral anterior cingulate cortex (rACC) is important in pain expectation. Previous studies demonstrated that mechanical stimulus-induced withdrawal behaviors are spinally-mediated nocifensive reflexes in rats, but it is not known whether pain expectation is influenced by withdrawal behaviors. Material/Methods We reanalyzed previous mechanosensitivity measurements of 244 rats measured 5 times in succession. To study neural oscillation in the rACC, 1 recording microwire array was surgically implanted. Then, we simultaneously recorded the local field potential (LFP) of the rACC over the course of multiple withdrawal behaviors in unanesthetized rats. Results From our previous withdrawal behavioral data in 244 rats, we observed that the distributions of paw withdrawal thresholds (PWTs) were denser and more concentrated after the first withdrawal behavior. Compared to the first mechanical stimulus, increased neuronal synchrony and a stronger delta band component existed in each pre-stimulus LFP in the rACC during subsequent stimuli. Conclusions Pain expectation could be involved in withdrawal behaviors, which is related to increased total power and delta band power of the subsequent pre-stimulus LFPs in the rACC. PMID:28250407

  13. Divergent regulation of the human atrial natriuretic peptide gene by c-jun and c-fos.

    PubMed Central

    Kovacic-Milivojević, B; Gardner, D G

    1992-01-01

    Employing transient transfection analysis in neonatal rat cardiocytes, we have demonstrated that overexpression of c-jun results in a dose-dependent induction of the human atrial natriuretic peptide (hANP) gene promoter. Studies using a series of mutations in the hANP gene promoter identified a TRE-like, cis-acting regulatory sequence which conferred c-jun sensitivity. This same region was shown to interact with the c-jun/c-fos complex in an in vitro gel mobility shift assay. Selective mutation of this site suppressed basal activity of the hANP promoter and significantly reduced c-jun-dependent activation. Overexpression of c-fos had a biphasic effect on hANP gene promoter activity. At low levels, in concert with c-jun, it activated, while at higher levels it suppressed, transcription from the hANP gene promoter. This inhibition was both cell and promoter specific. hANP gene promoter sequences which mediate c-fos-dependent inhibition appear to be separable from those responsible for the induction. In addition, the protein domains on c-fos responsible for transcriptional activation and repression can be segregated topographically, with the inhibitory activity being localized to the carboxy-terminal domain. Thus, c-fos can activate or repress hANP gene expression through two separate functional domains that act on distinct regulatory elements in the hANP gene promoter. These data imply that the ANP gene may be a physiological target for c-fos- and c-jun-dependent activity in the heart and suggest a potential mechanism linking environmental stimuli to its expression. Images PMID:1530876

  14. Modulation of c-jun and c-fos transcription by UVB and UVA radiations in human dermal fibroblasts and KB cells.

    PubMed

    Soriani, M; Hejmadi, V; Tyrrell, R M

    2000-05-01

    We have previously demonstrated that the oxidizing component of ultraviolet-A (UVA) plays a central role in the activation of the nuclear oncogene and transcription factor, c-fos, in cultured human skin fibroblasts. We have now shown that expression of both c-jun and c-fos (AP-1) family of transcription factors is modulated by short and long wavelength solar ultraviolet (UV) radiation in human fibroblasts and human KB cells. UVA radiation activated c-jun and c-fos in both fibroblasts and KB cells, whereas ultraviolet-B (UVB) radiation activates such oncogenes only in KB cells. Moreover, decreasing the intracellular levels of reducing equivalents in human fibroblasts by glutathione (GSH) depletion lowered the UVA dose threshold for c-jun and c-fos activation several-fold and greatly amplified the UVA-mediated activation of such genes. A more modest effect was observed in GSH-depleted KB cells. In both GSH-depleted fibroblasts and KB cells, UVB radiation failed to amplify c-jun and c-fos activation indicating that the oxidative component of UVB plays a minor role in the modulation of such oncogene expression. These findings clearly indicate that both c-jun and c-fos are activated by the oxidizing component of UVA radiation in human fibroblasts and KB cells, while UVB-mediated modulation seems to be restricted to human epithelial cells and does not involve oxidizing intermediates.

  15. Oncogene N-ras mediates selective inhibition of c-fos induction by nerve growth factor and basic fibroblast growth factor in a PC12 cell line.

    PubMed Central

    Thomson, T M; Green, S H; Trotta, R J; Burstein, D E; Pellicer, A

    1990-01-01

    A cell line was generated from U7 cells (a subline of PC12 rat pheochromocytoma cells) that contains a stably integrated transforming mouse N-ras (Lys-61) gene under the control of the long terminal repeat from mouse mammary tumor virus. Such cells, designated UR61, undergo neuronal differentiation upon exposure to nanomolar concentrations of dexamethasone, as a consequence of expression of the activated N-ras gene (I. Guerrero, A. Pellicer, and D.E. Burstein, Biochem, Biophys. Res. Commun. 150:1185-1192, 1988). Exposure of UR61 cells to either nerve growth factor (NGF) or basic fibroblast growth factor (bFGF) results in a marked induction of c-fos RNA, with kinetics paralleling those of NGF- or bFGF-induced expression of c-fos RNA in PC12 cells. Dexamethasone-induced expression of activated N-ras p21 results in blocking of c-fos RNA induction by NGF or bFGF in a time-dependent manner. Activated N-ras p21-mediated inhibition of c-fos RNA induction in UR61 cells is selective for NGF and bFGF and is not due to selective degradation of c-fos RNA. Normal and transforming N-ras can trans activate the chloramphenicol acetyltransferase gene linked to mouse c-fos regulatory sequences when transient expression assays are performed. Our observations suggest that N-ras p21 selectively interacts with pathways involved in induction of c-fos expression which initiate at the receptors for NGF and bFGF. Images PMID:2108319

  16. Differential regulation of prodynophin, c-fos, and serotonin transporter mRNA following withdrawal from a chronic, escalating dose regimen of D-amphetamine.

    PubMed

    Horner, Kristen A; Noble, Erika S; Lauterbach, Edward C

    2009-04-01

    Several lines of evidence suggest that D-amphetamine (D-AMPH) withdrawal induces a syndrome with symptoms similar to major depressive disorder (MDD). Upregulation of dynorphin (DYN) may underlie the symptoms of MDD and contribute to the negative emotional symptoms associated with psychostimulant withdrawal. Changes in the serotonin transporter (SERT) have also been reported in MDD, and changes in the immediate early gene c-fos have been observed in the context of psychostimulant withdrawal. This study examined the effects of chronic, escalating doses of D-AMPH followed by 24 h of withdrawal on the expression of prodynorphin (PD) and c-fos mRNA in limbic regions of the brain, caudate putamen (CPu), and brainstem and SERT mRNA expression in the dorsal raphe nucleus (DRN). Male Sprague-Dawley rats were treated three times a day for 4 days with escalating doses of D-AMPH (1-10 mg/kg) and sacrificed 24 h after the last injection. Following 24 h of withdrawal, there was an increase in PD and c-fos mRNA expression in the CPu and nucleus accumbens (NAc), and a decrease in PD and c-fos expression in hippocampus and amygdala. SERT mRNA expression was decreased in the DRN, and PD mRNA expression was increased in the adjacent ventrolateral periaqueductal gray (VLPAG) following D-AMPH withdrawal. These data indicate that region-specific changes in PD and c-fos expression occur after withdrawal, while SERT mRNA expression is suppressed, similar to what has been reported in MDD. Alterations in PD, c-fos, and SERT expression could contribute to the depression-like syndrome associated with psychostimulant withdrawal.

  17. Chronic unpredictable mild stress alters an anxiety-related defensive response, Fos immunoreactivity and hippocampal adult neurogenesis.

    PubMed

    de Andrade, J S; Céspedes, I C; Abrão, R O; Dos Santos, T B; Diniz, L; Britto, L R G; Spadari-Bratfisch, R C; Ortolani, D; Melo-Thomas, L; da Silva, R C B; Viana, M B

    2013-08-01

    Previous results show that elevated T-maze (ETM) avoidance responses are facilitated by acute restraint. Escape, on the other hand, was unaltered. To examine if the magnitude of the stressor is an important factor influencing these results, we investigated the effects of unpredictable chronic mild stress (UCMS) on ETM avoidance and escape measurements. Analysis of Fos protein immunoreactivity (Fos-ir) was used to map areas activated by stress exposure in response to ETM avoidance and escape performance. Additionally, the effects of the UCMS protocol on the number of cells expressing the marker of migrating neuroblasts doublecortin (DCX) in the hippocampus were investigated. Corticosterone serum levels were also measured. Results showed that UCMS facilitates ETM avoidance, not altering escape. In unstressed animals, avoidance performance increases Fos-ir in the cingulate cortex, hippocampus (dentate gyrus) and basomedial amygdala, and escape increases Fos-ir in the dorsolateral periaqueductal gray and locus ceruleus. In stressed animals submitted to ETM avoidance, increases in Fos-ir were observed in the cingulate cortex, ventrolateral septum, hippocampus, hypothalamus, amygdala, dorsal and median raphe nuclei. In stressed animals submitted to ETM escape, increases in Fos-ir were observed in the cingulate cortex, periaqueductal gray and locus ceruleus. Also, UCMS exposure decreased the number of DCX-positive cells in the dorsal and ventral hippocampus and increased corticosterone serum levels. These data suggest that the anxiogenic effects of UCMS are related to the activation of specific neurobiological circuits that modulate anxiety and confirm that this stress protocol activates the hypothalamus-pituitary-adrenal axis and decreases hippocampal adult neurogenesis.

  18. DeltaFosB accumulates in a GABAergic cell population in the posterior tail of the ventral tegmental area after psychostimulant treatment.

    PubMed

    Perrotti, Linda I; Bolaños, Carlos A; Choi, Kwang-Ho; Russo, Scott J; Edwards, Scott; Ulery, Paula G; Wallace, Deanna L; Self, David W; Nestler, Eric J; Barrot, Michel

    2005-05-01

    The transcription factor deltaFosB is induced in the nucleus accumbens and dorsal striatum by chronic exposure to several drugs of abuse, and increasing evidence supports the possibility that this induction is involved in the addiction process. However, to date there has been no report of deltaFosB induction by drugs of abuse in the ventral tegmental area (VTA), which is also a critical brain reward region. In the present study, we used immunohistochemistry to demonstrate that chronic forced administration of cocaine induces deltaFosB in the rat VTA. This induction occurs selectively in a gamma-aminobutyric acid (GABA) cell population within the posterior tail of the VTA. A similar effect is seen after chronic cocaine self-administration. Induction of deltaFosB in the VTA occurs after psychostimulant treatment only: it is seen with both chronic cocaine and amphetamine, but not with chronic opiates or stress. The expression of deltaFosB appears to be mediated by dopamine systems, as repeated administration of a dopamine uptake inhibitor induced deltaFosB in the VTA, while administration of serotonin or norepinephrine uptake inhibitors failed to produce this effect. Time course analysis showed that, following 14 days of cocaine administration, deltaFosB persists in the VTA for almost 2 weeks after cocaine withdrawal. This accumulation and persistence may account for some of the long-lasting changes in the brain associated with chronic drug use. These results provide the first evidence of deltaFosB induction in a discrete population of GABA cells in the VTA, which may regulate the functioning of the brain's reward mechanisms.

  19. The hallucinogen d-lysergic acid diethylamide (d-LSD) induces the immediate-early gene c-Fos in rat forebrain.

    PubMed

    Frankel, Paul S; Cunningham, Kathryn A

    2002-12-27

    The hallucinogen d-lysergic acid diethylamide (d-LSD) evokes dramatic somatic and psychological effects. In order to analyze the neural activation induced by this unique psychoactive drug, we tested the hypothesis that expression of the immediate-early gene product c-Fos is induced in specific regions of the rat forebrain by a relatively low, behaviorally active, dose of d-LSD (0.16 mg/kg, i.p.); c-Fos protein expression was assessed at 30 min, and 1, 2 and 4 h following d-LSD injection. A time- and region-dependent expression of c-Fos was observed with a significant increase (P<0.05) in the number of c-Fos-positive cells detected in the anterior cingulate cortex at 1 h, the shell of the nucleus accumbens at 1 and 2 h, the bed nucleus of stria terminalis lateral at 2 h and the paraventricular hypothalamic nucleus at 1, 2 and 4 h following systemic d-LSD administration. These data demonstrate a unique pattern of c-Fos expression in the rat forebrain following a relatively low dose of d-LSD and suggest that activation of these forebrain regions contributes to the unique behavioral effects of d-LSD.

  20. Fos is an essential component of the mammalian UV response.

    PubMed Central

    Schreiber, M; Baumann, B; Cotten, M; Angel, P; Wagner, E F

    1995-01-01

    Mouse 3T3 fibroblasts lacking c-fos were employed to demonstrate an essential function of the UV-inducible transcription factor AP-1 (Fos/Jun) in the response to the cytotoxic effects of short-wavelength ultraviolet (UVC) radiation. Clonogenic survival and proliferation of cells lacking c-fos were drastically reduced following UV irradiation. This UV hypersensitivity manifests itself primarily in increased cell death, partly by apoptosis, and prolonged recovery time from UV-induced cell cycle arrest. Co-culture with wild-type cells did not ameliorate the hypersensitivity of mutant cells. Transcriptional induction of the c-Fos target genes collagenase I, stromelysin-1 and stromelysin-2 by UV is almost absent in cells lacking c-fos which correlates with a reduced UV induction of AP-1 DNA-binding and transactivation activity. The repair of UV-induced DNA lesions was not affected, as shown by unscheduled DNA synthesis and host cell reactivation assays. These data demonstrate that c-Fos is involved in a novel protective function other than DNA repair against the harmful consequences of UVC. Images PMID:7489723

  1. Effects of epidermal growth factor and platelet-derived growth factor on c-fos and c-myc mRNA levels in normal human fibroblasts

    SciTech Connect

    Paulsson, Y.; Bywater, M.; Westermark, B. ); Heldin, C.H. )

    1987-07-01

    The mRNA levels of two proto-oncogenes, c-fos and c-myc, were determined in human foreskin fibroblasts exposed to epidermal growth factor (EGF) or platelet-derived growth factor (PDGF) in a serum-free, defined medium (MCDB 104). Untreated, quiescent cells were found to have low or undetectable levels of c-fos and c-myc mRNA. Within 10 min after the addition of EGF or PDGF the c-fos mRNA level increased, reached a peak at 30 min, and then declined to the control level after 60 min. The level of c-myc mRNA increased somewhat later and peaked after 8 h in cultures treated with either of the growth factors. The c-myc mRNA level remained elevated throughout the 24 h of investigation. The concentrations of EGF and PDGF required for a maximal effect on c-fos or c-myc expression were found to be similar to those that give maximal effect on cell proliferation. Both c-fos and c-myc mRNA expression were superinduced by the addition of cycloheximide. The present results conform to the view that the c-fos and c-myc proto-oncogenes may be important (or necessary) but not sufficient for the initiation of DNA synthesis. Moreover, the finding that both EGF and PDGF increase c-fos and c-myc expression supports the previous suggestion that these two growth factors may in part act via a common intracellular pathway in the prereplicative phase of human fibroblasts.

  2. Changes of c-fos, malondialdehyde and lactate in brain tissue after global cerebral ischemia under different brain temperatures.

    PubMed

    Zhang, Hong; Li, Li; Xu, Guo-ying; Mei, Yuan-wu; Zhang, Jun-jian; Murong, Shen-xing; Sun, Sheng-gang; Tong, E-tang

    2014-06-01

    Under global cerebral ischemia, the effect of different brain temperature on cerebral ischemic injury was studied. Male Sprague-Dawley rats were divided into normothermic (37-38°C) ischemia, mild hypothermic (31-32°C) ischemia, hyperthermic (41-42°C) ischemia and sham-operated groups. Global cerebral ischemia was established using the Pulsinelli four-vessel occlusion model and brain temperature was maintained at defined level for 60 min after 20-min ischemia. The expression of c-fos protein and the levels of malondialdehyde (MDA) and lactate in brain regions were detected by immunochemistry and spectrophotometrical methods, respectively. C-fos positive neurons were found in the hippocampus and cerebral cortex after cerebral ischemia reperfusion. Mild hypothermia increased the expression of c-fos protein in both areas, whereas hyperthermia decreased the expression of c-fos protein in the hippocampus at 24 h reperfusion, and the cerebral cortex at 48 h reperfusion when compared to normothermic conditions. In normothermic, mild hypothermic and hyperthermic ischemia groups, the levels of MDA and lactate in brain tissue were increased at 24, 48 and 72 h reperfusion following 20-min ischemia as compared with the sham-operated group (P<0.01). The levels of MDA and lactate in mild hypothermic group were significantly lower than those in normothermic group (P<0.01). It is suggested that brain temperature influences the translation of the immunoreactive protein product of c-fos after global cerebral ischemia, and MDA and lactate are also affected by hypothermia and hyperthermia.

  3. Increase in c-Fos and Arc protein in retrosplenial cortex after memory-improving lateral hypothalamic electrical stimulation treatment.

    PubMed

    Kádár, Elisabeth; Vico-Varela, Eva; Aldavert-Vera, Laura; Huguet, Gemma; Morgado-Bernal, Ignacio; Segura-Torres, Pilar

    2016-02-01

    Post-training Intracranial self-stimulation (ICSS) of the lateral hypothalamus (LH), a kind of rewarding deep-brain stimulation, potentiates learning and memory and increases c-Fos protein expression in specific memory-related brain regions. In a previous study, Aldavert-Vera et al. (2013) reported that post-acquisition LH-ICSS improved 48 h retention of a delay two-way active avoidance conditioning (TWAA) and induced c-Fos expression increase in CA3 at 90 min after administration. Nevertheless, this c-Fos induction was only observed after the acquisition session and not after the retention test at 48 h, when the ICSS improving effect was observed on memory. This current study aims to examine the hypothesis that post-training ICSS treatment may stimulate c-Fos expression at the time of the TWAA retention test in retrosplenial cortex (RSC), a hippocampus-related brain region more closely related with long-lasting memory storage. Effects of ICSS on Arc protein, a marker of memory-associated synaptic plasticity, were also measured by immunohistochemistry in granular and agranular RSC. The most innovative results are that the ICSS treatment potentiates the c-Fos induction across TWAA conditions (no conditioning, acquisition and retention), specifically in layer V of the granular RSC, along with increases of Arc protein levels in the granular but not in agranular areas of RSC ipsilaterally few hours after ICSS. This leads us to suggest that plasticity-related protein activation in the granular RSC could be involved in the positive modulatory effects of ICSS on TWAA memory consolidation, opening a new approach for future research in ICSS memory facilitation.

  4. Reduction of c-Fos via Overexpression of miR-34a Results in Enhancement of TNF- Production by LPS in Neutrophils from Myelodysplastic Syndrome Patients

    PubMed Central

    Shikama, Yayoi; Cao, Meiwan; Ono, Tomoyuki; Feng, Xiaomin; Noji, Hideyoshi; Kimura, Hideo; Ogawa, Kazuei; Suzuki, Yuko; Ikeda, Kazuhiko; Takeishi, Yasuchika; Kimura, Junko

    2016-01-01

    Although increased TNF-α has been considered to cause ineffective hematopoiesis in myelodysplastic syndromes (MDS), the mechanisms of TNF-α elevation are not known. We recently found that c-Fos mRNA stabilization under translation-inhibiting stimuli was impaired in MDS-derived neutrophilic granulocytes. In the current study, we identified overexpression of c-Fos-targeting miR-34a and miR-155 as the cause of impairment. Expression levels of miR-34a but not miR-155 inversely correlated with ratios of c-Fos-positive cells in MDS-derived CD16+ neutrophils (r = -0.618, P<0.05), which were analyzed by flow cytometry. Among the seventeen patients, c-Fos was detectable in less than 60% of CD16+ cells in eight patients (Group A), while five (Group B) expressed c-Fos in more than 80% of CD16+ cells, which was consistent with the controls (88.6 ± 7.8%). Group A-derived granulocytes secreted more TNF-α in response to 1 μM LPS for 3 hours (735.4 ± 237.5 pg/mL) than Group B (143.5 ± 65.7 pg/mL, P<0.05) and healthy controls (150.8 ± 91.5 pg/mL, P<0.05). Knockdown of c-Fos in neutrophil-like differentiated HL60 increased the binding of NF-κB p65 to the promoter region of TNF-α DNA. Thus, c-Fos reduction via overexpression of miR-34a contributes to TNF-α overproduction under inflammatory stimuli in MDS. PMID:27513856

  5. Repression of PDGF-R-α after cellular injury involves TNF-α, formation of a c-Fos-YY1 complex, and negative regulation by HDAC.

    PubMed

    Zhang, Ning; Chan, Cecilia W S; Sanchez-Guerrero, Estella; Khachigian, Levon M

    2012-06-01

    Wound healing is a complex dynamic process involving a variety of cell types, including fibroblasts that express and respond to cytokines and growth factors in the local microenvironment. The mechanisms controlling gene expression after injury at a transcriptional level are poorly understood. Here we show that decreased expression of a key receptor, PDGF-receptor (R)-α, after fibroblast injury is due to the release and paracrine activity of TNF-α. TNF-α inhibits PDGF-R-α expression and this involves formation of a c-Fos-Yin Yang 1 (YY1) complex and histone deacetylase (HDAC) activity. c-Fos, induced by TNF-α, negatively regulates PDGF-R-α transcription. Small interfering RNA (siRNA) targeting c-Fos or the zinc finger transcription factor YY1 inhibits TNF-α suppression of PDGF-R-α expression. Coimmunoprecipitation studies show that TNF-α stimulates the formation of a complex between c-Fos with YY1. Furthermore, chromatin immunoprecipitation (ChIP) analysis reveals the enrichment of c-Fos, YY1, and HDAC-1 at the PDGF-R-α promoter in cells exposed to TNF-α. With suberoylanilide hydroxamic acid (SAHA) and HDAC-1 siRNA, we demonstrate that HDAC mediates TNF-α repression of PDGF-R-α. These findings demonstrate that transcriptional repression of PDGF-R-α after fibroblast injury involves paracrine activity of endogenous TNF-α, the formation of a c-Fos-YY1 complex, and negative regulatory activity by HDAC.

  6. Chronic Stress Is Associated with Pain Precipitation and Elevation in DeltaFosb Expression

    PubMed Central

    Wang, Hang; Tao, Xinrong; Huang, Si-Ting; Wu, Liang; Tang, Hui-Li; Song, Ying; Zhang, Gongliang; Zhang, Yong-Mei

    2016-01-01

    A number of acute or repeated stimuli can induce expression of DeltaFosB (ΔFosB), a transcription factor derived from the fosB gene (an osteosarcoma viral oncogene) via alternative splicing. ΔFosB protein is currently viewed as a ‘molecular switch’ to repeated stimuli that gradually converts acute responses into relatively stable adaptations underlying long-term neural and behavioral plasticity. ΔFosB has received extensive attention in drug addition, depression, and stress adaptation, but changes in ΔFosB protein expression during pain is not fully understood. In this study we explored ΔFosB expression in the medial prefrontal cortex (mPFC) of rats experiencing chronic or acute stress-induced pain. Our data reveal that chronic pain induced by neonatal colorectal distension, chronic constriction injury (CCI) of the sciatic nerve, or maternal separation was associated with an increase in ΔfosB protein expression in mPFC, but acute application of acetic acid or zymosan did not alter the ΔFosB protein expression. ΔFosB expression in the rat visual cortex, a non pain-related brain region, did not change in response to (CCI) of the sciatic nerve and acetic acid treatment. In conclusion, our results indicate that ΔFosB protein expression is significantly elevated in rats that have experienced chronic pain and stress, but not acute pain. The ΔFosB protein may serve as an important transcription factor for chronic stress-induced pain. Further research is needed to improve the understanding of both the upstream signaling leading to ΔFosB protein expression as well as the regulation of ΔFosB gene expression in cortical neurons. PMID:27303299

  7. Pain fiber anesthetic reduces brainstem Fos after tooth extraction.

    PubMed

    Badral, B; Davies, A J; Kim, Y H; Ahn, J S; Hong, S D; Chung, G; Kim, J S; Oh, S B

    2013-11-01

    We recently demonstrated that pain-sensing neurons in the trigeminal system can be selectively anesthetized by co-application of QX-314 with the TRPV1 receptor agonist, capsaicin (QX cocktail). Here we examined whether this new anesthetic strategy can block the neuronal changes in the brainstem following molar tooth extraction in the rat. Adult male Sprague-Dawley rats received infiltration injection of anesthetic 10 min prior to lower molar tooth extraction. Neuronal activation was determined by immunohistochemistry for the proto-oncogene protein c-Fos in transverse sections of the trigeminal subnucleus caudalis (Sp5C). After tooth extraction, c-Fos-like immunoreactivity (Fos-LI) detected in the dorsomedial region of bilateral Sp5C was highest at 2 hrs (p < .01 vs. naïve ipsilateral) and declined to pre-injury levels by 8 hrs. Pre-administration of the QX cocktail significantly reduced to sham levels Fos-LI examined 2 hrs after tooth extraction; reduced Fos-LI was also observed with the conventional local anesthetic lidocaine. Pulpal anesthesia by infiltration injection was confirmed by inhibition of the jaw-opening reflex in response to electrical tooth pulp stimulation. Our results suggest that the QX cocktail anesthetic is effective in reducing neuronal activation following tooth extraction. Thus, a selective pain fiber 'nociceptive anesthetic' strategy may provide an effective local anesthetic option for dental patients in the clinic.

  8. c-Fos induction by a 14T magnetic field in visceral and vestibular relays of the female rat brainstem is modulated by estradiol

    PubMed Central

    Cason, Angie M.; Kwon, Bumsup; Smith, James C.; Houpt, Thomas A.

    2010-01-01

    There is increasing evidence that high magnetic fields interact with the vestibular system of humans and rodents. In rats, exposure to high magnetic fields of 7T or above induces locomotor circling and leads to a conditioned taste aversion if paired with a novel taste. Sex differences in the behavioral responses to magnetic field exposure have been found, such that female rats show more locomotor circling and enhanced conditioned taste aversion compared to male rats. To determine if estrogen modulates the neural response to high magnetic fields, c-Fos expression after 14T magnetic field exposure was compared in ovariectomized rats and ovariectomized rats with estradiol replacement. Compared to sham exposure, magnetic field exposure induced significantly more c-Fos positive cells in the nucleus of the solitary tract and the parabrachial, medial vestibular, prepositus, and supragenualis nuclei. Furthermore, there was a significant asymmetry in c-Fos induction between sides of the brainstem in several regions. In ovariectomized rats, there was more c-Fos expressed in the right side compared to left side in the locus coeruleus and parabrachial, superior vestibular, and supragenualis nuclei; less expression in the right compared to left side of the medial vestibular; and no asymmetry in the prepositus nucleus and the nucleus of the solitary tract. Chronic estradiol treatment modulated the neural response in some regions: less c-Fos was induced in the superior vestibular nucleus and locus coeruleus after estradiol replacement; estradiol treatment eliminated the asymmetry of c-Fos expression in the locus coeruleus and supragenualis nucleus, created an asymmetry in the prepositus nucleus and reversed the asymmetry in the parabrachial nucleus. These results suggest that ovarian steroids may mediate sex differences in the behavioral responses to magnetic field exposure at the level of visceral and vestibular nuclei of the brainstem. PMID:20553875

  9. Topography of methylphenidate (ritalin)-induced gene regulation in the striatum: differential effects on c-fos, substance P and opioid peptides.

    PubMed

    Yano, Motoyo; Steiner, Heinz

    2005-05-01

    Dopamine action alters gene regulation in striatal neurons. Methylphenidate increases extracellular levels of dopamine. We investigated the effects of acute methylphenidate treatment on gene expression in the striatum of adult rats. Molecular changes were mapped in 23 striatal sectors mostly defined by their predominant cortical inputs in order to determine the functional domains affected. Acute administration of 5 and 10 mg/kg (i.p.) of methylphenidate produced robust increases in the expression of the transcription factor c-fos and the neuropeptide substance P. Borderline effects were found with 2 mg/kg, but not with 0.5 mg/kg. For 5 mg/kg, c-fos mRNA levels peaked at 40 min and returned to baseline by 3 h after injection, while substance P mRNA levels peaked at 40-60 min and were back near control levels by 24 h. These molecular changes occurred in most sectors of the caudate-putamen, but were maximal in dorsal sectors that receive sensorimotor and medial agranular cortical inputs, on middle to caudal levels. In rostral and ventral striatal sectors, changes in c-fos and substance P expression were weaker or absent. No effects were seen in the nucleus accumbens, with the exception of c-fos induction in the lateral part of the shell. In contrast to c-fos and substance P, acute methylphenidate treatment had minimal effects on the opioid peptides dynorphin and enkephalin. These results demonstrate that acute methylphenidate alters the expression of c-fos and substance P preferentially in the sensorimotor striatum. These molecular changes are similar, but not identical, to those produced by other psychostimulants.

  10. Neuronal activity (c-Fos) delineating interactions of the cerebral cortex and basal ganglia

    PubMed Central

    Qiu, Mei-Hong; Chen, Michael C.; Huang, Zhi-Li; Lu, Jun

    2014-01-01

    The cerebral cortex and basal ganglia (BG) form a neural circuit that is disrupted in disorders such as Parkinson’s disease. We found that neuronal activity (c-Fos) in the BG followed cortical activity, i.e., high in arousal state and low in sleep state. To determine if cortical activity is necessary for BG activity, we administered atropine to rats to induce a dissociative state resulting in slow-wave electroencephalography but hyperactive motor behaviors. Atropine blocked c-Fos expression in the cortex and BG, despite high c-Fos expression in the sub-cortical arousal neuronal groups and thalamus, indicating that cortical activity is required for BG activation. To identify which glutamate receptors in the BG that mediate cortical inputs, we injected ketamine [N-methyl-d-aspartate (NMDA) receptor antagonist] and 6-cyano-nitroquinoxaline-2, 3-dione (CNQX, a non-NMDA receptor antagonist). Systemic ketamine and CNQX administration revealed that NMDA receptors mediated subthalamic nucleus (STN) input to internal globus pallidus (GPi) and substantia nigra pars reticulata (SNr), while non-NMDA receptor mediated cortical input to the STN. Both types of glutamate receptors were involved in mediating cortical input to the striatum. Dorsal striatal (caudoputamen, CPu) dopamine depletion by 6-hydroxydopamine resulted in reduced activity of the CPu, globus pallidus externa (GPe), and STN but increased activity of the GPi, SNr, and putative layer V neurons in the motor cortex. Our results reveal that the cortical activity is necessary for BG activity and clarifies the pathways and properties of the BG-cortical network and their putative role in the pathophysiology of BG disorders. PMID:24723855

  11. Interplay among Drosophila transcription factors Ets21c, Fos and Ftz-F1 drives JNK-mediated tumor malignancy

    PubMed Central

    Külshammer, Eva; Mundorf, Juliane; Kilinc, Merve; Frommolt, Peter; Wagle, Prerana; Uhlirova, Mirka

    2015-01-01

    ABSTRACT Cancer initiation and maintenance of the transformed cell state depend on altered cellular signaling and aberrant activities of transcription factors (TFs) that drive pathological gene expression in response to cooperating genetic lesions. Deciphering the roles of interacting TFs is therefore central to understanding carcinogenesis and for designing cancer therapies. Here, we use an unbiased genomic approach to define a TF network that triggers an abnormal gene expression program promoting malignancy of clonal tumors, generated in Drosophila imaginal disc epithelium by gain of oncogenic Ras (RasV12) and loss of the tumor suppressor Scribble (scrib1). We show that malignant transformation of the rasV12scrib1 tumors requires TFs of distinct families, namely the bZIP protein Fos, the ETS-domain factor Ets21c and the nuclear receptor Ftz-F1, all acting downstream of Jun-N-terminal kinase (JNK). Depleting any of the three TFs improves viability of tumor-bearing larvae, and this positive effect can be enhanced further by their combined removal. Although both Fos and Ftz-F1 synergistically contribute to rasV12scrib1 tumor invasiveness, only Fos is required for JNK-induced differentiation defects and Matrix metalloprotease (MMP1) upregulation. In contrast, the Fos-dimerizing partner Jun is dispensable for JNK to exert its effects in rasV12scrib1 tumors. Interestingly, Ets21c and Ftz-F1 are transcriptionally induced in these tumors in a JNK- and Fos-dependent manner, thereby demonstrating a hierarchy within the tripartite TF network, with Fos acting as the most upstream JNK effector. Of the three TFs, only Ets21c can efficiently substitute for loss of polarity and cooperate with RasV12 in inducing malignant clones that, like rasV12scrib1 tumors, invade other tissues and overexpress MMP1 and the Drosophila insulin-like peptide 8 (Dilp8). While rasV12ets21c tumors require JNK for invasiveness, the JNK activity is dispensable for their growth. In conclusion, our study

  12. PFOS or PreFOS? Are perfluorooctane sulfonate precursors (PreFOS) important determinants of human and environmental perfluorooctane sulfonate (PFOS) exposure?

    PubMed

    Martin, Jonathan W; Asher, Brian J; Beesoon, Sanjay; Benskin, Jonathan P; Ross, Matthew S

    2010-11-01

    The extent to which perfluorooctanesulfonate precursors (PreFOS) play a role in human or environmental exposure to perfluorooctanesulfonate (PFOS) is not well characterized. The diversity of manufactured PreFOS and its degradation products (e.g. C(8)F(17)SO(2)R and C(8)F(17)SO(2)NR'R'', where R is H or F, and R' and R'' are various) has made it difficult to track their fate. Temporal trends of PFOS in both humans and wildlife are discrepant, thus it is difficult to predict future exposure, and hypotheses about the role of PreFOS have been raised. Although abiotic degradation of commercially important PreFOS materials requires further research, current data suggest that the yield of PFOS is negligible or minor. On the other hand, in vivo biotransformation of PreFOS yields PFOS as the major metabolite, and >32% yields have been observed. In Canadians, exposure to PreFOS was equivalent or greater than direct PFOS exposure prior to 2002. In most ocean water, PFOS is dominant to PreFOS, but in the oceans east of Greenland there may be more PreFOS than PFOS, consistent with the fact that whales and humans in this region also show evidence of substantial PreFOS exposure. Quantitative assessments of PFOS body-burdens coming from PreFOS are complicated by the fact that PreFOS partitions to the cellular fraction of blood, thus biomonitoring in serum under predicts PreFOS relative to PFOS. Many unknowns exist that prevent accurate modelling, thus analytical methods that can distinguish directly manufactured PFOS, from PFOS that has been biotransformed from PreFOS, should be applied in future human and environmental monitoring. Two new source tracking principles are presented and applied to human serum.

  13. FOS-1 functions as a transcriptional activator downstream of the C. elegans JNK homolog KGB-1.

    PubMed

    Zhang, Zhe; Liu, Limeng; Twumasi-Boateng, Kwame; Block, Dena H S; Shapira, Michael

    2017-01-01

    JNK proteins are conserved stress-activated MAP kinases. In C. elegans, the JNK-homolog KGB-1 plays essential roles in protection from heavy metals and protein folding stress. However, the contributions of KGB-1 are age-dependent, providing protection in larvae, but reducing stress resistance and shortening lifespan in adults. Attenuation of DAF-16 was linked to the detrimental contributions of KGB-1 in adults, but its involvement in KGB-1-dependent protection in larvae remains unclear. To characterize age-dependent contributions of KGB-1, we used microarray analysis to measure gene expression following KGB-1 activation either in developing larvae or in adults, achieved by knocking down its negative phosphatase regulator vhp-1. This revealed a robust KGB-1 regulon, most of which consisting of genes induced following KGB-1 activation regardless of age; a smaller number of genes was regulated in an age-dependent manner. We found that the bZIP transcription factor FOS-1 was essential for age-invariant KGB-1-dependent gene induction, but not for age-dependent expression. The latter was more affected by DAF-16, which was further found to be required for KGB-1-dependent cadmium resistance in larvae. Our results identify FOS-1 as a transcriptional activator mediating age-invariant contributions of KGB-1, including a regulatory loop of KGB-1 signaling, but also stress the importance of DAF-16 as a mediator of age-dependent contributions.

  14. Body Sodium Overload Modulates the Firing Rate and Fos Immunoreactivity of Serotonergic Cells of Dorsal Raphe Nucleus

    PubMed Central

    Godino, Andrea; Pitra, Soledad; Carrer, Hugo F.; Vivas, Laura

    2013-01-01

    In order to determine whether serotonergic (5HT) dorsal raphe nucleus (DRN) cells are involved in body sodium status regulation, the effect of a s.c. infusion of either 2 M or 0.15 M NaCl on 5HT DRN neuron firing was studied using single unit extracellular recordings. In separate groups of 2 M and 0.15 M NaCl-infused rats, water intake, oxytocin (OT) plasma concentration, urine and plasma sodium and protein concentrations were also measured. Also, to determine the involvement of particular brain nuclei and neurochemical systems in body sodium overload (SO), animals from both groups were perfused for brain immunohistochemical detection of Fos, Fos-OT and Fos-5HT expression. SO produced a significant increase in serotonergic DRN neuron firing rate compared to baseline and 0.15 M NaCl-infused rats. As expected, 2 M NaCl s.c. infusion also induced a significant increase of water intake, diuresis and natriuresis, plasma sodium concentration and osmolality, even though plasma volume did not increase as indicated by changes in plasma protein concentration. The distribution of neurons along the forebrain and brainstem expressing Fos after SO showed the participation of the lamina terminalis, extended amygdala, supraoptic and paraventricular hypothalamic nuclei in the neural network that controls osmoregulatory responses. Both Fos-OT immunoreactive and plasma OT concentration increased after s.c. hypertonic sodium infusion. Finally, matching the “in vivo” electrophysiological study, SO doubled the number of Fos-5HT immunolabeled cells within the DRN. In summary, the results characterize the behavioral, renal and endocrine responses after body sodium overload without volume expansion and specify the cerebral nuclei that participate at different CNS levels in the control of these responses. The electrophysiological approach also allows us to determine in an “in vivo" model that DRN 5HT neurons increase their firing frequency during an increase in systemic sodium

  15. Nutritional status modulates behavioural and olfactory bulb Fos responses to isoamyl acetate or food odour in rats: roles of orexins and leptin.

    PubMed

    Prud'homme, M J; Lacroix, M C; Badonnel, K; Gougis, S; Baly, C; Salesse, R; Caillol, M

    2009-09-15

    Food odours are major determinants for food choice, and their detection depends on nutritional status. The effects of different odour stimuli on both behavioural responses (locomotor activity and sniffing) and Fos induction in olfactory bulbs (OB) were studied in satiated or 48-h fasted rats. We focused on two odour stimuli: isoamyl acetate (ISO), as a neutral stimulus either unknown or familiar, and food pellet odour, that were presented to quiet rats during the light phase of the day. We found significant effects of nutritional status and odour stimulus on both behavioural and OB responses. The locomotor activity induced by odour stimuli was always more marked in fasted than in satiated rats, and food odour induced increased sniffing activity only in fasted rats. Fos expression was quantified in periglomerular, mitral and granular OB cell layers. As a new odour, ISO induced a significant increase in Fos expression in all OB layers, similar in fasted and satiated rats. Significant OB responses to familiar odours were only observed in fasted rats. Among the numerous peptides shown to vary after 48 h of fasting, we focused on orexins (for which immunoreactive fibres are present in the OB) and leptin, as a peripheral hormone linked to adiposity, and tested their effects of food odour. The administration of orexin A in satiated animals partially mimicked fasting, since food odour increased OB Fos responses, but did not induce sniffing. The treatment of fasted animals with either an orexin receptors antagonist (ACT-078573) or leptin significantly decreased both locomotor activity, time spent sniffing food odour and OB Fos induction in all cell layers, thus mimicking a satiated status. We conclude that orexins and leptin are some of the factors that can modify behavioural and OB Fos responses to a familiar food odour.

  16. c-Fos activity mapping reveals differential effects of noradrenaline and serotonin depletion on the regulation of ocular dominance plasticity in rats.

    PubMed

    Nakadate, K; Imamura, K; Watanabe, Y

    2013-04-03

    The roles of the central noradrenergic and serotonergic system in the activity-dependent regulation of ocular dominance plasticity have been a contentious issue. Using c-Fos activity mapping, we have developed a new, straightforward method to measure the strength of ocular dominance plasticity: the number of c-Fos-immunopositive cells in layer IV of rat visual cortex (Oc1B), ipsilateral to the stimulated eye, is a sensitive and reliable measure of the effects of monocular deprivation. Applying this new method, here we studied the unique modification of the degree of c-Fos expression induced in the visual cortex, in that endogenous noradrenaline (NA) and serotonin (5HT) in the cortex were significantly reduced, respectively by specific pharmacological agents. Intraperitoneal injections of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) and p-chlorophenylalanine (pCPA) selectively impair NA- and 5HT-containing nerve terminals and fibers, respectively. In the visual cortex with strongly reduced NA, the number of c-Fos-immunopositive cells was found remaining significantly decreased in response to stimulation of the deprived eye, while by open eye stimulation the expected increase in c-Fos-immunoreactivity was strongly suppressed, showing values not different from those obtained by monocular stimulation in the normal rats. In contrast, in the visual cortex with strongly reduced 5HT no expected decrease was found in response to stimulation of the deprived eye, while, as is usually the case for the normal animals, a significant increase was still induced in response to open eye stimulation. These findings suggest that the noradrenergic and serotonergic system regulate ocular dominance (OD) plasticity differently: in the NA-depleted cortex the expected increase in c-Fos expression by open eye stimulation was not seen due to strong suppression, whereas in 5HT-depletion, the expected decrease in c-Fos expression was not materialized due to strong suppression. The

  17. AP-1/Fos-TGase2 Axis Mediates Wounding-induced Plasmodium falciparum Killing in Anopheles gambiae*

    PubMed Central

    Nsango, Sandrine E.; Pompon, Julien; Xie, Ting; Rademacher, Annika; Fraiture, Malou; Thoma, Martine; Awono-Ambene, Parfait H.; Moyou, Roger S.; Morlais, Isabelle; Levashina, Elena A.

    2013-01-01

    Anopheline mosquitoes are the only vectors of human malaria worldwide. It is now widely accepted that mosquito immune responses play a crucial role in restricting Plasmodium development within the vector; therefore, further dissection of the molecular mechanisms underlying these processes should inform new vector control strategies urgently needed to roll back the disease. Here, using genome-wide transcriptional profiling, bioinformatics, and functional gene analysis, we identify a new axis of mosquito resistance to monoclonal Plasmodium falciparum infections that includes the AP-1 transcription factor Fos and the transglutaminase 2 (TGase2), a cross-linking enzyme with known roles in wound responses. We demonstrate that Fos regulates induction of TGase2 expression after wounding but does not affect expression of the components of the well characterized complement-like system. Silencing of Fos or of TGase2 aborts the wounding-induced mosquito killing of P. falciparum. These results reveal multiple signaling pathways that are required for efficient Plasmodium killing in Anopheles gambiae. PMID:23592781

  18. Rat vagus nerve stimulation model of seizure suppression: nNOS and ΔFos B changes in the brainstem.

    PubMed

    Rijkers, K; Majoie, H J M; Aalbers, M W; Philippens, M; Doenni, V M; Vles, J S H; Steinbusch, H M W; Moers-Hornikx, V M P; Hopkins, D A; Hoogland, G

    2012-12-01

    Vagus nerve stimulation (VNS) is a moderately effective treatment for intractable epilepsy. However, the mechanism of action is poorly understood. The effect of left VNS in amygdala kindled rats was investigated by studying changes in nNOS and ΔFos B expression in primary and secondary vagus nerve projection nuclei: the nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus nerve (DMV), parabrachial nucleus (PBN) and locus coeruleus (LC). Rats were fully kindled by stimulation of the amygdala. Subsequently, when the fully kindled state was reached and then maintained for ten days, rats received a single 3-min train of VNS starting 1min prior to the kindling stimulus and lasting for 2min afterwards. In control animals the vagus nerve was not stimulated. Animals were sacrificed 48h later. The brainstems were stained for neuronal nitric oxide synthase (nNOS) and ΔFos B. VNS decreased seizure duration with more than 25% in 21% of rats. No VNS associated changes in nNOS immunoreactivity were observed in the NTS and no changes in ΔFos B were observed in the NTS, PBN, or LC. High nNOS immunopositive cell densities of >300cells/mm(2) were significantly more frequent in the left DMV than in the right (χ(2)(1)=26.2, p<0.01), independent of whether the vagus nerve was stimulated. We conclude that the observed nNOS immunoreactivity in the DMV suggests surgery-induced axonal damage. A 3-min train of VNS in fully kindled rats does not affect ΔFos B expression in primary and secondary projection nuclei of the vagus nerve.

  19. Natural and Drug Rewards Act on Common Neural Plasticity Mechanisms with ΔFosB as a Key Mediator

    PubMed Central

    Pitchers, Kyle K.; Vialou, Vincent; Nestler, Eric J.; Laviolette, Steven R.; Lehman, Michael N.

    2013-01-01

    Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. Recent evidence suggests that natural rewards may cause similar changes in the NAc, suggesting that drugs may activate mechanisms of plasticity shared with natural rewards, and allowing for unique interplay between natural and drug rewards. In this study, we demonstrate that sexual experience in male rats when followed by short or prolonged periods of loss of sex reward causes enhanced amphetamine reward, indicated by sensitized conditioned place preference for low-dose (0.5 mg/kg) amphetamine. Moreover, the onset, but not the longer-term expression, of enhanced amphetamine reward was correlated with a transient increase in dendritic spines in the NAc. Next, a critical role for the transcription factor ΔFosB in sex experience-induced enhanced amphetamine reward and associated increases in dendritic spines on NAc neurons was established using viral vector gene transfer of the dominant-negative binding partner ΔJunD. Moreover, it was demonstrated that sexual experience-induced enhanced drug reward, ΔFosB, and spinogenesis are dependent on mating-induced dopamine D1 receptor activation in the NAc. Pharmacological blockade of D1 receptor, but not D2 receptor, in the NAc during sexual behavior attenuated ΔFosB induction and prevented increased spinogenesis and sensitized amphetamine reward. Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. PMID:23426671

  20. Region-specific increases in FosB/ΔFosB immunoreactivity in the rat brain in response to chronic sleep restriction.

    PubMed

    Hall, Shannon; Deurveilher, Samüel; Ko, Kristin Robin; Burns, Joan; Semba, Kazue

    2017-03-30

    Using a rat model of chronic sleep restriction (CSR) featuring periodic sleep deprivation with slowly rotating wheels (3h on/1h off), we previously observed that 99h of this protocol induced both homeostatic and allostatic (adaptive) changes in physiological and behavioural measures. Notably, the initial changes in sleep intensity and attention performance gradually adapted during CSR despite accumulating sleep loss. To identify brain regions involved in these responses, we used FosB/ΔFosB immunohistochemistry as a marker of chronic neuronal activation. Adult male rats were housed in motorized activity wheels and underwent the 3/1 CSR protocol for 99h, or 99h followed by 6 or 12days of recovery. Control rats were housed in home cages, locked activity wheels, or unlocked activity wheels that the animals could turn freely. Immunohistochemistry was conducted using an antibody that recognized both FosB and ΔFosB, and 24 brain regions involved in sleep/wake, autonomic, and limbic functions were examined. The number of darkly-stained FosB/ΔFosB-immunoreactive cells was increased immediately following 99h of CSR in 8/24 brain regions, including the medial preoptic and perifornical lateral hypothalamic areas, dorsomedial and paraventricular hypothalamic nuclei, and paraventricular thalamic nucleus. FosB/ΔFosB labeling was at control levels in all 8 brain areas following 6 or 12 recovery days, suggesting that most of the immunoreactivity immediately after CSR reflected FosB, the more transient marker of chronic neuronal activation. This region-specific induction of FosB/ΔFosB following CSR may be involved in the mechanisms underlying the allostatic changes in behavioural and physiological responses to CSR.

  1. Medial prefrontal cortex neuronal activation and synaptic alterations after stress-induced reinstatement of palatable food seeking: a study using c-fos-GFP transgenic female rats.

    PubMed

    Cifani, Carlo; Koya, Eisuke; Navarre, Brittany M; Calu, Donna J; Baumann, Michael H; Marchant, Nathan J; Liu, Qing-Rong; Khuc, Thi; Pickel, James; Lupica, Carl R; Shaham, Yavin; Hope, Bruce T

    2012-06-20

    Relapse to maladaptive eating habits during dieting is often provoked by stress and there is evidence for a role of ovarian hormones in stress responses and feeding. We studied the role of these hormones in stress-induced reinstatement of food seeking and medial prefrontal cortex (mPFC) neuronal activation in c-fos-GFP transgenic female rats, which express GFP in strongly activated neurons. Food-restricted ovariectomized or sham-operated c-fos-GFP rats were trained to lever-press for palatable food pellets. Subsequently, lever-pressing was extinguished and reinstatement of food seeking and mPFC neuronal activation was assessed after injections of the pharmacological stressor yohimbine (0.5-2 mg/kg) or pellet priming (1-4 noncontingent pellets). Estrous cycle effects on reinstatement were also assessed in wild-type rats. Yohimbine- and pellet-priming-induced reinstatement was associated with Fos and GFP induction in mPFC; both reinstatement and neuronal activation were minimally affected by ovarian hormones in both c-fos-GFP and wild-type rats. c-fos-GFP transgenic rats were then used to assess glutamatergic synaptic alterations within activated GFP-positive and nonactivated GFP-negative mPFC neurons following yohimbine-induced reinstatement of food seeking. This reinstatement was associated with reduced AMPA receptor/NMDA receptor current ratios and increased paired-pulse facilitation in activated GFP-positive but not GFP-negative neurons. While ovarian hormones do not appear to play a role in stress-induced relapse of food seeking in our rat model, this reinstatement was associated with unique synaptic alterations in strongly activated mPFC neurons. Our paper introduces the c-fos-GFP transgenic rat as a new tool to study unique synaptic changes in activated neurons during behavior.

  2. Impairment of FOS mRNA stabilization following translation arrest in granulocytes from myelodysplastic syndrome patients.

    PubMed

    Feng, Xiaomin; Shikama, Yayoi; Shichishima, Tsutomu; Noji, Hideyoshi; Ikeda, Kazuhiko; Ogawa, Kazuei; Kimura, Hideo; Takeishi, Yasuchika; Kimura, Junko

    2013-01-01

    Although quantitative and qualitative granulocyte defects have been described in myelodysplastic syndromes (MDS), the underlying molecular basis of granulocyte dysfunction in MDS is largely unknown. We recently found that FOS mRNA elevation under translation-inhibiting stimuli was significantly smaller in granulocytes from MDS patients than in healthy individuals. The aim of this study is to clarify the cause of the impaired FOS induction in MDS. We first examined the mechanisms of FOS mRNA elevation using granulocytes from healthy donors cultured with the translation inhibitor emetine. Emetine increased both transcription and mRNA stability of FOS. p38 MAPK inhibition abolished the emetine-induced increase of FOS transcription but did not affect FOS mRNA stabilization. The binding of an AU-rich element (ARE)-binding protein HuR to FOS mRNA containing an ARE in 3'UTR was increased by emetine, and the knockdown of HuR reduced the FOS mRNA stabilizing effect of emetine. We next compared the emetine-induced transcription and mRNA stabilization of FOS between MDS patients and healthy controls. Increased rates of FOS transcription by emetine were similar in MDS and controls. In the absence of emetine, FOS mRNA decayed to nearly 17% of initial levels in 45 min in both groups. In the presence of emetine, however, 76.7±19.8% of FOS mRNA remained after 45 min in healthy controls, versus 37.9±25.5% in MDS (P<0.01). To our knowledge, this is the first report demonstrating attenuation of stress-induced FOS mRNA stabilization in MDS granulocytes.

  3. Spatial memory extinction: a c-Fos protein mapping study.

    PubMed

    Méndez-Couz, M; Conejo, N M; Vallejo, G; Arias, J L

    2014-03-01

    While the neuronal basis of spatial memory consolidation has been thoroughly studied, the substrates mediating the process of extinction remain largely unknown. This study aimed to evaluate the functional contribution of selected brain regions during the extinction of a previously acquired spatial memory task in the Morris water maze. For that purpose, we used adult male Wistar rats trained in a spatial reference memory task. Learning-related changes in c-Fos inmunoreactive cells after training were evaluated in cortical and subcortical regions. Results show that removal of the hidden platform in the water maze induced extinction of the previously reinforced escape behavior after 16 trials, without spontaneous recovery 24h later. Extinction was related with significantly higher numbers of c-Fos positive nuclei in amygdala nuclei and prefrontal cortex. On the other hand, the lateral mammillary bodies showed higher number of c-Fos positive cells than the control group. Therefore, in contrast with the results obtained in studies of classical conditioning, we show the involvement of diencephalic structures mediating this kind of learning. In summary, our findings suggest that medial prefrontal cortex, the amygdala complex and diencephalic structures like the lateral mammillary nuclei are relevant for the extinction of spatial memory.

  4. Determinants that contribute to cytoplasmic stability of human c-fos and. beta. -globin mRNAs are located at several sites in each mRNA

    SciTech Connect

    Kabnick, K.S.; Housman, D.E.

    1988-08-01

    The authors have analyzed the contributions to cytoplasmic stability in an mRNA species with a very short half-life (human c-fos) and an mRNA species with a very long half-life (human ..beta..-globin). When the human c-fos promoter was used to drive the expression of human c-fos, ..beta..-globin, and chimeric DNAs between c-fos and ..beta..-globin in transfected cells, a pulse of mRNA synthesis was obtained following induction of transcription by refeeding quiescent cells with medium containing 15% calf serum. The mRNA half-life was determined by using Northern (RNA) blot analysis of mRNAs prepared at various times following the pulse of transcription. Under these conditions human c-fos mRNA exhibited a half-life of 6.6 min and human ..beta..-globin mRNA exhibited a half-life of 17.5 h. Replacement of the 3' end of the c-fos mRNA with the 3' end of the ..beta..-globin mRNA increased the half-life of the resultant RNA from 6.6 to 34 min. The reciprocal chimera had a half-life of 34.6 min compared with the 17.5-half-life of ..beta..-globin mRNA. These results suggest that sequences which make a major contribution to mRNA stability reside in the 3' end of either or both molecules. A chimera in which the 5' untranslated region of globin was replaced by part of the 5' untranslated region of fos led to destabilization of the encoded mRNA. This construct produced an mRNA with a half-life of 6.8 h instead of the 17.5-h half-life of globin. This result suggests that additional determinants of stability reside in the 5' end of these mRNA molecules. Substitution of part of the 5' untranslated region of fox by the 5' untranslated region of ..beta..-globin yielded an mRNA with stability similar to fos mRNA. These results suggest that interactions among sequences within each mRNA contribute to the stability of the respective molecules.

  5. c-Fos Repression by Piwi Regulates Drosophila Ovarian Germline Formation and Tissue Morphogenesis

    PubMed Central

    Klein, Jonathon D.; Qu, Chunxu; Yang, Xiaoyang; Fan, Yiping; Tang, Chunlao; Peng, Jamy C.

    2016-01-01

    Drosophila melanogaster Piwi functions within the germline stem cells (GSCs) and the somatic niche to regulate GSC self-renewal and differentiation. How Piwi influences GSCs is largely unknown. We uncovered a genetic interaction between Piwi and c-Fos in the somatic niche that influences GSCs. c-Fos is a proto-oncogene that influences many cell and developmental processes. In wild-type ovarian cells, c-Fos is post-transcriptionally repressed by Piwi, which destabilized the c-Fos mRNA by promoting the processing of its 3′ untranslated region (UTR) into Piwi-interacting RNAs (piRNAs). The c-Fos 3′ UTR was sufficient to trigger Piwi-dependent destabilization of a GFP reporter. Piwi represses c-Fos in the somatic niche to regulate GSC maintenance and differentiation and in the somatic follicle cells to affect somatic cell disorganization, tissue dysmorphogenesis, oocyte maturation arrest, and infertility. PMID:27622269

  6. Induction of c-fos and c-myc mRNA by epidermal growth factor or calcium ionophore is cAMP dependent.

    PubMed Central

    Ran, W; Dean, M; Levine, R A; Henkle, C; Campisi, J

    1986-01-01

    Phorbol esters activate protein kinase C and induce expression of the c-fos and c-myc protooncogenes in density-arrested BALB/c 3T3 (A31) cells; in contrast, epidermal growth factor (EGF) does not activate protein kinase C and is a poor inducer of c-fos and c-myc in these confluent cells. We show that, when A31 cells were subconfluent and made quiescent by serum deprivation, the phorbol ester phorbol 12-myristate 13-acetate induced c-fos and c-myc mRNA poorly, whereas EGF was a better inducer. Another platelet-derived growth factor-inducible gene, JE, did not show this differential regulation by phorbol 12-myristate 13-acetate and EGF. The ability of EGF to induce protooncogene mRNA was associated with elevated levels of intracellular cAMP. First, serum-deprived cells maintained cAMP at about 2-fold higher level than density-arrested cells. Second, induction was greatly enhanced by cholera toxin and 3-isobutyl-1-methylxanthine, which increased intracellular cAMP 3- to 10-fold. The calcium ionophore A23187 mimicked EGF in that it elevated c-fos and c-myc mRNA when administered with cholera toxin and isobutylmethylxanthine. Neither cholera toxin and isobutyl-methylxanthine nor A23187 appreciably induced these mRNAs when used alone. Our results suggest that c-fos and c-myc expression can be regulated by an EGF-directed pathway that utilizes calcium and cAMP as cooperating cytoplasmic messengers. Images PMID:2430281

  7. Housing condition-related changes involved in reversal learning and its c-Fos associated activity in the prefrontal cortex.

    PubMed

    Sampedro-Piquero, P; Zancada-Menendez, C; Begega, A

    2015-10-29

    Our study examined how different housing conditions modulated the acquisition of a spatial reference memory task and also, a reversal task in the 4-radial arm water maze (4-RAWM). The animals were randomly assigned to standard or enriched cages, and, as a type of complementary stimulation along with the environmental enrichment (EE), a group of rats also ran 15 min/day in a Rotarod. Elevated-zero maze results allowed us to discard that our exercise training increased anxiety-related behaviors. 4-RAWM results revealed that the non-enriched group had a worse performance during the acquisition and also, during the first trial of each session with respect to the enriched groups. Regarding the reversal task, this group made more perseverative errors in the previous platform position. Interestingly, we hardly found differences between the two enriched groups (with and without exercise). We also analyzed how the reversal learning, depending on the previous housing condition, modulated the expression of c-Fos-positive nuclei in different subdivisions of the medial prefrontal cortex (cingulate (Cg), prelimbic (PL) and infralimbic (IL) cortices) and in the orbitofrontal (OF) cortex. The enriched groups had higher c-Fos expression in the Cg and OF cortices and lower in the IL cortex respect to the non-enriched animals. In the PL cortex, we did not find significant differences between the groups that performed the reversal task. Therefore, our short EE protocol improved the performance in a spatial memory and a reversal task, whereas the exercise training, combined with the EE, did not produce a greater benefit. This better performance seemed to be related with the specific pattern of c-Fos expression in brain regions involved in cognitive flexibility.

  8. Mapping brain Fos immunoreactivity in response to water deprivation and partial rehydration: Influence of sodium intake.

    PubMed

    Dalmasso, Carolina; Antunes-Rodrigues, José; Vivas, Laura; De Luca, Laurival A

    2015-11-01

    Water deprivation (WD) followed by water intake to satiety, produces satiation of thirst and partial rehydration (PR). Thus, WD-PR is a natural method to differentiate thirst from sodium appetite. WD-PR also produces Fos immunoreactivity (Fos-ir) in interconnected areas of a brain circuit postulated to subserve sodium appetite. In the present work, we evaluated the effect of sodium intake on Fos-ir produced by WD-PR in brain areas operationally defined according to the literature as either facilitatory or inhibitory to sodium intake. Isotonic NaCl was available for ingestion in a sodium appetite test performed immediately after a single episode of WD-PR. Sodium intake decreased Fos-ir in facilitatory areas such as the lamina terminalis (particularly subfornical organ and median preoptic nucleus), central amygdala and hypothalamic parvocellular paraventricular nucleus in the forebrain. Sodium intake also decreased Fos-ir in inhibitory areas such as the area postrema, lateral parabrachial nucleus and nucleus of the solitary tract in the hindbrain. In contrast, sodium intake further increased Fos-ir that was activated by water deprivation in the dorsal raphe nucleus, another inhibitory area localized in the hindbrain. WD-PR increased Fos-ir in the core and shell of the nucleus accumbens. Sodium intake reduced Fos-ir in both parts of the accumbens. In summary, sodium intake following WD-PR reduced Fos-ir in most facilitatory and inhibitory areas, but increased Fos-ir in another inhibitory area. It also reduced Fos-ir in a reward area (accumbens). The results suggest a functional link between sodium intake and the activity of the hindbrain-forebrain circuitry subserving reward and sodium appetite in response to water deprivation.

  9. Selective participation of c-Jun with Fra-2/c-Fos promotes aggressive tumor phenotypes and poor prognosis in tongue cancer

    PubMed Central

    Gupta, Shilpi; Kumar, Prabhat; Kaur, Harsimrut; Sharma, Nishi; Saluja, Daman; Bharti, Alok C.; Das, Bhudev C.

    2015-01-01

    Tongue squamous cell carcinoma (TSCC) is most aggressive head and neck cancer often associated with HR-HPV infection. The role of AP-1 which is an essential regulator of HPV oncogene expression and tumorigenesis is not reported in tongue cancer. One hundred tongue tissue biopsies comprising precancer, cancer and adjacent controls including two tongue cancer cell lines were employed to study the role of HPV infection and AP-1 family proteins. An exclusive prevalence (28%) of HR-HPV type 16 was observed mainly in well differentiated tongue carcinomas (78.5%). A higher expression and DNA binding activity of AP-1 was observed in tongue tumors and cancer cell lines with c-Fos and Fra-2 as the major binding partners forming the functional AP-1 complex but c-Jun participated only in HPV negative and poorly differentiated carcinoma. Knocking down of Fra-2 responsible for aggressive tongue tumorigenesis led to significant reduction in c-Fos, c-Jun, MMP-9 and HPVE6/E7 expression but Fra-1 and p53 were upregulated. The binding and expression of c-Fos/Fra-2 increased as a function of severity of tongue lesions, yet selective participation of c-Jun appears to promote poor differentiation and aggressive tumorigenesis only in HPV negative cases while HPV infection leads to well differentiation and better prognosis preferably in nonsmokers. PMID:26581505

  10. Ambient Temperature and 17β-Estradiol Modify Fos Immunoreactivity in the Median Preoptic Nucleus, a Putative Regulator of Skin Vasomotion

    PubMed Central

    Dacks, Penny A.; Krajewski, Sally J.

    2011-01-01

    Estrogen has pronounced effects on thermoregulation, but the anatomic sites of integration between the reproductive and thermoregulatory axes are unknown. In this study, we tested whether estradiol-17β (E2) treatment would alter the activity of thermoregulatory brain regions responding to mild changes in ambient temperature (TAMBIENT). Core and tail skin temperatures were recorded at the ambient temperatures of 20, 24, or 31 C in ovariectomized (OVX) rats with and without E2. Neuronal activity was evaluated by counting the number of Fos-immunoreactive cells in the brains of rats killed 90 min after exposure to one of the three ambient temperatures. Of 14 brain areas examined, the median preoptic nucleus (MnPO) was the only site that exhibited increased Fos immunoreactivity at the high TAMBIENT of 31 C. At 24 C, OVX rats exhibited increased numbers of MnPO Fos-immunoreactive cells, compared with OVX + E2 rats. Interestingly, tail skin vasomotion and MnPO Fos expression were affected in a similar manner by TAMBIENT and E2 treatment. In the arcuate nucleus and anteroventral periventricular nucleus (AVPV), Fos immunoreactivity was highest at the low TAMBIENT of 20 C, with inhibitory (arcuate nucleus) and stimulatory (AVPV) effects of E2. No other areas responded to both TAMBIENT and E2 treatment. These results implicate the MnPO, the arcuate nucleus, and the AVPV as sites of integration between the reproductive and thermoregulatory axes. Combined with studies showing the importance of MnPO neurons in heat-defense pathways, the MnPO emerges as a likely site for E2 modulation of thermoregulatory vasomotion. PMID:21521752

  11. Ambient temperature and 17β-estradiol modify Fos immunoreactivity in the median preoptic nucleus, a putative regulator of skin vasomotion.

    PubMed

    Dacks, Penny A; Krajewski, Sally J; Rance, Naomi E

    2011-07-01

    Estrogen has pronounced effects on thermoregulation, but the anatomic sites of integration between the reproductive and thermoregulatory axes are unknown. In this study, we tested whether estradiol-17β (E(2)) treatment would alter the activity of thermoregulatory brain regions responding to mild changes in ambient temperature (T(AMBIENT)). Core and tail skin temperatures were recorded at the ambient temperatures of 20, 24, or 31 C in ovariectomized (OVX) rats with and without E(2). Neuronal activity was evaluated by counting the number of Fos-immunoreactive cells in the brains of rats killed 90 min after exposure to one of the three ambient temperatures. Of 14 brain areas examined, the median preoptic nucleus (MnPO) was the only site that exhibited increased Fos immunoreactivity at the high T(AMBIENT) of 31 C. At 24 C, OVX rats exhibited increased numbers of MnPO Fos-immunoreactive cells, compared with OVX + E(2) rats. Interestingly, tail skin vasomotion and MnPO Fos expression were affected in a similar manner by T(AMBIENT) and E(2) treatment. In the arcuate nucleus and anteroventral periventricular nucleus (AVPV), Fos immunoreactivity was highest at the low T(AMBIENT) of 20 C, with inhibitory (arcuate nucleus) and stimulatory (AVPV) effects of E(2). No other areas responded to both T(AMBIENT) and E(2) treatment. These results implicate the MnPO, the arcuate nucleus, and the AVPV as sites of integration between the reproductive and thermoregulatory axes. Combined with studies showing the importance of MnPO neurons in heat-defense pathways, the MnPO emerges as a likely site for E(2) modulation of thermoregulatory vasomotion.

  12. Dimeric combinations of MafB, cFos and cJun control the apoptosis-survival balance in limb morphogenesis.

    PubMed

    Suda, Natsuno; Itoh, Takehiko; Nakato, Ryuichiro; Shirakawa, Daisuke; Bando, Masashige; Katou, Yuki; Kataoka, Kohsuke; Shirahige, Katsuhiko; Tickle, Cheryll; Tanaka, Mikiko

    2014-07-01

    Apoptosis is an important mechanism for sculpting morphology. However, the molecular cascades that control apoptosis in developing limb buds remain largely unclear. Here, we show that MafB was specifically expressed in apoptotic regions of chick limb buds, and MafB/cFos heterodimers repressed apoptosis, whereas MafB/cJun heterodimers promoted apoptosis for sculpting the shape of the limbs. Chromatin immunoprecipitation sequencing in chick limb buds identified potential target genes and regulatory elements controlled by Maf and Jun. Functional analyses revealed that expression of p63 and p73, key components known to arrest the cell cycle, was directly activated by MafB and cJun. Our data suggest that dimeric combinations of MafB, cFos and cJun in developing chick limb buds control the number of apoptotic cells, and that MafB/cJun heterodimers lead to apoptosis via activation of p63 and p73.

  13. Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix compartments and limbic subdivisions of the striatum.

    PubMed Central

    Graybiel, A M; Moratalla, R; Robertson, H A

    1990-01-01

    Amphetamine and cocaine are stimulant drugs that act on central monoaminergic neurons to produce both acute psychomotor activation and long-lasting behavioral effects including addiction and psychosis. Here we report that single doses of these drugs induce rapid expression of the nuclear proto-oncogene c-fos in the forebrain and particularly in the striatum, an extrapyramidal structure implicated in addiction and in long-term drug-induced changes in motor function. The two drugs induce strikingly different patterns of c-fos expression in the striosome-matrix compartments and limbic subdivisions of the striatum, and their effects are pharmacologically distinct, although both are sensitive to dopamine receptor blockade. We propose that differential activation of immediate-early genes by psychostimulants may be an early step in drug-specific molecular cascades contributing to acute and long-lasting psychostimulant-induced changes in behavior. Images PMID:2118661

  14. Stimulus-specific combinatorial functionality of neuronal c-fos enhancers

    PubMed Central

    Joo, Jae-Yeol; Schaukowitch, Katie; Farbiak, Lukas; Kilaru, Gokhul; Kim, Tae-Kyung

    2015-01-01

    The c-fos gene is induced by a broad range of stimuli, and has been commonly used as a reliable marker for neural activity. Its induction mechanism and available reporter mouse lines are exclusively based on the c-fos promoter activity. Here, we demonstrate that multiple enhancers surrounding the c-fos gene are critical for ensuring robust c-fos response to various stimuli. Membrane depolarization, brain-derived neurotrophic factor (BDNF), and Forskolin activate distinct subsets of the enhancers to induce c-fos transcription in neurons, suggesting that stimulus-specific combinatorial activation of multiple enhancers underlies the broad inducibility of the c-fos gene. Accordingly, the functional requirement of key transcription factors varies depending on the type of stimulation. Combinatorial enhancer activation also occurs in the brain. Providing a comprehensive picture of the c-fos induction mechanism beyond the minimal promoter, our study should help in understanding the physiological nature of c-fos induction in relation to neural activity and plasticity. PMID:26595656

  15. Rapid and reversible changes in nucleosome structure accompany the activation, repression, and superinduction of murine fibroblast protooncogenes c-fos and c-myc

    SciTech Connect

    Chen, T.A.; Allfrey, V.G.

    1987-08-01

    A procedure for the isolation of transcriptionally active nucleosomes was used to monitor changes in chromatin structure during the activation, repression, and superinduction of the protooncogenes c-fos and c-myc. Nuclei were isolated from murine fibroblasts at successive times after stimulation of quiescent cell cultures with serum or platelet-derived growth factor. The nucleosomes released by a brief micrococcal nuclease digestion were fractionated by Hg/sup II/-affinity chromatography to separate the unfolded nucleosomes of transcriptionally active genes (in which the sulfhydryl groups of histone H3 are accessible for binding to Hg/sup II/) from the compactly beaded nucleosomes of transcriptionally inert DNA sequences (in which the H3 sulfhydryl groups are not accessible). The DNA sequence contents of the Hg/sup II/-bound and unbound nucleosome fractions were compared by slot-blot hybridizations to /sup 32/P-labeled cloned probes for c-fos and c-myc. The binding of the c-fos and c-myc nucleosomes to the Hg/sup II/ column accurately reflected both the timing and the degree of their expression, as determined by run-off transcription assays with the isolated nuclei. The superinduction of c-fos and c-myc expression by an inhibitor of protein synthesis (cycloheximide) was reflected in the persistence of the unfolded, transcriptionally active state of their component nucleosomes. These results provide direct evidence that rapid and reversible changes in nucleosome topography accompany the program of oncogene expression, and they suggest a way to monitor aberrant gene activity during malignant transformation

  16. Fos-tau-LacZ mice expose light-activated pathways in the visual system.

    PubMed

    Greferath, Ursula; Nag, Nupur; Zele, Andrew J; Bui, Bang V; Wilson, Yvette; Vingrys, Algis J; Murphy, Mark

    2004-11-01

    We have employed fos-tau-LacZ (FTL) transgenic mice to examine functional activation in the visual areas of the nervous system. The FTL mice express the marker gene lacZ in neurons and their processes following many different stimuli, and allow the imaging of activation from the level of the entire brain surface through individual neurons and their projections. Analysis of FTL expression in the retinas of mice following diurnal exposure to light shows that bipolar cells, specific classes of amacrine cells, ganglion cells, and a dense network of processes in the inner plexiform layer are functionally activated. In animals deprived of light, there is almost no activity in the retina. In the lateral geniculate nucleus (LGN), light exposure appears responsible for FTL expression in dorsal nuclei, but not for expression in the ventral nuclei or the intergeniculate leaflet. In the superficial layers of the superior colliculus, FTL expression is highly dependent on light exposure. Similarly, light exposure is required for FTL expression in primary visual cortex (area 17), but some expression remains in area 18 of dark-adapted animals. Finally, using mice with one or both eyes missing, we have determined which parts of the visual system are dependent on the presence of a functional connectivity from the eye. These data demonstrate the usefulness of the FTL mice to map functional activation within the entire visual system. Furthermore, we can capture visual activation in a conscious animal. Our findings give an insight into the architecture of activity within the retina and throughout the visual system.

  17. DNA binding of Jun and Fos bZip domains: homodimers and heterodimers induce a DNA conformational change in solution.

    PubMed Central

    John, M; Leppik, R; Busch, S J; Granger-Schnarr, M; Schnarr, M

    1996-01-01

    We constructed plasmids encoding the sequences for the bZip modules of c-Jun and c-Fos which could then be expressed as soluble proteins in Escherichia coli. The purified bZip modules were tested for their binding capacities of synthetic oligonucleotides containing either TRE or CRE recognition sites in electrophoretic mobility shift assays and circular dichroism (CD). Electrophoretic mobility shift assays showed that bZip Jun homodimers and bZip Jun/Fos heterodimers bind a collagenase-like TRE (CTGACTCAT) with dissociation constants of respectively 1.4 x 10(-7) M and 5 x 10(-8) M. As reported earlier [Patel et al. (1990) Nature 347, 572-575], DNA binding induces a marked change of the protein structure. However, we found that the DNA also undergoes a conformational change. This is most clearly seen with small oligonucleotides of 13 or 14 bp harboring respectively a TRE (TGACTCA) or a CRE (TGACGTCA) sequence. In this case, the positive DNA CD signal at 280 nm increases almost two-fold with a concomitant blue-shift of 3-4 nm. Within experimental error the same spectral changes are observed for TRE and CRE containing DNA fragments. The spectral changes observed with a non-specific DNA fragment are weaker and the signal of free DNA is recovered upon addition of much smaller salt concentrations than required for a specific DNA fragment. Surprisingly the spectral changes induced by Jun/Jun homodimers are not identical to those induced by Jun/Fos heterodimers. However, in both cases the increase of the positive CD band and the concomitant blue shift would be compatible with a B to A-transition of part of the binding site or a DNA conformation intermediate between the canonical A and B structures. PMID:8948639

  18. Control of c-fos and c-myc proto-oncogene induction in rat thyroid cells in culture

    SciTech Connect

    Isozaki, O.; Kohn, L.D. )

    1987-11-01

    Removal of TSH, insulin, and cortisol from the medium, and decreasing the serum content to 0.2%, abolishes both the proliferate and differentiated state of FRTL-5 rat thyroid cells in culture. In these basal conditions, the individual addition of TSH, insulin, insulin-like growth factor-I (IGF-I), phorbol 12-myristate 13-acetate (TPA), alpha 1-adrenergic agents, or A23187, increase c-myc and/or c-fos proto-oncogene expression. Under the same conditions, only the addition of TSH increased cAMP levels; 8-bromo-cAMP can increase c-myc or c-fos mRNA levels. Pretreatment of cells with phorbol 12,13-dibutyrate, an agent which down regulates the C-kinase, completely inhibits the effect of TPA on proto-oncogene expression but has no affect on the A23187 induced-increase. The sum of these results indicate that at least four separate signal systems independently increase c-myc or c-fos gene expression in FRTL-5 cells cAMP (TSH), C-kinase (TPA), Ca++/phosphoinositide (A23187), and that influenced by insulin/IGF-I. None of the ligands, when individually returned to cells in basal medium (no TSH, insulin, or cortisol and only 0.2% serum), increases cell number; norepinephrine, and A23187 do not increase (3H)thymidine incorporation into DNA under these conditions; and combinations of the ligands can be more than additive in effecting (3H)thymidine incorporation into DNA but are only additive in effecting proto-oncogene expression. Insulin/IGF-I plus TSH or insulin/IGF-I plus norepinephrine can increase both proto-oncogene expression and (3H)thymidine incorporation into DNA to the same extent; however, the former combination can increase cell number whereas the latter cannot. There is therefore no simple correlation between the ability of the above ligands to increase proto-oncogene expression and their ability to increase cell number or induce DNA synthesis.

  19. Repeated immobilization stress increases the binding of c-Fos-like proteins to a rat dopamine beta-hydroxylase promoter enhancer sequence.

    PubMed

    Nankova, B; Devlin, D; Kvetnanský, R; Kopin, I J; Sabban, E L

    1993-08-01

    Repeated immobilization stress elicits a large elevation in adrenal dopamine beta-hydroxylase (DBH) mRNA levels. This study attempts to analyze the molecular mechanism of increased DBH gene expression in stress. Adrenomedullary nuclear proteins were prepared from controls and rats exposed to various intervals of immobilization stress. Electrophoretic mobility shift assays showed that repeated stress led to increased binding of adrenomedullary nuclear factors to a cis-acting regulatory element in the rat DBH promoter (DBH-1). One of the partners in the DNA-protein complex is c-Fos or a Fos-related protein. There was a correlation between promoter binding activity and elevated steady-state levels of DBH mRNA. Our data indicate that this cis regulatory element in the rat DBH promoter is functional in vivo, and increased binding of AP1-like transcription factors to this motif is induced by immobilization stress.

  20. Single-dose and chronic corticosterone treatment alters c-Fos or FosB immunoreactivity in the rat cerebral cortex.

    PubMed

    Szakács, Réka; Fazekas, Ildikó; Mihály, András; Krisztin-Péva, Beáta; Juhász, Anna; Janka, Zoltán

    2010-03-01

    The aim of this study was to examine the effects of single-dose and chronic corticosterone treatment on the inducible transcription factor c-Fos and FosB, and thereby to estimate the effects of high-doses of corticosterone on calcium-dependent neuronal responses in the rat cerebral cortex. At the same time we investigated the distribution of interneurons containing calretinin (CR), vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY) in chronically treated animals in order to collect data on the involvement of inhibitory neurons in this process. Adult male rats were injected subcutaneously with 10mg corticosterone, whereas controls received the vehicle (sesame oil). The animals were fixed by transcardial perfusion 12 and 24h following single corticosterone injection, and the brains were processed for c-Fos and FosB immunohistochemistry. To investigate the effects of repeated corticosterone administration, rats were daily treated with the same amount of corticosterone (10mg/animal, subcutaneously) for 21 days. Controls were injected with vehicle. At the end of the experiment, the rats were perfused and immunohistochemistry was used to detect the presence of the FosB protein, CR, VIP and NPY. Quantitative evaluation of immunolabelled cells was performed in the neocortex and the hippocampus. The number of immunoreactive nuclei per unit area was used as a quantitative measure of the effects of corticosterone. It was found that a single-dose administration of corticosterone resulted in a significant, time-dependent increase of c-Fos protein immunoreactivity in the granule cell layer of the dentate gyrus, as well as in regions CA1 and CA3 of the hippocampus 12 and 24h post-injection with respect to control animals. Significant enhancement of c-Fos immunoreactivity was also observed in the neocortex at 12 and 24h post-injection. Single-dose treatment did not significantly alter FosB immunolabelling. Repeated administration of corticosterone produced a complex

  1. Increased sucrose intake and corresponding c-Fos in amygdala and parabrachial nucleus of dietary obese rats.

    PubMed

    Li, Jinrong; Chen, Ke; Yan, Jianqun; Wang, Qian; Zhao, Xiaolin; Yang, Xuejuan; Yang, Dejun; Zhao, Shiru; Zhu, Guangjing; Sun, Bo

    2012-09-13

    The intake-excitatory effects of caloric foods are mainly due to the palatable taste and the ensuing positive postingestive effects. Dietary obese individuals are inclined to overeat high caloric foods. However, it is still unclear whether the taste or postingestive reinforcement mainly contributes to the excessive intake by obese individuals. In the present study, we measured 10- or 120-min sucrose solution drunk by dietary obese rats and measured c-Fos expression following 120-min tests in the central nucleus of amygdala (CeA), a forebrain nucleus involved in the hedonic reward and craving, and the parabrachial nucleus (PBN), a taste relay area responsive to positive postingestive effects. Dietary obese rats, compared with those fed normal chow, ingested larger amounts of sucrose solution (0.25 M) in the 120-min test, but not in the 10-min test. In addition, significantly more sucrose-induced c-Fos positive cells were found in the CeA, but much less in the external lateral subnucleus of the PBN of dietary obese rats. Our results demonstrate that increased sucrose intake in dietary obese rats is mainly due to the alteration of postingestive effects. The differences in these postingestive effects in obesity may involve greater positive/excitatory signals in which the CeA may play a role, and less negative/inhibitory signals in which the el-PBN may be involved.

  2. Apolipoprotein E inhibits osteoclast differentiation via regulation of c-Fos, NFATc1 and NF-κB

    SciTech Connect

    Kim, Woo-Shin; Kim, Hyung Joon; Lee, Zang Hee; Lee, Youngkyun; Kim, Hong-Hee

    2013-02-15

    Apolipoprotein E (ApoE) plays a major role in the transport and metabolism of lipid. Other functions of ApoE include modulation of innate and adaptive immune responses. The expression of ApoE in osteoblasts and its relevance with bone formation have also been reported. However, the effect of ApoE on osteoclasts has not yet been examined. Here, we investigated the role of ApoE in osteoclast differentiation using bone marrow-derived macrophages (BMMs) and RAW264.7 cells. We found a down-regulation of ApoE gene expression during osteoclastic differentiation of those cells. Overexpression of ApoE in BMMs and RAW264.7 cells significantly blocked the induction of c-Fos and nuclear factor of activated T cell c1 (NFATc1), transcription factors critical for expression of osteoclast marker genes, by receptor activator of nuclear factor κB ligand (RANKL), the osteoclast differentiation factor. ApoE inhibited osteoclast differentiation, as measured by decreased number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells (MNCs). In addition, ApoE reduced the expression of dendritic cell-specific transmembrane protein (DC-STAMP) and ATPase, H{sup +} transporting, lysosomal 38 kDa, V0 subunit d2 (ATP6v0d2), genes involved in cell–cell fusion during osteoclastogenesis. Knock-down of ApoE using a specific siRNA promoted the RANKL-mediated induction of osteoclast differentiation. While ApoE did not affect the activation of ERK, JNK, and p38 MAPK signaling pathways by RANKL, the phosphorylation of p65 trans-activation domain on serine 536 and transcription activity of NF-κB were reduced by ApoE overexpression. These findings suggest that ApoE plays an inhibitory role in osteoclast differentiation via the suppression of RANKL-dependent activation of NF-κB and induction of c-Fos and NFATc1. - Highlights: ► Apolipoprotein E (ApoE) significantly inhibited osteoclast differentiation and activation of NF-κB. ► ApoE decreased the induction of osteoclast marker

  3. c-fos mRNA in mouse brain after MPTP treatment.

    PubMed

    Duchemin, A M; Gudehithlu, K P; Neff, N H; Hadjiconstantinou, M

    1992-04-01

    The neurotoxin, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces a transient increase of mRNA for the immediate-early gene c-fos in the mouse brain. The c-fos mRNA level is MPTP dose-dependent and is evident in all brain regions tested including striatum, hypothalamus, cortex, hippocampus, cerebellum and midbrain. There are regional differences in the time-course for the rise of c-fos mRNA. Pretreatment with deprenyl, a selective monoamine oxidase B inhibitor, pargyline, a nonselective monoamine oxidase inhibitor, or mazindol, a dopamine uptake transport inhibitor, does not prevent the c-fos mRNA increase, suggesting that the elevation is due to the action of MPTP and not its neurotoxic metabolite MPP+.

  4. Prolactin and estrogen enhance the activity of activating protein 1 in breast cancer cells: role of extracellularly regulated kinase 1/2-mediated signals to c-fos.

    PubMed

    Gutzman, Jennifer H; Nikolai, Sarah E; Rugowski, Debra E; Watters, Jyoti J; Schuler, Linda A

    2005-07-01

    Despite the important roles of both prolactin (PRL) and 17beta-estradiol (E2) in normal mammary development as well as in breast cancer, and coexpression of the estrogen receptor (ER) and PRL receptor in many mammary tumors, the interactions between PRL and E2 in breast cancer have not been well studied. The activating protein 1 (AP-1) transcription factor, a known regulator of processes essential for normal growth and development as well as carcinogenesis, is a potential site for cross-talk between these hormones in breast cancer cells. Here we demonstrate that PRL and E2 cooperatively enhance the activity of AP-1 in MCF-7-derived cells. In addition to the acute PRL-induced ERK1/2 activation, PRL and E2 also individually elicited delayed, sustained rises in levels of phosphorylated p38 and especially ERK1/2. Together, these hormones increased the dynamic phosphorylation of ERK1/2 and c-Fos, and induced c-fos promoter activity. Synergistic activation of the transcription factor, Elk-1, reflected the PRL-E2 interaction at ERK1/2 and is a likely mechanism for activation of the c-fos promoter via the serum response element. The enhanced AP-1 activity resulting from the interaction of these hormones may increase expression of many target genes that are critical for oncogenesis and may contribute to neoplastic progression.

  5. Methyl supplementation attenuates cocaine-seeking behaviors and cocaine-induced c-Fos activation in a DNA methylation-dependent manner.

    PubMed

    Wright, Katherine N; Hollis, Fiona; Duclot, Florian; Dossat, Amanda M; Strong, Caroline E; Francis, T Chase; Mercer, Roger; Feng, Jian; Dietz, David M; Lobo, Mary Kay; Nestler, Eric J; Kabbaj, Mohamed

    2015-06-10

    Epigenetic mechanisms, such as histone modifications, regulate responsiveness to drugs of abuse, such as cocaine, but relatively little is known about the regulation of addictive-like behaviors by DNA methylation. To investigate the influence of DNA methylation on the locomotor-activating effects of cocaine and on drug-seeking behavior, rats receiving methyl supplementation via chronic l-methionine (MET) underwent either a sensitization regimen of intermittent cocaine injections or intravenous self-administration of cocaine, followed by cue-induced and drug-primed reinstatement. MET blocked sensitization to the locomotor-activating effects of cocaine and attenuated drug-primed reinstatement, with no effect on cue-induced reinstatement or sucrose self-administration and reinstatement. Furthermore, upregulation of DNA methyltransferase 3a and 3b and global DNA hypomethylation were observed in the nucleus accumbens core (NAc), but not in the medial prefrontal cortex (mPFC), of cocaine-pretreated rats. Glutamatergic projections from the mPFC to the NAc are critically involved in the regulation of cocaine-primed reinstatement, and activation of both brain regions is seen in human addicts when reexposed to the drug. When compared with vehicle-pretreated rats, the immediate early gene c-Fos (a marker of neuronal activation) was upregulated in the NAc and mPFC of cocaine-pretreated rats after cocaine-primed reinstatement, and chronic MET treatment blocked its induction in both regions. Cocaine-induced c-Fos expression in the NAc was associated with reduced methylation at CpG dinucleotides in the c-Fos gene promoter, effects reversed by MET treatment. Overall, these data suggest that drug-seeking behaviors are, in part, attributable to a DNA methylation-dependent process, likely occurring at specific gene loci (e.g., c-Fos) in the reward pathway.

  6. Long-term ethanol self-administration induces ΔFosB in male and female adolescent, but not in adult, Wistar rats.

    PubMed

    Wille-Bille, Aranza; de Olmos, Soledad; Marengo, Leonardo; Chiner, Florencia; Pautassi, Ricardo Marcos

    2017-03-06

    Early-onset ethanol consumption predicts later development of alcohol use disorders. Age-related differences in reactivity to ethanol's effects may underlie this effect. Adolescent rats are more sensitive and less sensitive than adults to the appetitive and aversive behavioral effects of ethanol, respectively, and more sensitive to the neurotoxic effects of experimenter-administered binge doses of ethanol. However, less is known about age-related differences in the neural consequences of self-administered ethanol. ΔFosB is a transcription factor that accumulates after chronic drug exposure and serves as a molecular marker of neural plasticity associated with the transition to addiction. We analyzed the impact of chronic (18 two-bottle choice intake sessions spread across 42days, session length: 18h) ethanol [or only vehicle (control group)] self-administration during adolescence or adulthood on the induction of ΔFosB in several brain areas, anxiety-like behavior, and ethanol-induced locomotor activity and conditioned place preference (CPP) in Wistar rats. Adolescent rats exhibited a progressive escalation of ethanol intake and preference, whereas adult rats exhibited a stable pattern of ingestion. Few behavioral differences in the open field or light-dark test were observed after the intake test. Furthermore, ethanol self-administration did not promote the expression of ethanol-induced CPP. There were, however, large age-related differences in the neural consequences of ethanol drinking: a significantly greater number of ethanol-induced ΔFosB-positive cells was found in adolescents vs. adults in the prelimbic cortex, dorsolateral striatum, nucleus accumbens core and shell, and central amygdala nucleus capsular and basolateral amygdala, with sex-related differences found at central amygdala. This greater ethanol-induced ΔFosB induction may represent yet another age-related difference in the sensitivity to ethanol that may put adolescents at higher risk for

  7. The time course of systems consolidation of spatial memory from recent to remote retention: A comparison of the Immediate Early Genes Zif268, c-Fos and Arc.

    PubMed

    Barry, Daniel N; Coogan, Andrew N; Commins, Sean

    2016-02-01

    Systems consolidation is a process involving the stabilisation of memory traces in the neocortex over time. The medial prefrontal cortex becomes increasingly important during the retrieval of older memories, however the timescale of its involvement is unclear, and the contribution of other neocortical brain regions to remote memory have received little attention. The Immediate Early Genes (IEGs) Zif268, c-Fos and Arc have been utilised as markers of neural activity during spatial memory retrieval, however the lack of a direct comparison between them hinders the interpretation of results. To address these questions, we examined the expression of Zif268, Arc and c-Fos protein in the medial prefrontal cortex, as well as the hippocampus, and the entorhinal, perirhinal, retrosplenial and parietal cortices of male Wistar rats following a probe trial of the Morris water maze either one day, seven days, 14 days or 30 days after acquisition. Activity of the medial prefrontal cortex during retrieval, as measured by all three IEGs, increased in correspondence with the age of the memory, reaching significance between 14 and 30 days. Similar increases in c-Fos and Arc were observed over the course of consolidation in other neocortical and parahippocampal areas, however this pattern was not observed with Zif268. Activity of the hippocampus remained largely unchanged across retention intervals. These findings suggest that systems consolidation of spatial memory takes at least two weeks, are consistent with an ongoing role for the hippocampus in the retrieval of spatial memory, and suggest that c-Fos and Arc may be a more sensitive measure of neural activity in response to behavioural tasks than Zif268.

  8. Methyl Supplementation Attenuates Cocaine-Seeking Behaviors and Cocaine-Induced c-Fos Activation in a DNA Methylation-Dependent Manner

    PubMed Central

    Wright, Katherine N.; Hollis, Fiona; Duclot, Florian; Dossat, Amanda M.; Strong, Caroline E.; Francis, T. Chase; Mercer, Roger; Feng, Jian; Dietz, David M.; Lobo, Mary Kay; Nestler, Eric J.

    2015-01-01

    Epigenetic mechanisms, such as histone modifications, regulate responsiveness to drugs of abuse, such as cocaine, but relatively little is known about the regulation of addictive-like behaviors by DNA methylation. To investigate the influence of DNA methylation on the locomotor-activating effects of cocaine and on drug-seeking behavior, rats receiving methyl supplementation via chronic l-methionine (MET) underwent either a sensitization regimen of intermittent cocaine injections or intravenous self-administration of cocaine, followed by cue-induced and drug-primed reinstatement. MET blocked sensitization to the locomotor-activating effects of cocaine and attenuated drug-primed reinstatement, with no effect on cue-induced reinstatement or sucrose self-administration and reinstatement. Furthermore, upregulation of DNA methyltransferase 3a and 3b and global DNA hypomethylation were observed in the nucleus accumbens core (NAc), but not in the medial prefrontal cortex (mPFC), of cocaine-pretreated rats. Glutamatergic projections from the mPFC to the NAc are critically involved in the regulation of cocaine-primed reinstatement, and activation of both brain regions is seen in human addicts when reexposed to the drug. When compared with vehicle-pretreated rats, the immediate early gene c-Fos (a marker of neuronal activation) was upregulated in the NAc and mPFC of cocaine-pretreated rats after cocaine-primed reinstatement, and chronic MET treatment blocked its induction in both regions. Cocaine-induced c-Fos expression in the NAc was associated with reduced methylation at CpG dinucleotides in the c-Fos gene promoter, effects reversed by MET treatment. Overall, these data suggest that drug-seeking behaviors are, in part, attributable to a DNA methylation-dependent process, likely occurring at specific gene loci (e.g., c-Fos) in the reward pathway. PMID:26063926

  9. Evidence for Homodimerization of the c-Fos Transcription Factor in Live Cells Revealed by Fluorescence Microscopy and Computer Modeling.

    PubMed

    Szalóki, Nikoletta; Krieger, Jan Wolfgang; Komáromi, István; Tóth, Katalin; Vámosi, György

    2015-11-01

    The c-Fos and c-Jun transcription factors, members of the activator protein 1 (AP-1) complex, form heterodimers and bind to DNA via a basic leucine zipper and regulate the cell cycle, apoptosis, differentiation, etc. Purified c-Jun leucine zipper fragments could also form stable homodimers, whereas c-Fos leucine zipper homodimers were found to be much less stable in earlier in vitro studies. The importance of c-Fos overexpression in tumors and the controversy in the literature concerning c-Fos homodimerization prompted us to investigate Fos homodimerization. Förster resonance energy transfer (FRET) and molecular brightness analysis of fluorescence correlation spectroscopy data from live HeLa cells transfected with fluorescent-protein-tagged c-Fos indicated that c-Fos formed homodimers. We developed a method to determine the absolute concentrations of transfected and endogenous c-Fos and c-Jun, which allowed us to determine dissociation constants of c-Fos homodimers (Kd = 6.7 ± 1.7 μM) and c-Fos-c-Jun heterodimers (on the order of 10 to 100 nM) from FRET titrations. Imaging fluorescence cross-correlation spectroscopy (SPIM-FCCS) and molecular dynamics modeling confirmed that c-Fos homodimers were stably associated and could bind to the chromatin. Our results establish c-Fos homodimers as a novel form of the AP-1 complex that may be an autonomous transcription factor in c-Fos-overexpressing tissues and could contribute to tumor development.

  10. Differential induction of c-Jun and Fos-like proteins in rat hippocampus and dorsal striatum after training in two water maze tasks.

    PubMed

    Teather, Lisa A; Packard, Mark G; Smith, Diane E; Ellis-Behnke, Rutledge G; Bazan, Nicolas G

    2005-09-01

    Research examining the neuroanatomical bases of memory in mammals suggests that the hippocampus and dorsal striatum are parts of independent memory systems that mediate "cognitive" and stimulus-response "habit" memory, respectively. At the molecular level, increasing evidence indicates a role for immediate early gene (IEG) expression in memory formation. The present experiment examined whether acquisition of cognitive and habit memory result in differential patterns of IEG protein product expression in these two brain structures. Adult male Long-Evans rats were trained in either a hippocampal-dependent spatial water maze task, or a dorsal striatal-dependent cued water maze task. Ninety minutes after task acquisition, brains were removed and processed for immunocytochemical procedures, and the number of cells expressing Fos-like immunoreactivity (Fos-like-IR) and c-Jun-IR in sections from the dorsal hippocampus and the dorsal striatum were counted. In the dorsal hippocampus of rats trained in the spatial task, there were significantly more c-Jun-IR pyramidal cells in the CA1 and CA3 regions, relative to rats that had acquired the cued task, yoked controls (free-swim), or naïve (home cage) rats. Relative to rats receiving cued task training and control conditions, increases in Fos-like IR were also observed in the CA1 region of rats trained in the spatial task. In rats that had acquired the cued task, patches of c-Jun-IR were observed in the posteroventral striatum; no such patches were evident in rats trained in the spatial task, yoked-control rats, or naïve rats. The results demonstrate that IEG protein product expression is up-regulated in a task-dependent and brain structure-specific manner shortly after acquisition of cognitive and habit memory tasks.

  11. Central Renin Injections: Effects on Drinking and Expression of Immediate Early Genes

    NASA Technical Reports Server (NTRS)

    Xu, Zhice; Johnson, Alan Kim

    1998-01-01

    This study investigated the drinking response and the expression of Fos- and Egr-1-immunoreactivity (Fos-ir, Egr-1-ir) in the brain induced by endogenous angiotensin generated by intracerebroventricular (i.c.v.) injection of renin. Renin induced Fos-ir in the subformical organ (SFO), median preoptic (MnPO), supraoptic and paraventricular nuclei (SON and PVN), area postrema (AP), nuclei of the solitary tract (NTS) and lateral parabrachial nuclei (LPBN). Renin-induced Egr-1-ir exhibited a similar pattern of distribution as that observed for Fos-ir. The dose of i.c.v. renin that induced expression of immediate early gene (IEG) product immunoreactivity also produced vigorous drinking. When renin-injected rats were pretreated with captopril, an angiotensin converting enzyme inhibitor, drinking was blocked. With the same captopril pretreatment, both Fos- and Egr-1-ir in the SFO, MnPO, SON, PVN, AP and LPBN were also significantly reduced.

  12. Inhibiting AP-1 activity alters cocaine induced gene expression and potentiates sensitization

    PubMed Central

    Paletzki, Ronald F.; Myakishev, Max V.; Polesskaya, Oksana; Orosz, Andras; Hyman, Steven E.; Vinson, Charles

    2008-01-01

    We have expressed A-FOS, an inhibitor of AP-1 DNA binding, in adult mouse striatal neurons. We observe normal behavior including locomotion and exploratory activities. Following a single injection of cocaine, locomotion increased similarly in both the A-FOS expressing and littermate controls. However, following repeated injections of cocaine, the A-FOS expressing mice showed increased locomotion relative to littermate controls, an increase that persisted following a week of withdrawal and subsequent cocaine administration. These results indicate that AP-1 suppresses this behavioral responses to cocaine. We analyzed mRNA from the striatum before and 4 and 24 hours after a single cocaine injection in both A-FOS and control striata using Affymetrix microarrays (430 2.0 Array) to identify genes mis-regulated by A-FOS that may mediate the increased locomotor sensitization to cocaine. A-FOS expression did not change gene expression in the basal state or 4 hours following cocaine treatment relative to controls. However, 24 hours after an acute cocaine treatment, 84 genes were identified that were differentially expressed between the A-FOS and control mice. 56 gene are down regulated while 28 genes are up regulated including previously identified candidates for addiction including BDNF and Per1. Using a random sample of identified genes, quantitative PCR was used to verify the microarray studies. The chromosomal location of these 84 genes was compared to human genome scans of addiction to identify potential genes in humans that are involved in addiction. PMID:18355967

  13. Acute restraint differently alters defensive responses and fos immunoreactivity in the rat brain.

    PubMed

    de Andrade, J S; Abrão, R O; Céspedes, I C; Garcia, M C; Nascimento, J O G; Spadari-Bratfisch, R C; Melo, L L; da Silva, R C B; Viana, M B

    2012-06-15

    Results from a previous study show that rats exposed to acute restraint display anxiogenic-like behavior, evidenced by facilitation of avoidance responses in the elevated T-maze (ETM) model of anxiety. In contrast, escape responses were unaltered by stress exposure. Since ETM avoidance and escape tasks seem to activate distinct sets of brain structures, it is possible that the differences observed with acute restraint are due to particularities in the neurobiological mechanisms which modulate these responses. In the present study, analysis of fos protein immunoreactivity (fos-ir) was used to map areas activated by exposure of male Wistar rats to restraint stress (30 min) previously (30 min) to the ETM. Corticosterone levels were also measured in stressed and non-stressed animals. Confirming previous observations restraint facilitated avoidance performance, an anxiogenic result, while leaving escape unaltered. Performance of the avoidance task increased fos-ir in the frontal cortex, intermediate lateral septum, basolateral amygdala, basomedial amygdala, lateral amygdala, anterior hypothalamus and dorsal raphe nucleus. In contrast, performance of escape increased fos-ir in the ventromedial hypothalamus, dorsolateral periaqueductal gray and locus ceruleus. Both behavioral tasks also increased fos-ir in the dorsomedial hypothalamus. Restraint significantly raised corticosterone levels. Additionally after restraint, fos-ir was predominantly seen in the basolateral amygdala and dorsal raphe of animals submitted to the avoidance task. This data confirms that different sets of brain structures are activated by ETM avoidance and escape tasks and suggests that acute restraint differently alters ETM behavior and the pattern of fos activation in the brain.

  14. CB1 Cannabinoid Agonist (WIN55,212-2) Within the Basolateral Amygdala Induced Sensitization to Morphine and Increased the Level of μ-Opioid Receptor and c-fos in the Nucleus Accumbens.

    PubMed

    Molaei, Marzieh; Fatahi, Zahra; Zaringhalam, Jalal; Haghparast, Abbas

    2016-04-01

    The basolateral amygdala (BLA) is rich of CB1 cannabinoid receptors (CB1R) and has reciprocal connections with the nucleus accumbens (NAc) which is involved in opioid sensitization. In this study, effects of intra-BLA administration of CB1R agonist on sensitization to antinociceptive effect of morphine and changes in the levels of μ-opioid receptor (MOR), p-CREB, and c-fos in the NAc were investigated. Animals received intra-BLA microinjection of CB1R agonist (WIN55,212-2) once daily for 3 days consecutively (sensitization period). After 5 days free of drug, tail-flick test was performed before and after the administration of an ineffective dose of morphine. Afterward, the levels of MOR, p-CREB, and c-fos proteins were measured in the NAc by Western blot analysis. The results indicated that intra-BLA injection of WIN55,212-2 during sensitization period resulted in the induction of antinociceptive responses by ineffective dose of morphine and caused a significant increase in the MOR and c-fos levels but not p-CREB/CREB ratio in the NAc. These finding revealed that CB1 receptor agonist in the BLA induces development of morphine sensitization and increases expression of MOR in the NAc. It seems that c-fos is one of the important factors involved in the induction of sensitization to antinociceptive effect of morphine.

  15. The recognition of a novel-object in a novel context leads to hippocampal and parahippocampal c-Fos involvement.

    PubMed

    Arias, N; Méndez, M; Arias, J L

    2015-10-01

    Contextual memory implies recognition based on the association between past and present events experienced. It is important for daily functioning and dysfunctional in many neuropsychological disturbances. The network related to this memory is still open for debate, even though it has been associated with medial temporal lobe regions, including the perirhinal, entorhinal and temporal association cortices, as well as the hippocampus and prefrontal cortex. Our work tries to elucidate whether a change in the context, such as differences in the amount of stimuli presented on the walls and floor of an open field during object exploration, affects the recognition of an object that has been experienced before, and whether this context manipulation could be linked to changes in c-Fos expression. For this purpose, we used a one-trial novel-object recognition task. The animals were divided into two different experimental conditions; in the OR-NORMAL group, the sample and probe test were performed in the same context. However, in the OR-CONTEXT group, the probe test was performed in a different context. Our results showed that the OR-NORMAL group presented a greater exploration of objects than the OR-CONTEXT group. However, both groups presented significant exploration of the novel object. To label the brain regions involved in novel-object recognition under these conditions, we marked the expression of c-Fos protein. Results suggest that a neural circuit that includes the hippocampus, entorhinal and temporal association cortices is involved in the recognition of the novel-object in a novel context.

  16. Signalling in inflammatory skin disease by AP-1 (Fos/Jun).

    PubMed

    Uluçkan, Özge; Guinea-Viniegra, Juan; Jimenez, Maria; Wagner, Erwin F

    2015-01-01

    Skin inflammation is a physiological reaction to tissue injury, pathogen invasion and irritants. During this process, innate and/or adaptive immune cells are activated and recruited to the site of inflammation to either promote or suppress inflammation. The sequential recruitment and activation of immune cells is modulated by a combination of cytokines and chemokines, which are regulated by transcription factors, such as AP-1 (Fos/Jun), NF-κB, NFATs, and STATs. Here we review the present evidence and the underlying mechanisms of how Jun/AP-1 proteins control skin inflammation. Genetically engineered mouse models (GEMMs) in which AP-1 proteins are deleted in the epidermis have revealed that these proteins control cytokine expression at multiple levels. Constitutive epidermal deletion of JunB in mice leads to a multi-organ disease characterised by increased levels of pro-inflammatory cytokines. These JunB-deficient mutant mice display several phenotypes from skin inflammation to a G-CSF-dependent myeloproliferative disease, as well as kidney atrophy and bone loss, reminiscent of psoriasis and systemic lupus erythematosus. Importantly, epidermal deletion of both JunB and c-Jun in an inducible manner in adult mice leads to a psoriasis-like disease, in which the epidermal proteome expression profile is comparable to the one from psoriasis patient samples. In this GEMM and in psoriasis patient-derived material, S100A8/A9-dependent C3/CFB complement activation, as well as a miR-21-dependent TIMP-3/TACE pathway leading to TNF-α shedding, plays causal roles in disease development. The newly identified therapeutic targets from GEMMs together with investigations in human patient samples open up new avenues for therapeutic interventions for psoriasis and related inflammatory skin diseases.

  17. Modulation in the activity of lactate dehydrogenase and level of c-Myc and c-Fos by modified base queuine in cancer.

    PubMed

    Pathak, Chandramani; Jaiswal, Yogesh K; Vinayak, Manjula

    2008-01-01

    Cancer is characterized by uncontrolled cell growth, which results from unlimited proliferation and disturbs various cellular activities. Queuine is a highly modified base analogue of guanine found at first anti-codon position of specific tRNAs i.e. tRNA(Tyr), tRNA(His), tRNA(Asp) and tRNA(Asn). These tRNAs are known as Q-family of tRNA. The tRNAs of Q-family are completely modified to Q-tRNAs in terminally differentiated somatic cells, however hypomodification of Q-tRNA is closely associated with cell proliferation and malignancy. Queuosine modification of tRNAs may be essential for normal development, differentiation and cellular functions. Physiological role of queuine remains ill defined but direct or indirect evidences suggest that queuine or Q-tRNA participates in many cellular functions such as regulation of cell proliferation, control of glycolytic metabolism, alteration in expression of proto-oncogenes, modulation of signal transduction pathways but the mechanism is not well known. Increase in LDH-A expression regulated by c-myc is well documented in a variety of tumor cells. Overexpression of proto-oncogenes cause deregulated cellular responses which may lead to development of cancer. The cellular proto-oncogenes like c-myc and c-fos have important role in cell growth, proliferation and differentiation. The present study is aimed to investigate queuine mediated modulation in the activity of lactate dehydrogenase and expression of proto-oncogenes like c-myc and c-fos in T-cell lymphoma (DLAT) induced cancerous mouse. The results indicate that elevated lactate dehydrogenase activity is brought down by queuine treatments and the elevated levels of c-Myc and c-Fos in DLAT cancerous mouse are down-regulated, suggesting that queuine inhibits anaerobic metabolism and cell proliferation.

  18. Retrieval of morphine-associated context induces cFos in dentate gyrus neurons.

    PubMed

    Rivera, Phillip D; Raghavan, Ramya K; Yun, Sanghee; Latchney, Sarah E; McGovern, Mary-Katherin; García, Emily F; Birnbaum, Shari G; Eisch, Amelia J

    2015-04-01

    Addiction has been proposed to emerge from associations between the drug and the reward-associated contexts. This associative learning has a cellular correlate, as there are more cFos+ neurons in the hippocampal dentate gyrus (DG) after psychostimulant conditioned place preference (CPP) versus saline controls. However, it is unknown whether morphine CPP leads to a similar DG activation, or whether DG activation is due to locomotion, handling, pharmacological effects, or-as data from contextual fear learning suggests-exposure to the drug-associated context. To explore this, we employed an unbiased, counterbalanced, and shortened CPP design that led to place preference and more DG cFos+ cells. Next, mice underwent morphine CPP but were then sequestered into the morphine-paired (conditioned stimulus+ [CS+]) or saline-paired (CS-) context on test day. Morphine-paired mice sequestered to CS+ had ∼30% more DG cFos+ cells than saline-paired mice. Furthermore, Bregma analysis revealed morphine-paired mice had more cFos+ cells in CS+ compared to CS- controls. Notably, there was no significant difference in DG cFos+ cell number after handling alone or after receiving morphine in home cage. Thus, retrieval of morphine-associated context is accompanied by activation of hippocampal DG granule cell neurons.

  19. Role of Dopamine Type 1 Receptors and Dopamine- and cAMP-Regulated Phosphoprotein Mr 32 kDa in Δ9-Tetrahydrocannabinol–Mediated Induction of ΔFosB in the Mouse Forebrain

    PubMed Central

    Lazenka, Matthew F.; Tomarchio, Aaron J.; Lichtman, Aron H.; Greengard, Paul; Flajolet, Marc; Selley, Dana E.

    2015-01-01

    Δ9-Tetrahydrocannabinol (THC), the main psychoactive component of marijuana, produces motor and motivational effects via interactions with the dopaminergic system in the caudate-putamen and nucleus accumbens. However, the molecular events that underlie these interactions after THC treatment are not well understood. Our study shows that pretreatment with dopamine D1 receptor (D1R) antagonists before repeated administration of THC attenuated induction of Δ FBJ murine osteosarcoma viral oncogene homolog B (ΔFosB) in the nucleus accumbens, caudate-putamen, amygdala, and prefrontal cortex. Anatomical studies showed that repeated THC administration induced ΔFosB in D1R-containing striatal neurons. Dopamine signaling in the striatum involves phosphorylation-specific effects of the dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa (DARPP-32), which regulates protein kinase A signaling. Genetic deletion of DARPP-32 attenuated ΔFosB expression measured after acute, but not repeated, THC administration in both the caudate-putamen and nucleus accumbens. THC was then acutely or repeatedly administered to wild-type (WT) and DARPP-32 knockout (KO) mice, and in vivo responses were measured. DARPP-32 KO mice exhibited enhanced acute THC-mediated hypolocomotion and developed greater tolerance to this response relative to the WT mice. Agonist-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding showed that cannabinoid-stimulated G-protein activity did not differ between DARPP-32 KO and WT mice treated with vehicle or repeated THC. These results indicate that D1Rs play a major role in THC-mediated ΔFosB induction in the forebrain, whereas the role of DARPP-32 in THC-mediated ΔFosB induction and modulation of motor activity appears to be more complex. PMID:26099530

  20. Lack of estradiol modulation of sleep deprivation-induced c-Fos in the rat brain.

    PubMed

    Mashoodh, Rahia; Stamp, Jennifer A; Wilkinson, Michael; Rusak, Benjamin; Semba, Kazue

    2008-11-28

    Women recover from sleep deprivation more efficiently than men, but the mechanism for this difference is unknown. Effects of estrogen on sleep suggest that it could play a role, but the brain targets on which estrogen may act to have this effect have not been identified. Sleep deprivation increases levels of the immediate-early gene protein c-Fos in selected brain regions, but it is unknown whether estrogen modulates this response. We investigated the influence of different levels of exogenous estradiol on the c-Fos response to sleep deprivation in ovariectomized female rats. Female rats were treated with low or high levels of estradiol (mimicking diestrous and proestrous levels, respectively) delivered via subcutaneous silastic tubes. Control ovariectomized females and sham-operated males were implanted with tubes filled with cholesterol. One week after surgery, half of the rats underwent a 3 h period of sleep deprivation during the light phase in a motorized Wahmann activity wheel that rotated constantly at a slow speed, while half were confined to fixed wheels. Immediately after sleep deprivation, animals were killed and their brains processed to detect c-Fos using immunohistochemistry. Sleep deprivation increased the number of c-Fos positive cells in a number of brain areas, including the caudate putamen, medial preoptic area, perifornical hypothalamus, and anterior paraventricular thalamic nucleus. Other areas, including the suprachiasmatic nucleus, posterior paraventricular hypothalamic nucleus, posterior paraventricular thalamic nucleus, arcuate nucleus, and central amygdala, did not respond to 3 h sleep deprivation with a significant increase in c-Fos levels. Levels of c-Fos induced in the selected brain regions by sleep deprivation were not modulated by estrogen levels, nor by sex.

  1. Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on the EGF receptor-MAP kinase-fos signalling pathway.

    PubMed Central

    Migliaccio, E; Mele, S; Salcini, A E; Pelicci, G; Lai, K M; Superti-Furga, G; Pawson, T; Di Fiore, P P; Lanfrancone, L; Pelicci, P G

    1997-01-01

    Shc proteins are targets of activated tyrosine kinases and are implicated in the transmission of activation signals to Ras. The p46shc and p52shc isoforms share a C-terminal SH2 domain, a proline- and glycine-rich region (collagen homologous region 1; CH1) and a N-terminal PTB domain. We have isolated cDNAs encoding for a third Shc isoform, p66shc. The predicted amino acid sequence of p66shc overlaps that of p52shc and contains a unique N-terminal region which is also rich in glycines and prolines (CH2). p52shc/p46shc is found in every cell type with invariant reciprocal relationship, whereas p66shc expression varies from cell type to cell type. p66shc differs from p52shc/p46shc in its inability to transform mouse fibroblasts in vitro. Like p52shc/p46shc, p66shc is tyrosine-phosphorylated upon epidermal growth factor (EGF) stimulation, binds to activated EGF receptors (EGFRs) and forms stable complexes with Grb2. However, unlike p52shc/p46shc it does not increase EGF activation of MAP kinases, but inhibits fos promoter activation. The isolated CH2 domain retains the inhibitory effect of p66shc on the fos promoter. p52shc/p46shc and p66shc, therefore, appear to exert different effects on the EGFR-MAP kinase and other signalling pathways that control fos promoter activity. Regulation of p66shc expression might, therefore, influence the cellular response to growth factors. PMID:9049300

  2. Increased analgesic tolerance to acute morphine in fosB knock-out mice: a gender study.

    PubMed

    Solecki, Wojciech; Krowka, Tomasz; Kubik, Jakub; Kaczmarek, Leszek; Przewlocki, Ryszard

    2008-10-01

    The proteins of Fos family are a potential candidate to link molecular mechanisms of morphine action with behavioural effects such as morphine-induced reward, dependence and tolerance. We used both male and female mice lacking fosB gene to study its contribution to morphine effects. Morphine analgesia (tail-flick test) and hypothermia were studied using morphine at cumulative doses in morphine-naive and morphine-tolerant (tolerance induced by 24 h prior 100 mg/kg morphine administration) mice. FosB -/- mice, as compared to fosB +/+ mice, developed enhanced tolerance to morphine-induced analgesia. No effects of genotype or gender on tolerance to morphine-induced hypothermia were observed. These results suggest that fosB may be involved in the development of tolerance to morphine analgesia but not hypothermia. The gender study implicates that lack of FosB proteins in female fosB -/- mice enhanced morphine analgesic potency. In conclusion, we show that fosB gene is important to analgesia but not hypothermia phenotype indicating its role in morphine effects.

  3. KDM2B/FBXL10 targets c-Fos for ubiquitylation and degradation in response to mitogenic stimulation.

    PubMed

    Han, X-R; Zha, Z; Yuan, H-X; Feng, X; Xia, Y-K; Lei, Q-Y; Guan, K-L; Xiong, Y

    2016-08-11

    KDM2B (also known as FBXL10) controls stem cell self-renewal, somatic cell reprogramming and senescence, and tumorigenesis. KDM2B contains multiple functional domains, including a JmjC domain that catalyzes H3K36 demethylation and a CxxC zinc-finger that recognizes CpG islands and recruits the polycomb repressive complex 1. Here, we report that KDM2B, via its F-box domain, functions as a subunit of the CUL1-RING ubiquitin ligase (CRL1/SCF(KDM2B)) complex. KDM2B targets c-Fos for polyubiquitylation and regulates c-Fos protein levels. Unlike the phosphorylation of other SCF (SKP1-CUL1-F-box)/CRL1 substrates that promotes substrates binding to F-box, epidermal growth factor (EGF)-induced c-Fos S374 phosphorylation dissociates c-Fos from KDM2B and stabilizes c-Fos protein. Non-phosphorylatable and phosphomimetic mutations at S374 result in c-Fos protein which cannot be induced by EGF or accumulates constitutively and lead to decreased or increased cell proliferation, respectively. Multiple tumor-derived KDM2B mutations impaired the function of KDM2B to target c-Fos degradation and to suppress cell proliferation. These results reveal a novel function of KDM2B in the negative regulation of cell proliferation by assembling an E3 ligase to targeting c-Fos protein degradation that is antagonized by mitogenic stimulations.

  4. Regulation of proto-oncogene expression in adult and developing lungs.

    PubMed Central

    Molinar-Rode, R; Smeyne, R J; Curran, T; Morgan, J I

    1993-01-01

    Activation of immediate-early gene expression has been associated with mitogenesis, differentiation, nerve cell depolarization, and recently, terminal differentiation processes and programmed cell death. Previous evidence also suggested that immediate-early genes play a role in the physiology of the lungs (J. I. Morgan, D. R. Cohen, J. L. Hempstead, and T. Curran, Science 237:192-197, 1987). Therefore, we analyzed c-fos expression in adult and developing lung tissues. Seizures elicited by chemoconvulsants induced expression of mRNA for c-fos, c-jun, and junB and Fos-like immunoreactivity in lung tissue. The use of pharmacological antagonists and adrenalectomy indicated that this increased expression was neurogenic. Interestingly, by using a fos-lacZ transgenic mouse, it was shown that Fos-LacZ expression in response to seizure occurred preferentially in clusters of epithelial cells at the poles of the bronchioles. This was the same location of Fos-LacZ expression detected during early lung development. These data imply that pharmacological induction of immediate-early gene expression in adult mice recapitulates an embryological program of gene expression. Images PMID:8497249

  5. Fos-activation of FoxP2 and Lmx1b neurons in the parabrachial nucleus evoked by hypotension and hypertension in conscious rats

    PubMed Central

    Miller, Rebecca L.; Knuepfer, Mark M.; Wang, Michelle H.; Denny, George O.; Gray, Paul A.; Loewy, Arthur D.

    2012-01-01

    The parabrachial nucleus (PB) is a brainstem cell group that receives a strong input from the nucleus tractus solitarius regarding the physiological status of the internal organs and sends efferent projections throughout the forebrain. Since the neuroanatomical organization of the PB remains unclear, our first step was to use specific antibodies against two neural lineage transcription factors: Forkhead box protein2 (FoxP2) and LIM homeodomain transcription factor 1 beta (Lmx1b) to define the PB in adult rats. This allowed us to construct a cytoarchitectonic PB map based on the distribution of neurons that constitutively express these two transcription factors. Second, the in situ hybridization method combined with immunohistochemistry demonstrated that mRNA for glutamate vesicular transporter Vglut2 (Slc17a6) was present in most of the Lmx1b+ and FoxP2+ parabrachial neurons, indicating these neurons use glutamate as a transmitter. Third, conscious rats were maintained in a hypotensive or hypertensive state for two hours, and then, their brainstems were prepared by the standard c-Fos method which is a measure of neuronal activity. Both hypotension and hypertension resulted in c-Fos activation of Lmx1b+ neurons in the external lateral-outer subdivision of the PB (PBel-outer). Hypotension, but not hypertension, caused c-Fos activity in the FoxP2+ neurons of the central lateral PB (PBcl) subnucleus. The Kölliker-Fuse nucleus as well as the lateral crescent PB and rostralmost part of the PBcl contain neurons that co-express FoxP2+ and Lmx1b+, but none of these were activated after blood pressure changes. Salt-sensitive FoxP2 neurons in the pre-locus coeruleus and PBel-inner were not c-Fos activated following blood pressure changes. In summary, the present study shows that the PBel-outer and PBcl subnuclei originate from two different neural progenitors, contain glutamatergic neurons, and are affected by blood pressure changes, with the PBel-outer reacting to both hypo

  6. Anti-Osteoclastogenic Activity of Praeruptorin A via Inhibition of p38/Akt-c-Fos-NFATc1 Signaling and PLCγ-Independent Ca2+ Oscillation

    PubMed Central

    Choi, Sik-Won; Moon, Seong-Hee; Park, Young Sik; Ryu, Byung Jun; Oh, Jaemin; Kim, Min Seuk; Erkhembaatar, Munkhsoyol; Son, Young-Jin; Kim, Seong Hwan

    2014-01-01

    Background A decrease of bone mass is a major risk factor for fracture. Several natural products have traditionally been used as herbal medicines to prevent and/or treat bone disorders including osteoporosis. Praeruptorin A is isolated from the dry root extract of Peucedanum praeruptorum Dunn and has several biological activities, but its anti-osteoporotic activity has not been studied yet. Materials and Methods The effect of praeruptorin A on the differentiation of bone marrow–derived macrophages into osteoclasts was examined by phenotype assay and confirmed by real-time PCR and immunoblotting. The involvement of NFATc1 in the anti-osteoclastogenic action of praeruptorin A was evaluated by its lentiviral ectopic expression. Intracellular Ca2+ levels were also measured. Results Praeruptorin A inhibited the RANKL-stimulated osteoclast differentiation accompanied by inhibition of p38 and Akt signaling, which could be the reason for praeruptorin A-downregulated expression levels of c-Fos and NFATc1, transcription factors that regulate osteoclast-specific genes, as well as osteoclast fusion-related molecules. The anti-osteoclastogenic effect of praeruptorin A was rescued by overexpression of NFATc1. Praeruptorin A strongly prevented the RANKL-induced Ca2+ oscillation without any changes in the phosphorylation of PLCγ. Conclusion Praeruptorin A could exhibit its anti-osteoclastogenic activity by inhibiting p38/Akt-c-Fos-NFATc1 signaling and PLCγ-independent Ca2+ oscillation. PMID:24586466

  7. Changes of calcium binding proteins, c-Fos and COX in hippocampal formation and cerebellum of Niemann-Pick, type C mouse.

    PubMed

    Byun, Kyunghee; Kim, Daesik; Bayarsaikhan, Enkhjaigal; Oh, Jeehyun; Kim, Jisun; Kwak, Grace; Jeong, Goo-Bo; Jo, Seung-Mook; Lee, Bonghee

    2013-09-01

    Niemann-Pick disease, type C (NPC) is an intractable disease that is accompanied by ataxia, dystonia, neurodegeneration, and dementia due to an NPC gene defect. Disruption of calcium homeostasis in neurons is important in patients with NPC. Thus, we used immunohistochemistry to assess the expression levels of calcium binding proteins (calbindin D28K, parvalbumin, and calretinin), c-Fos and cyclooxygenase-1,2 (COX-1,2) in the hippocampal formation and cerebellum of 4 and 8 week old NPC+/+, NPC+/-, and NPC-/- mice. General expression of these proteins decreased in the hippocampus and cerebellum of NPC-/- compared to that in both young and adult NPC+/+ or NPC+/- mice. Parvalbumin, COX-1,2 or c-Fos-immunoreactive neurons were widely detected in the CA1, CA3, and DG of the hippocampus, but the immunoreactivities were decreased sharply in all areas of hippocampus of NPC-/- compared to NPC+/+ and NPC+/- mice. Taken together, reduction of these proteins may be one of the strong phenotypes related to the neuronal degeneration in NPC-/- mice.

  8. Hippocampal activation of immediate early genes Zenk and c-Fos in zebra finches (Taeniopygia guttata) during learning and recall of a spatial memory task.

    PubMed

    Mayer, Uwe; Watanabe, Shigeru; Bischof, Hans-Joachim

    2010-03-01

    Zebra finches (Taeniopygia guttata) are able to learn the position of food by orienting on spatial cues in a 'dry water maze'. In the course of spatial learning, the hippocampus shows high expression of the immediate early genes (IEGs) Zenk and c-Fos, indicating high activation of this area during learning. In contrast, the IEG activity is nearly absent if the birds do not have to rely on spatial cues. In the present experiment it was investigated whether hippocampal activation can also be observed if the learned spatial task is recalled. For this purpose, the hippocampal Zenk and c-Fos activation of birds in an early learning stage was compared with that of others having well reached their maximal performance. The results show that the avian hippocampus is also active during recall of a learned spatial task, but the activation is significantly lower than in animals learning actually. As in previous experiments, hippocampal IEG expression showed strong variation not only in the position of the active patches of neurons, but also in size and cell density. The observed difference contributes to the view that immediate early genes may not be indicators of activation alone, but may be due to a combination of activation and plastic changes.

  9. Wedelolactone enhances osteoblastogenesis by regulating Wnt/β-catenin signaling pathway but suppresses osteoclastogenesis by NF-κB/c-fos/NFATc1 pathway

    PubMed Central

    Liu, Yan-Qiu; Hong, Zhi-Lai; Zhan, Li-Bin; Chu, Hui-Ying; Zhang, Xiao-Zhe; Li, Guo-Hui

    2016-01-01

    Bone homeostasis is maintained by formation and destruction of bone, which are two processes tightly coupled and controlled. Targeting both stimulation on bone formation and suppression on bone resorption becomes a promising strategy for treating osteoporosis. In this study, we examined the effect of wedelolactone, a natural product from Ecliptae herba, on osteoblastogenesis as well as osteoclastogenesis. In mouse bone marrow mesenchymal stem cells (BMSC), wedelolactone stimulated osteoblast differentiation and bone mineralization. At the molecular level, wedelolactone directly inhibited GSK3β activity and enhanced the phosphorylation of GSK3β, thereafter stimulated the nuclear translocation of β-catenin and runx2. The expression of osteoblastogenesis-related marker gene including osteorix, osteocalcin and runx2 increased. At the same concentration range, wedelolactone inhibited RANKL-induced preosteoclastic RAW264.7 actin-ring formation and bone resorption pits. Further, wedelolactone blocked NF-kB/p65 phosphorylation and abrogated the NFATc1 nuclear translocation. As a result, osteoclastogenesis-related marker gene expression decreased, including c-src, c-fos, and cathepsin K. In ovariectomized mice, administration of wedelolactone prevented ovariectomy-induced bone loss by enhancing osteoblast activity and inhibiting osteoclast activity. Together, these data demonstrated that wedelolactone facilitated osteoblastogenesis through Wnt/GSK3β/β-catenin signaling pathway and suppressed RANKL-induced osteoclastogenesis through NF-κB/c-fos/NFATc1 pathway. These results suggested that wedelolacone could be a novel dual functional therapeutic agent for osteoporosis. PMID:27558652

  10. Hypothalamic ΔFosB prevents age-related metabolic decline and functions via SNS

    PubMed Central

    Nagano, Kenichi; Rowe, Glenn C.; Gori, Francesca; Baron, Roland

    2017-01-01

    The ventral hypothalamus (VHT) integrates several physiological cues to maintain glucose homeostasis and energy balance. Aging is associated with increased glucose intolerance but the underlying mechanisms responsible for age-related metabolic decline, including neuronal signaling in the VHT, remain elusive. We have shown that mice with VHT-targeted overexpression of ΔFosB, a splice variant of the AP1 transcription factor FosB, exhibit increased energy expenditure, leading to decreased adiposity. Here, we show that VHT-targeted overexpression of ΔFosB also improves glucose tolerance, increases insulin sensitivity in target organs and thereby suppresses insulin secretion. These effects are also observed by the overexpression of dominant negative JunD, demonstrating that they occur via AP1 antagonism within the VHT. Furthermore, the improved glucose tolerance and insulin sensitivity persisted in aged animals overexpressing ΔFosB in the VHT. These beneficial effects on glucose metabolism were abolished by peripheral sympathectomy and α-adrenergic, but not β-adrenergic, blockade. Taken together, our results show that antagonizing AP1 transcription activity in the VHT leads to a marked improvement in whole body glucose homeostasis via activation of the SNS, conferring protection against age-related impairment in glucose metabolism. These findings may open novel avenues for therapeutic intervention in diabetes and age-related glucose intolerance. PMID:28121620

  11. Upregulation of miR-181 decreases c-Fos and SIRT-1 in the hippocampus of 3xTg-AD mice.

    PubMed

    Rodriguez-Ortiz, Carlos J; Baglietto-Vargas, David; Martinez-Coria, Hilda; LaFerla, Frank M; Kitazawa, Masashi

    2014-01-01

    MicroRNAs are a group of small RNAs that regulate diverse cellular processes including neuronal function. Recent studies have shown that dysregulation of specific microRNAs is critically involved in the development of Alzheimer's disease (AD). Most of these reports have focused on microRNAs implicated in alterations of amyloid-β and tau. However, studies exploring the relation between microRNAs dysregulation in AD and synaptic plasticity are scarce despite the well-known involvement of microRNAs in synaptic plasticity. Since impairments in synaptic plasticity and neuronal loss are two important features displayed in AD patients, it is feasible to hypothesize that alterations in plasticity-related microRNAs underlie AD progression. Here, levels of a small number of microRNAs implicated in normal neuronal function and/or plasticity were examined in an AD model. Twelve-month old 3xTg-AD mice with plaques and tangles presented a significant upregulation of miR-181 in the hippocampus compared to age-matched wild type mice. Increased miR-181 was not detected in pre-pathological 3xTg-AD mice. Analysis of predicted targets of miR-181 identified c-Fos and SIRT-1, proteins critically involved in memory formation. Both c-Fos and SIRT-1 levels were significantly decreased in the ventral hippocampus of twelve-month old 3xTg-AD mice. Overexpression of miR-181 in SH-SY5Y cells significantly decreased c-Fos and SIRT-1, strongly suggesting that miR-181 directly regulates the expression of these two proteins. These findings indicate a connection between miR-181 and proteins involve in synaptic plasticity and memory processing in a transgenic mouse model of AD. Our results suggest that microRNAs involved in synaptic plasticity might be an important factor that contributes to AD neuropathology.

  12. Myeloid-Specific Fos-Related Antigen-1 Regulates Cigarette Smoke–Induced Lung Inflammation, Not Emphysema, in Mice

    PubMed Central

    Vaz, Michelle; Rajasekaran, Subbiah; Potteti, Haranatha R.

    2015-01-01

    Heightened lung inflammation is a cardinal feature of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS)-induced macrophage recruitment and activation, accompanied by abnormal secretion of a number of inflammatory cytokines and matrix metalloproteinases, play a major role in the pathophysiology of COPD. The Fos-related antigen-1 (Fra-1) transcription factor differentially regulates several cellular processes that are implicated in COPD, such as inflammation and immune responses, cell proliferation and death, and extracellular remodeling. Although CS stimulates Fra-1 expression in the lung, the precise role of this transcription factor in the regulation of CS-induced lung inflammation in vivo is poorly understood. Here, we report that myeloid-specific Fra-1 signaling is important for CS-induced lung macrophagic inflammatory response. In response to chronic CS exposure, mice with Fra-1 specifically deleted in myeloid cells showed reduced levels of CS-induced lung macrophagic inflammation, accompanied by decreased expression levels of proinflammatory cytokines compared with their wild-type counterparts. Consistent with this result, bone marrow–derived Fra-1–null macrophages treated with CS showed decreased levels of proinflammatory mediators and matrix metalloproteinases. Interestingly, deletion of Fra-1 in myeloid cells did not affect the severity of emphysema. We propose that Fra-1 plays a key role in promoting chronic CS-induced lung macrophagic inflammation in vivo, and that targeting this transcription factor may be useful in dampening persistent lung inflammation in patients with COPD. PMID:25489966

  13. Reciprocal regulation of transcription factors and PLC isozyme gene expression in adult cardiomyocytes.

    PubMed

    Singal, Tushi; Dhalla, Naranjan S; Tappia, Paramjit S

    2010-06-01

    By employing a pharmacological approach, we have shown that phospholipase C (PLC) activity is involved in the regulation of gene expression of transcription factors such as c-Fos and c-Jun in cardiomyocytes in response to norepinephrine (NE). However, there is no information available regarding the identity of specific PLC isozymes involved in the regulation of c-Fos and c-Jun or on the involvement of these transcription factors in PLC isozyme gene expression in adult cardiomyocytes. In this study, transfection of cardiomyocytes with PLC isozyme specific siRNA was found to prevent the NE-mediated increases in the corresponding PLC isozyme gene expression, protein content and activity. Unlike PLC gamma(1) gene, silencing of PLC beta(1), beta(3) and delta(1) genes with si RNA prevented the increases in c-Fos and c-Jun gene expression in response to NE. On the other hand, transfection with c-Jun si RNA suppressed the NE-induced increase in c-Jun as well as PLC beta(1), beta(3) and delta(1) gene expression, but had no effect on PLC gamma(1) gene expression. Although transfection of cardiomyocytes with c-Fos si RNA prevented NE-induced expression of c-Fos, PLC beta(1) and PLC beta(3) genes, it did not affect the increases in PLC delta(1) and PLC gamma(1) gene expression. Silencing of either c-Fos or c-Jun also depressed the NE-mediated increases in PLC beta(1), beta(3) and gamma(1) protein content and activity in an isozyme specific manner. Furthermore, silencing of all PLC isozymes as well as of c-Fos and c-Jun resulted in prevention of the NE-mediated increase in atrial natriuretic factor gene expression. These findings, by employing gene silencing techniques, demonstrate that there occurs a reciprocal regulation of transcription factors and specific PLC isozyme gene expression in cardiomyocytes.

  14. ΔFosB induction in striatal medium spiny neuron subtypes in response to chronic pharmacological, emotional, and optogenetic stimuli.

    PubMed

    Lobo, Mary Kay; Zaman, Samir; Damez-Werno, Diane M; Koo, Ja Wook; Bagot, Rosemary C; DiNieri, Jennifer A; Nugent, Alexandria; Finkel, Eric; Chaudhury, Dipesh; Chandra, Ramesh; Riberio, Efrain; Rabkin, Jacqui; Mouzon, Ezekiell; Cachope, Roger; Cheer, Joseph F; Han, Ming-Hu; Dietz, David M; Self, David W; Hurd, Yasmin L; Vialou, Vincent; Nestler, Eric J

    2013-11-20

    The transcription factor, ΔFosB, is robustly and persistently induced in striatum by several chronic stimuli, such as drugs of abuse, antipsychotic drugs, natural rewards, and stress. However, very few studies have examined the degree of ΔFosB induction in the two striatal medium spiny neuron (MSN) subtypes. We make use of fluorescent reporter BAC transgenic mice to evaluate induction of ΔFosB in dopamine receptor 1 (D1) enriched and dopamine receptor 2 (D2) enriched MSNs in ventral striatum, nucleus accumbens (NAc) shell and core, and in dorsal striatum (dStr) after chronic exposure to several drugs of abuse including cocaine, ethanol, Δ(9)-tetrahydrocannabinol, and opiates; the antipsychotic drug, haloperidol; juvenile enrichment; sucrose drinking; calorie restriction; the serotonin selective reuptake inhibitor antidepressant, fluoxetine; and social defeat stress. Our findings demonstrate that chronic exposure to many stimuli induces ΔFosB in an MSN-subtype selective pattern across all three striatal regions. To explore the circuit-mediated induction of ΔFosB in striatum, we use optogenetics to enhance activity in limbic brain regions that send synaptic inputs to NAc; these regions include the ventral tegmental area and several glutamatergic afferent regions: medial prefrontal cortex, amygdala, and ventral hippocampus. These optogenetic conditions lead to highly distinct patterns of ΔFosB induction in MSN subtypes in NAc core and shell. Together, these findings establish selective patterns of ΔFosB induction in striatal MSN subtypes in response to chronic stimuli and provide novel insight into the circuit-level mechanisms of ΔFosB induction in striatum.

  15. Thermodynamic analysis of the heterodimerization of leucine zippers of Jun and Fos transcription factors

    SciTech Connect

    Seldeen, Kenneth L.; McDonald, Caleb B.; Deegan, Brian J.

    2008-10-31

    Jun and Fos are components of the AP1 family of transcription factors and bind to the promoters of a diverse multitude of genes involved in critical cellular responses such as cell growth and proliferation, cell cycle regulation, embryonic development and cancer. Here, using the powerful technique of isothermal titration calorimetry, we characterize the thermodynamics of heterodimerization of leucine zippers of Jun and Fos. Our data suggest that the heterodimerization of leucine zippers is driven by enthalpic forces with unfavorable entropy change at physiological temperatures. Furthermore, the basic regions appear to modulate the heterodimerization of leucine zippers and may undergo at least partial folding upon heterodimerization. Large negative heat capacity changes accompanying the heterodimerization of leucine zippers are consistent with the view that leucine zippers do not retain {alpha}-helical conformations in isolation and that the formation of the native coiled-coil {alpha}-helical dimer is attained through a coupled folding-dimerization mechanism.

  16. TATA-Binding Protein (TBP)-Like Factor (TLF) Is a Functional Regulator of Transcription: Reciprocal Regulation of the Neurofibromatosis Type 1 and c-fos Genes by TLF/TRF2 and TBP

    PubMed Central

    Chong, Jayhong A.; Moran, Magdalene M.; Teichmann, Martin; Kaczmarek, J. Stefan; Roeder, Robert; Clapham, David E.

    2005-01-01

    The lack of direct targets for TATA-binding protein (TBP)-like factors (TLFs) confounds the understanding of their role in gene expression. Here we report that human TLF (also called TBP-related factor 2 [TRF2]) activates a number of different genes, including the neurofibromatosis type 1 (NF1) gene. The overexpression of TLF increases the amount of NF1 mRNA in cells. In vivo, TLF binds to and upregulates transcription from a fragment of the NF1 promoter. In vitro, purified TLF-TFIIA binds directly to the same NF1 promoter fragment that is required for TLF responsiveness in cells. Furthermore, targeted deletion of TLF in mice reduces NF1 levels. In contrast, TLF inhibits transcription driven by a fragment from the TATA-containing c-fos promoter by sequestering TFIIA. TBP affects the NF1 and c-fos promoters in a manner reciprocal to that of TLF, stimulating the c-fos promoter and inhibiting NF1 transcription. We conclude that TLF is a functional regulator of transcription with targets distinct from those of TBP. PMID:15767669

  17. Ethanol-induced alterations of c-Fos immunoreactivity in specific limbic brain regions following ethanol discrimination training.

    PubMed

    Besheer, Joyce; Schroeder, Jason P; Stevenson, Rebekah A; Hodge, Clyde W

    2008-09-26

    The discriminative stimulus properties of ethanol are functionally regulated by ionotropic GABA(A) and NMDA receptors in specific limbic brain regions including the nucleus accumbens, amygdala, and hippocampus, as determined by microinjection studies. The purpose of the present work was to further investigate potential neural substrates of ethanol's discriminative stimulus effects by examining if ethanol discrimination learning produces changes in brain regional response to ethanol. To accomplish this goal, immunohistochemistry was used to assess the effects of ethanol (2 g/kg) on c-Fos immunoreactivity (Fos-IR). Comparisons in ethanol-induced Fos-IR were made between a group of rats that was trained to discriminate the stimulus properties of ethanol (2 g/kg, IG) from water (IG) and a drug/behavior-matched control group that did not receive differential reinforcement for lever selection, which precluded acquisition of discriminative stimulus control by ethanol. In some brain regions discrimination training had no effect on ethanol-induced Fos-IR changes (caudate putamen, bed nucleus of the stria terminalis, and CA1 region of the hippocampus). In contrast, discrimination training altered the pattern of ethanol-induced Fos-IR in the nucleus accumbens (core), medial septum, and the hippocampus (dentate and CA3). These results indicate that having behavior under the stimulus control of ethanol can change ethanol-induced Fos-IR in some brain regions. This suggests that learning about the subjective properties of ethanol produces adaptive changes in how the brain responds to acute ethanol exposure.

  18. Behavioral alterations and Fos protein immunoreactivity in brain regions of bile duct-ligated cirrhotic rats.

    PubMed

    Le Sueur-Maluf, Luciana; Viana, Milena B; Nagaoka, Márcia R; Amorim, Ana Laura B; Cardoso, Amanda N; Rodrigues, Bruna C; Mendes, Natália F; Bittencourt, Jackson C; Céspedes, Isabel C

    2015-03-01

    Hepatic encephalopathy (HE) encompasses a variety of neuropsychiatric symptoms, including anxiety and psychomotor dysfunction. Although HE is a frequent complication of liver cirrhosis, the neurobiological substrates responsible for its clinical manifestations are largely unclear. In the present study, male Wistar rats were bile duct-ligated (BDL), a procedure which induces liver cirrhosis, and on the 21st day after surgery tested in the elevated plus-maze (EPM) and in an open field for anxiety and locomotor activity measurements. Analysis of Fos protein immunoreactivity (Fos-ir) was used to better understand the neurobiological alterations present in BDL animals. Plasma levels of ammonia were quantified and histopathological analysis of the livers was performed. BDL rats showed a significant decrease in the percentage of entries and time spent in the open arms of the EPM, an anxiogenic effect. These animals also presented significant decreases in Fos-ir in the lateral septal nucleus and medial amygdalar nucleus. Their ammonia plasma levels were significantly higher when compared to the sham group and the diagnosis of cirrhosis was confirmed by histopathological analysis. These results indicate that the BDL model induces anxiogenic results, possibly related to changes in the activation of anxiety-mediating circuitries and to increases in ammonia plasma levels.

  19. Impaired ventilatory acclimatization to hypoxia in mice lacking the immediate early gene fos B.

    PubMed

    Malik, Mohammad T; Peng, Ying-Jie; Kline, David D; Adhikary, Gautam; Prabhakar, Nanduri R

    2005-01-15

    Earlier studies on cell culture models suggested that immediate early genes (IEGs) play an important role in cellular adaptations to hypoxia. Whether IEGs are also necessary for hypoxic adaptations in intact animals is not known. In the present study we examined the potential importance of fos B, an IEG in ventilatory acclimatization to hypoxia. Experiments were performed on wild type and mutant mice lacking the fos B gene. Ventilation was monitored by whole body plethysmography in awake animals. Baseline ventilation under normoxia, and ventilatory response to acute hypoxia and hypercapnia were comparable between wild type and mutant mice. Hypobaric hypoxia (0.4 atm; 3 days) resulted in a significant elevation of baseline ventilation in wild type but not in mutant mice. Wild type mice exposed to hypobaric hypoxia manifested an enhanced hypoxic ventilatory response compared to pre-hypobaric hypoxia. In contrast, hypobaric hypoxia had no effect on the hypoxic ventilatory response in mutant mice. Hypercapnic ventilatory responses, however, were unaffected by hypobaric hypoxia in both groups of mice. These results suggest that the fos B, an immediate early gene, plays an important role in ventilatory acclimatization to hypoxia in mice.

  20. Esculetin attenuates receptor activator of nuclear factor kappa-B ligand-mediated osteoclast differentiation through c-Fos/nuclear factor of activated T-cells c1 signaling pathway

    SciTech Connect

    Baek, Jong Min; Park, Sun-Hyang; Cheon, Yoon-Hee; Ahn, Sung-Jun; Lee, Myeung Su; Oh, Jaemin; Kim, Ju-Young

    2015-05-29

    Esculetin exerts various biological effects on anti-oxidation, anti-tumors, and anti-inflammation. However, the involvement of esculetin in the bone metabolism process, particularly osteoclast differentiation has not yet been investigated. In the present study, we first confirmed the inhibitory effect of esculetin on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation. We then revealed the relationship between esculetin and the expression of osteoclast-specific molecules to elucidate its underlying mechanisms. Esculetin interfered with the expression of c-Fos and nuclear factor of activated T cell c1 (NFATc1) both at the mRNA and protein level with no involvement in osteoclast-associated early signaling pathways, suppressing the expression of various transcription factors exclusively expressed in osteoclasts such as tartrate-resistant acid phosphatase (Trap), osteoclast-associated receptor (Oscar), dendritic cell-specific transmembrane protein (Dcstamp), osteoclast stimulatory transmembrane protein (Ocstamp), cathepsin K, αvβ3 integrin, and calcitonin receptor (Ctr). Additionally, esculetin inhibited the formation of filamentous actin (F-actin) ring-positive osteoclasts during osteoclast differentiation. However, the development of F-actin structures and subsequent bone resorbing activity of mature osteoclasts, which are observed in osteoclast/osteoblast co-culture systems were not affected by esculetin. Taken together, our results indicate for the first time that esculetin inhibits RANKL-mediated osteoclastogenesis via direct suppression of c-Fos and NFATc1 expression and exerts an inhibitory effect on actin ring formation during osteoclastogenesis. - Highlights: • We first investigated the effects of esculetin on osteoclast differentiation and function. • Our data demonstrate for the first time that esculetin can suppress osteoclastogenesis in vitro. • Esculetin acts as an inhibitor of c-Fos and NFATc1 activation.

  1. Top-DER- and Dpp-dependent requirements for the Drosophila fos/kayak gene in follicular epithelium morphogenesis.

    PubMed

    Dequier, E; Souid, S; Pál, M; Maróy, P; Lepesant, J A; Yanicostas, C

    2001-08-01

    The Drosophila fos (Dfos)/kayak gene has been previously identified as a key regulator of epithelial cell morphogenesis during dorsal closure of the embryo and fusion of the adult thorax. We show here that it is also required for two morphogenetic movements of the follicular epithelium during oogenesis. Firstly, it is necessary for the proper posteriorward migration of main body follicle cells during stage 9. Secondly, it controls, from stage 11 onwards, the morphogenetic reorganization of the follicle cells that are committed to secrete the respiratory appendages. We demonstrate that DER pathway activation and a critical level of Dpp/TGFbeta signalling are required to pattern a high level of transcription of Dfos at the anterior and dorsal edges of the two groups of cells that will give rise to the respiratory appendages. In addition, we provide evidence that, within the dorsal-anterior territory, the level of paracrine Dpp/TGFbeta signalling controls the commitment of follicle cells towards either an operculum or an appendage secretion fate. Finally, we show that Dfos is required in follicle cells for the dumping of the nurse cell cytoplasm into the oocyte and the subsequent apoptosis of nurse cells. This suggests that in somatic follicle cells, Dfos controls the expression of one or several factors that are necessary for these processes in underlying germinal nurse cells.

  2. Control of appetitive and aversive taste-reactivity responses by an auditory conditioned stimulus in a devaluation task: a FOS and behavioral analysis.

    PubMed

    Kerfoot, Erin C; Agarwal, Isha; Lee, Hongjoo J; Holland, Peter C

    2007-09-01

    Through associative learning, cues for biologically significant reinforcers such as food may gain access to mental representations of those reinforcers. Here, we used devaluation procedures, behavioral assessment of hedonic taste-reactivity responses, and measurement of immediate-early gene (IEG) expression to show that a cue for food engages behavior and brain activity related to sensory and hedonic processing of that food. Rats first received a tone paired with intraoral infusion of sucrose. Then, in the absence of the tone, the value of sucrose was reduced (Devalue group) by pairing sucrose with lithium chloride (LiCl), or maintained (Maintain group) by presenting sucrose and LiCl unpaired. Finally, taste-reactivity responses to the tone were assessed in the absence of sucrose. Devalue rats showed high levels of aversive responses and minimal appetitive responses, whereas Maintain rats exhibited substantial appetitive responding but little aversive responding. Control rats that had not received tone-sucrose pairings did not display either class of behaviors. Devalue rats showed greater FOS expression than Maintain rats in several brain regions implicated in devaluation task performance and the display of aversive responses, including the basolateral amygdala, orbitofrontal cortex, gustatory cortex (GC), and the posterior accumbens shell (ACBs), whereas the opposite pattern was found in the anterior ACBs. Both Devalue and Maintain rats showed greater FOS expression than control rats in amygdala central nucleus, GC, and both subregions of ACBs. Thus, through associative learning, auditory cues for food gained access to neural processing in several brain regions importantly involved in the processing of taste memory information.

  3. Structural and chemical aspects of resistance to the antibiotic, fosfomycin, conferred by FosB from Bacillus cereus†,‡

    PubMed Central

    Thompson, Matthew K.; Keithly, Mary E.; Harp, Joel; Cook, Paul D.; Jagessar, Kevin L.; Sulikowski, Gary A.; Armstrong, Richard N.

    2014-01-01

    The fosfomycin resistance enzymes, FosB, from Gram-positive organisms, are M2+ dependent thiol tranferases that catalyze nucleophilic addition of either L-cysteine (L-cys) or bacillithiol (BSH) to the antibiotic, resulting in a modified compound with no bacteriacidal properties. Here we report the structural and functional characterization of FosB from Bacillus cereus (FosBBc). The overall structure of FosBBc, at 1.27 Å resolution, reveals that the enzyme belongs to the vicinal oxygen chelate (VOC) superfamily. Crystal structures of FosBBc co-crystallized with fosfomycin and a variety of divalent metals, including Ni2+, Mn2+, Co2+, and Zn2+, indicate that the antibiotic coordinates to the active site metal center in an orientation similar to that found in the structurally homologous manganese-dependent fosfomycin resistance enzyme, FosA. Surface analysis of the FosBBc structures show a well-defined binding pocket and an access channel to C1 of fosfomycin, the carbon to which nucleophilic addition of the thiol occurs. The pocket and access channel are appropriate in size and shape to accommodate L-cys or BSH. Further investigation of the structures revealed that the fosfomycin molecule, anchored by the metal, is surrounded by a cage of amino acids that hold the antibiotic in an orientation such that C1 is centered at the end of the solvent channel positioning the compound for direct nucleophilic attack by the thiol substrate. In addition, the structures of FosBBc in complex with the L-cysteine-fosfomycin product (1.55 Å resolution) and in complex with the bacillithiol-fosfomycin product (1.77 Å resolution) coordinated to a Mn2+ metal in the active site have been determined. The L-cysteine moiety of either product is located in the solvent channel, where the thiol has added to the backside of fosfomycin C1 located at the end of the channel. Concomitant kinetic analyses of FosBBc indicated that the enzyme has a preference for bacillithiol over L-cysteine when

  4. Vocalization Induced CFos Expression in Marmoset Cortex

    PubMed Central

    Miller, Cory T.; DiMauro, Audrey; Pistorio, Ashley; Hendry, Stewart; Wang, Xiaoqin

    2010-01-01

    All non-human primates communicate with conspecifics using vocalizations, a system involving both the production and perception of species-specific vocal signals. Much of the work on the neural basis of primate vocal communication in cortex has focused on the sensory processing of vocalizations, while relatively little data are available for vocal production. Earlier physiological studies in squirrel monkeys had shed doubts on the involvement of primate cortex in vocal behaviors. The aim of the present study was to identify areas of common marmoset (Callithrix jacchus) cortex that are potentially involved in vocal communication. In this study, we quantified cFos expression in three areas of marmoset cortex – frontal, temporal (auditory), and medial temporal – under various vocal conditions. Specifically, we examined cFos expression in these cortical areas during the sensory, motor (vocal production), and sensory–motor components of vocal communication. Our results showed an increase in cFos expression in ventrolateral prefrontal cortex as well as the medial and lateral belt areas of auditory cortex in the vocal perception condition. In contrast, subjects in the vocal production condition resulted in increased cFos expression only in dorsal premotor cortex. During the sensory–motor condition (antiphonal calling), subjects exhibited cFos expression in each of the above areas, as well as increased expression in perirhinal cortex. Overall, these results suggest that various cortical areas outside primary auditory cortex are involved in primate vocal communication. These findings pave the way for further physiological studies of the neural basis of primate vocal communication. PMID:21179582

  5. Effect of subtype-selective adenosine receptor antagonists on basal or haloperidol-regulated striatal function: studies of exploratory locomotion and c-Fos immunoreactivity in outbred and A(2A)R KO mice.

    PubMed

    Pardo, M; López-Cruz, L; Valverde, O; Ledent, C; Baqi, Y; Müller, C E; Salamone, J D; Correa, M

    2013-06-15

    Behavioral activation is regulated by dopamine (DA) in striatal areas. At low doses, while typical antipsychotic drugs produce psychomotor slowing, psychostimulants promote exploration. Minor stimulants such as caffeine, which act as adenosine receptor antagonists, can also potentiate behavioral activation. Striatal areas are rich in adenosine and DA receptors, and adenosine A2A receptors are mainly expressed in the striatum where they are co-localized with DA D2 receptors. Adenosine antagonists with different receptor-selectivity profiles were used to study spontaneous or haloperidol-impaired exploration and c-Fos expression in different striatal areas. Because A2A antagonists were expected to be more selective for reversing the effects of the D2 antagonist haloperidol, A2A receptor knockout (A2ARKO) mice were also assessed. CD1 and A2ARKO male mice were tested in an open field and in a running wheel. Only the A1/A2A receptor antagonist theophylline (5.0-15.0 mg/kg) and the A2A antagonist MSX-3 (2.0 mg/kg) increased spontaneous locomotion and rearing. Co-administration of theophylline (10.0-15.0 mg/kg), and MSX-3 (1.0-3.0 mg/kg) reversed haloperidol-induced suppression of locomotion. The A1 antagonist CPT was only marginally effective in reversing the effects of haloperidol. Although adenosine antagonists did not affect c-Fos expression on their own, theophylline and MSX-3, but not CPT, attenuated haloperidol induction of c-Fos expression. A2ARKO mice were resistant to the behavioral effects of haloperidol at intermediate doses (0.1 mg/kg) in the open field and in the running wheel. A2A receptors are important for regulating behavioral activation, and interact with D2 receptors in striatal areas to regulate neural processes involved in exploratory activity.

  6. Prebiotic consumption in pregnant and lactating women increases IL-27 expression in human milk.

    PubMed

    Kubota, Takayuki; Shimojo, Naoki; Nonaka, Ken; Yamashita, Masakatsu; Ohara, Osamu; Igoshi, Yuka; Ozawa, Naoko; Nakano, Taiji; Morita, Yoshinori; Inoue, Yuzaburo; Arima, Takayasu; Chiba, Kohki; Nakamura, Yoshitaka; Ikegami, Shuji; Masuda, Kentaro; Suzuki, Shuichi; Kohno, Yoichi

    2014-02-01

    The consumption of probiotics by pregnant and lactating women may prevent the onset of allergic disorders in their children by increasing the concentrations of immunoactive agents such as cytokines in breast milk. Prebiotics such as fructo-oligosaccharides (FOS) increase the number of beneficial organisms such as bifidobacteria. Thus, prebiotics may have an effect similar to that of probiotics. The objective of the present study was to carry out a comprehensive analysis of mRNA expression in human milk cells to identify changes in the concentrations of cytokines in breast milk after the consumption of FOS (4 g × 2 times/d) by pregnant and lactating women. The microarray analysis of human milk cells demonstrated that the expression levels of five genes in colostrum samples and fourteen genes in 1-month breast milk samples differed more than 3-fold between the FOS and control groups (sucrose group). The mRNA expression level of IL-27, a cytokine associated with immunoregulatory function, was significantly higher in 1-month breast milk samples obtained from the FOS group than in those obtained from the control group. In addition, the protein concentrations of IL-27 in colostrum and 1-month breast milk samples were significantly higher in the FOS group than in the control group. In conclusion, the consumption of FOS by pregnant and lactating women increases the production of IL-27 in breast milk. Future studies will address the association of this phenomenon with the onset of allergic disorders in children.

  7. D1 dopamine receptors modulate deltaFosB induction in rat striatum after intermittent morphine administration.

    PubMed

    Muller, Daniella L; Unterwald, Ellen M

    2005-07-01

    Induction of the transcription factor deltaFosB was studied to examine neurochemical adaptations produced by repeated opiate administration. The mechanism of this induction was also investigated. The 35- to 37-kDa isoforms of deltaFosB, also referred to as the chronic Fras, were measured in the nucleus accumbens, caudate putamen, and frontal cortex of male Sprague-Dawley rats after either an acute injection of morphine or an escalating dosing schedule of morphine for 10 days. Heroin was also tested to determine whether the findings extend to other opiates. Results from Western blot analysis using an anti-fosB antibody demonstrate that 10-day intermittent escalating dose morphine produced a significant increase in deltaFosB-immunoreactivity in the nucleus accumbens, caudate putamen and frontal cortex, whereas a single injection of morphine had no effect on Fra immunoreactivity. Heroin administered twice daily for 10 days by an intermittent escalating dose schedule also induced deltaFosB in the caudate putamen, but not in the nucleus accumbens or frontal cortex. Daily pretreatment with the selective D1-like dopamine receptor antagonist SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] significantly blocked morphine-induced deltaFosB induction in the nucleus accumbens and caudate putamen, but not in the frontal cortex. These results demonstrate that morphine-induced deltaFosB up-regulation in the striatum, but not in the frontal cortex, is modulated by D1 dopamine receptors, suggesting that the mechanisms involved in the up-regulation of these chronic Fras by morphine is brain region-specific.

  8. Nodule excitability in an animal model of periventricular nodular heterotopia: c-fos activation in organotypic hippocampal slices

    PubMed Central

    Doisy, Emily T.; Wenzel, H. Jürgen; Mu, Yi; Nguyen, Danh V.; Schwartzkroin, Philip A.

    2015-01-01

    Objective Aberrations in brain development may lead to dysplasic structures such as periventricular nodules. While these abnormal collections of neurons are often associated with difficult-to-control seizure activity, there is little consensus regarding the epileptogenicity of the nodules themselves. Since one common treatment option is surgical resection of suspected epileptic nodules, it is important to determine whether these structures in fact give rise, or essentially contribute, to epileptic activities. Methods To study the excitability of aberrant nodules, we have examined c-fos activation in organotypic hippocampal slice cultures generated from an animal model of periventricular nodular heterotopia created by treating pregnant rats with methylazoxymethanol. Using this preparation, we have also attempted to assess tissue excitability when the nodule is surgically removed from the culture. We then compared c-fos activation in this in vitro preparation to c-fos activation generated in an intact rat treated with kainic acid. Results Quantitative analysis of c-fos activation failed to show enhanced nodule excitability compared to neocortex or CA1 hippocampus. However, when we compared cultures with and without a nodule, presence of a nodule did affect the excitability of CA1 and cortex, at least as reflected in c-fos labeling. Surgical removal of the nodule did not result in a consistent decrease in excitability as reflected in the c-fos biomarker. Significance Our results from the organotypic culture were generally consistent with our observations on excitability in the intact rat – as seen not only with c-fos but also in previous electrophysiological studies. At least in this model, the nodule does not appear to be responsible for enhanced excitability (or, presumably, seizure initiation). Excitability is different in tissue that contains a nodule, suggesting altered network function, perhaps reflecting the abnormal developmental pattern that gave rise to

  9. Curcumin inhibits osteoclastogenic potential in PBMCs from rheumatoid arthritis patients via the suppression of MAPK/RANK/c-Fos/NFATc1 signaling pathways

    PubMed Central

    Shang, Wei; Zhao, Ling-Jie; Dong, Xiao-Lei; Zhao, Zhi-Ming; Li, Jing; Zhang, Bei-Bei; Cai, Hui

    2016-01-01

    The aim of the present study was to determine the effects of curcumin on the osteoclastogenic potential of peripheral blood mononuclear cells (PBMCs) obtained from patients with rheumatoid arthritis (RA), and to investigate the underlying molecular mechanisms. PBMCs from patients with RA (n=12) and healthy controls (n=10) were cultured to assess osteoclastogenic potential. The number of tartrate-resistant acid phosphatase-positive osteoclasts differentiated from PBMCs isolated from patients with RA was significantly increased compared with that of the healthy controls. In addition, the osteoclast number in patients with RA was correlated with the clinical indicators, Sharp score (r=0.810; P=0.001) and lumbar T-score (r=−0.685; P=0.014). Furthermore, the resorption area was increased in the RA group compared with the healthy controls. The mRNA and protein expression levels in PBMC-derived osteoclasts treated with curcumin were measured by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. Curcumin inhibited the osteoclastogenic potential of PBMCs, potentially by suppressing activation of extracellular signal-regulated kinases 1 and 2, p38 and c-Jun N-terminal kinase, and inhibiting receptor activator of nuclear factor κB (RANK), c-Fos and nuclear factor of activated T cells (NFATc1) expression. The results of the present study demonstrated that curcumin may inhibit the osteoclastogenic potential of PBMCs from patients with RA through the suppression of the mitogen-activated protein kinase/RANK/c-Fos/NFATc1 signaling pathways, and that curcumin may be a potential novel therapeutic agent for the treatment of bone deterioration in inflammatory diseases such as RA. PMID:27572279

  10. Heparin suppresses the induction of c-fos and c-myc mRNA in murine fibroblasts by selective inhibition of a protein kinase C-dependent pathway.

    PubMed Central

    Wright, T C; Pukac, L A; Castellot, J J; Karnovsky, M J; Levine, R A; Kim-Park, H Y; Campisi, J

    1989-01-01

    Heparin is a complex glycosaminoglycan that inhibits the proliferation of several cell types in culture and in vivo. To begin to define the mechanism(s) by which heparin exerts its antiproliferative effects, we asked whether heparin interferes with the expression of the growth factor-inducible protooncogenes c-fos and c-myc. We show that heparin suppressed the induction of c-fos and c-myc mRNA by serum in murine (BALB/c) 3T3 fibroblasts. Using purified mitogens, we further show that suppression was most marked when protooncogene expression was induced by phorbol 12-myristate 13-acetate, an activator of protein kinase C. By contrast, there was little or no suppression when the cells were stimulated by epidermal growth factor, which, in these cells, utilizes a protein kinase C-independent pathway for the induction of gene expression. Heparin also inhibited the change in cell morphology induced by the phorbol ester but had no effect on the morphological change induced by epidermal growth factor and agents that raise intracellular cAMP. Heparin did not inhibit intracellular protein kinase C activity, phorbol ester-induced down-regulation of protein kinase C, or phosphorylation of the 80-kDa intracellular protein kinase C substrate. These results suggest that heparin inhibits a protein kinase C-dependent pathway for cell proliferation and suppresses the induction of c-fos and c-myc mRNA at a site distal to activation of the kinase. Images PMID:2541434

  11. Fatigue and post-fatigue performance of Fabry-Perot FOS installed on CFRP-strengthened RC-beams

    NASA Astrophysics Data System (ADS)

    Gheorghiu, Catalin; Labossiere, Pierre; Proulx, Jean

    2004-07-01

    There is a growing need for built-in monitoring systems for civil engineering infrastructures, due to problems such as increasing traffic loads and rising costs of maintenance and repair. Fibre optic sensors (FOS), capable of reading various parameters are promising candidates for life-long health monitoring of these structures. However, since FOS have only been introduced recently into the field of structural monitoring, their acceptance and widespread implementation will be conditioned by their durability under severe climatic and loading conditions. This paper reports on the performance of strain extrinsic FOS attached to carbon fibre reinforced polymer (CFRP) plates used to strengthen concrete structures. The specimens tested in this project are reinforced concrete (RC) beams with an additional external CFRP reinforcement. The FOS-instrumented beams were first subjected to fatigue loading for various numbers of cycles and load amplitudes. Then, they were tested monotonically to failure under four-point-bending. The test results provide an insight on the fatigue and post-fatigue behaviour of FOS used for monitoring reinforced concrete structures.

  12. The Catalytic Efficiency of Lipin 1β Increases by Physically Interacting with the Proto-oncoprotein c-Fos*

    PubMed Central

    Cardozo Gizzi, Andres M.; Prucca, Cesar G.; Gaveglio, Virginia L.; Renner, Marianne L.; Pasquaré, Susana J.; Caputto, Beatriz L.

    2015-01-01

    Phosphatidic acid (PA) is a central precursor for membrane phospholipid biosynthesis. The lipin family is a magnesium-dependent type I PA phosphatase involved in de novo synthesis of neutral lipids and phospholipids. The regulation of lipin activity may govern the pathways by which these lipids are synthesized and control the cellular levels of important signaling lipids. Moreover, the proto-oncoprotein c-Fos has an emerging role in glycerolipid synthesis regulation; by interacting with key synthesizing enzymes it is able to increase overall phospho- and glycolipid synthesis. We studied the lipin 1β enzyme activity in a cell-free system using PA/Triton X-100 mixed micelles as substrate, analyzing it in the presence/absence of c-Fos. We found that lipin 1β kcat value increases around 40% in the presence of c-Fos, with no change in the lipin 1β affinity for the PA/Triton X-100 mixed micelles. We also probed a physical interaction between both proteins. Although the c-Fos domain involved in lipin activation is its basic domain, the interaction domain is mapped to the N-terminal c-Fos. In conclusion, we provide evidence for a novel positive regulator of lipin 1β PA phosphatase activity that is not achieved via altering its subcellular localization or affinity for membranes but rather through directly increasing its catalytic efficiency. PMID:26475860

  13. Social and environmental contexts modulate sleep deprivation-induced c-Fos activation in rats.

    PubMed

    Deurveilher, Samuel; Ryan, Nathan; Burns, Joan; Semba, Kazue

    2013-11-01

    People often sleep deprive themselves voluntarily for social and lifestyle reasons. Animals also appear to stay awake longer as a result of their natural curiosity to explore novel environments and interact socially with conspecifics. Although multiple arousal systems in the brain are known to act jointly to promote and maintain wakefulness, it remains unclear whether these systems are similarly engaged during voluntary vs. forced wakefulness. Using c-Fos immunohistochemistry, we compared neuronal responses in rats deprived of sleep for 2 h by gentle sensory stimulation, exploration under social isolation, or exploration with social interaction, and rats under undisturbed control conditions. In many arousal, limbic, and autonomic nuclei examined (e.g., anterior cingulate cortex and locus coeruleus), the two sleep deprivation procedures involving exploration were similarly effective, and both were more effective than sleep deprivation with sensory stimulation, in increasing the number of c-Fos immunoreactive neurons. However, some nuclei (e.g., paraventricular hypothalamic nucleus and select amygdala nuclei) were more responsive to exploration with social interaction, while others (e.g., histaminergic tuberomammillary nucleus) responded more strongly to exploration in social isolation. In the rostral basal forebrain, cholinergic and GABAergic neurons responded preferentially to exploration with social interaction, whereas resident neurons in general responded most strongly to exploration without social interaction. These results indicate that voluntary exploration with/without social interaction is more effective than forced sleep deprivation with gentle sensory stimulation for inducing c-Fos in arousal and limbic/autonomic brain regions, and suggest that these nuclei participate in different aspects of arousal during sustained voluntary wakefulness.

  14. Hydrocarbons in coastal sediments from the Mediterranean sea (Gulf of Fos area, France).

    PubMed

    Mille, Gilbert; Asia, Laurence; Guiliano, Michel; Malleret, Laure; Doumenq, Pierre

    2007-05-01

    Sedimentary hydrocarbons have been studied quantitatively and qualitatively in 11 coastal stations located in the Gulf of Fos (French Mediterranean coast). Hydrocarbon levels ranged from 10 to 260 mg kg(-1) sed. dry weight. A new parameter "NAR" (Natural n-alkane ratio) is proposed to evaluate the contribution of terrestrial inputs of hydrocarbons in the sediments. The origins of hydrocarbons are multiple: terrestrial inputs, biogenic, pyrolytic (industry emissions mainly steel and iron industries, ship and road traffic). Generally, the main source of contamination is not petroleum. Several ratios between parent polycyclic aromatic hydrocarbons show that the sources of hydrocarbons in the sediments are generally much more pyrolytic than petrogenic.

  15. Addition of positively charged tripeptide to N-terminus of the Fos basic region leucine zipper domain: implications on DNA bending, affinity, and specificity.

    PubMed

    Mahmoudi, T; Sarkar, B

    1999-09-01

    GKH-Fos(139-211)/Jun(248-334) (GKH: glycine-lysine-histidine) is a modified Fos/Jun heterodimer designed to contain a metal binding motif in the form of a GKH tripeptide at the amino terminus of Fos bZIP domain dimerized with the Jun basic region leucine zipper (bZIP) domain. We examined the effect of the addition of positively charged GKH motif to the N-terminus of Fos(139-211) on the DNA binding characteristics of the Fos(139-211)/Jun(248-334) heterodimer. Binding studies indicate that while the nonspecific DNA binding affinity of the GKH modified heterodimer increases 4-fold, it specifically binds the activating protein-1 (AP-1) site 6-fold less tightly than the control unmodified counterpart. Furthermore, helical phasing analysis indicates that GKH-Fos(139-211)/Jun(248-334) and control Fos(139-211)/Jun(248-334) both bend the DNA at the AP-1 site toward the minor groove. However, due to the presence of the positively charged GKH motif on Fos, the degree of the induced bend by GKH- Fos(139-211)/Jun(248-334) is greater than that induced by the unmodified Fos/Jun heterodimer. Our results suggest that the unfavorable energetic cost of the increased DNA bending by GKH-Fos(139-211)/Jun(248-334) results in a decrease in both specificity and affinity of binding of the heterodimer to the AP-1 site. These findings may have important implications in protein design as well in our understanding of DNA bending and factors responsible for the functional specificity of different members of the bZIP family of transcription factors.

  16. Express

    Integrated Risk Information System (IRIS)

    Express ; CASRN 101200 - 48 - 0 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic Effect

  17. Adult hippocampal neurogenesis and c-Fos induction during escalation of voluntary wheel running in C57BL/6J mice

    PubMed Central

    Clark, Peter J.; Kohman, Rachel A.; Miller, Daniel S.; Bhattacharya, Tushar K.; Haferkamp, Erik H.; Rhodes, Justin S.

    2010-01-01

    Voluntary wheel running activates dentate gyrus granule neurons and increases adult hippocampal neurogenesis. Average daily running distance typically increases over a period of 3 weeks in rodents. Whether neurogenesis and cell activation are greater at the peak of running as compared to the initial escalation period is not known. Therefore, adult C57BL/6J male mice received 5 days of BrdU injections, at the same age, to label dividing cells during the onset of wheel access or after 21 days during peak levels of running or in sedentary conditions. Mice were sampled either 24 hours or 25 days after the last BrdU injection to measure cell proliferation and survival, respectively. Immunohistochemistry was performed on brain sections to identify the numbers of proliferating BrdU labeled cells, and new neurons (BrdU/NeuN co-labeled) in the dentate gyrus. Ki67 was used as an additional mitotic marker. The induction of c-Fos was used to identify neurons activated from running. Mice ran approximately half as far during the first 5 days as compared to after 21 days. Running increased Ki67 cells at the onset but after 21 days levels were similar to sedentary. Numbers of BrdU cells were similar in all groups 24 hours after the final injection. However, after 25 days, running approximately doubled the survival of new neurons born either at the onset or peak of running. These changes co-varied with c-Fos expression. We conclude that sustained running maintains a stable rate of neurogenesis above sedentary via activity-dependent increases in differentiation and survival, not proliferation, of progenitor cells in the C57BL/6J model. PMID:20472002

  18. Laguerre Filter Analysis with Partial Least Square Regression Reveals a Priming Effect of ERK and CREB on c-FOS Induction

    PubMed Central

    Kudo, Takamasa; Uda, Shinsuke; Tsuchiya, Takaho; Wada, Takumi; Karasawa, Yasuaki; Fujii, Masashi; Saito, Takeshi H.; Kuroda, Shinya

    2016-01-01

    Signaling networks are made up of limited numbers of molecules and yet can code information that controls different cellular states through temporal patterns and a combination of signaling molecules. In this study, we used a data-driven modeling approach, the Laguerre filter with partial least square regression, to describe how temporal and combinatorial patterns of signaling molecules are decoded by their downstream targets. The Laguerre filter is a time series model used to represent a nonlinear system based on Volterra series expansion. Furthermore, with this approach, each component of the Volterra series expansion is expanded by Laguerre basis functions. We combined two approaches, application of a Laguerre filter and partial least squares (PLS) regression, and applied the combined approach to analysis of a signal transduction network. We applied the Laguerre filter with PLS regression to identify input and output (IO) relationships between MAP kinases and the products of immediate early genes (IEGs). We found that Laguerre filter with PLS regression performs better than Laguerre filter with ordinary regression for the reproduction of a time series of IEGs. Analysis of the nonlinear characteristics extracted using the Laguerre filter revealed a priming effect of ERK and CREB on c-FOS induction. Specifically, we found that the effects of a first pulse of ERK enhance the subsequent effects on c-FOS induction of treatment with a second pulse of ERK, a finding consistent with prior molecular biological knowledge. The variable importance of projections and output loadings in PLS regression predicted the upstream dependency of each IEG. Thus, a Laguerre filter with partial least square regression approach appears to be a powerful method to find the processing mechanism of temporal patterns and combination of signaling molecules by their downstream gene expression. PMID:27513954

  19. Maternal neglect with reduced depressive-like behavior and blunted c-fos activation in Brattleboro mothers, the role of central vasopressin.

    PubMed

    Fodor, Anna; Klausz, Barbara; Pintér, Ottó; Daviu, Nuria; Rabasa, Cristina; Rotllant, David; Balazsfi, Diana; Kovacs, Krisztina B; Nadal, Roser; Zelena, Dóra

    2012-09-01

    Early mother-infant relationships exert important long-term effects in offspring and are disturbed by factors such as postpartum depression. We aimed to clarify if lack of vasopressin influences maternal behavior paralleled by the development of a depressive-like phenotype. We compared vasopressin-deficient Brattleboro mothers with heterozygous and homozygous normal ones. The following parameters were measured: maternal behavior (undisturbed and separation-induced); anxiety by the elevated plus maze; sucrose and saccharin preference and forced swim behavior. Underlying brain areas were examined by c-fos immunocytochemistry among rest and after swim-stress. In another group of rats, vasopressin 2 receptor agonist was used peripherally to exclude secondary changes due to diabetes insipidus. Results showed that vasopressin-deficient rats spend less time licking-grooming their pups through a centrally driven mechanism. There was no difference between genotypes during the pup retrieval test. Vasopressin-deficient mothers tended to explore more the open arms of the plus maze, showed more preference for sucrose and saccharin and struggled more in the forced swim test, suggesting that they act as less depressive. Under basal conditions, vasopressin-deficient mothers had more c-fos expression in the medial preoptic area, shell of nucleus accumbens, paraventricular nucleus of the hypothalamus and amygdala, but not in other structures. In these areas the swim-stress-induced activation was smaller. In conclusion, vasopressin-deficiency resulted in maternal neglect due to a central effect and was protective against depressive-like behavior probably as a consequence of reduced activation of some stress-related brain structures. The conflicting behavioral data underscores the need for more sex specific studies.

  20. Fast regulation of AP-1 activity through interaction of lamin A/C, ERK1/2, and c-Fos at the nuclear envelope

    PubMed Central

    González, José María; Navarro-Puche, Ana; Casar, Berta; Crespo, Piero; Andrés, Vicente

    2008-01-01

    Sequestration of c-Fos at the nuclear envelope (NE) through interaction with A-type lamins suppresses AP-1–dependent transcription. We show here that c-Fos accumulation within the extraction-resistant nuclear fraction (ERNF) and its interaction with lamin A are reduced and enhanced by gain-of and loss-of ERK1/2 activity, respectively. Moreover, hindering ERK1/2-dependent phosphorylation of c-Fos attenuates its release from the ERNF induced by serum and promotes its interaction with lamin A. Accordingly, serum stimulation rapidly releases preexisting c-Fos from the NE via ERK1/2-dependent phosphorylation, leading to a fast activation of AP-1 before de novo c-Fos synthesis. Moreover, lamin A–null cells exhibit increased AP-1 activity and reduced levels of c-Fos phosphorylation. We also find that active ERK1/2 interacts with lamin A and colocalizes with c-Fos and A-type lamins at the NE. Thus, NE-bound ERK1/2 functions as a molecular switch for rapid mitogen-dependent AP-1 activation through phosphorylation-induced release of preexisting c-Fos from its inhibitory interaction with lamin A/C. PMID:19015316

  1. c-Fos positive nucleus reveals that contextual specificity of latent inhibition is dependent of insular cortex.

    PubMed

    Quintero, Esperanza; Vargas, Juan Pedro; Diaz, Estrella; Escarabajal, María Dolores; Carrasco, Manuel; López, Juan Carlos

    2014-09-01

    The present study analyzed the functional activity of granular and agranular insular cortices in contextual specificity of latent inhibition using a conditioned taste aversion paradigm. c-Fos immunolabeling was examined in insular cortex in preexposed and no preexposed groups under similar and different context conditions. Result showed that the exposition to a novel taste increased c-fos activity in insular cortex. However, a context shift caused an increase in immunolabeling in animals preexposed to saccharine. These results suggest insular cortex is part of a complex system to evaluate taste-response, and it may read the meaning of taste stimuli depending on the context.

  2. Results in standardization of FOS to support the use of SHM systems

    NASA Astrophysics Data System (ADS)

    Habel, Wolfgang R.; Krebber, Katerina; Daum, Werner

    2016-05-01

    Measurement and data recording systems are important parts of a holistic Structural Health Monitoring (SHM) system. New sensor technologies such as fiber-optic sensors are often used; however, standards (or at least guidelines) are not yet available or internationally approved. This lack in standardization makes the acceptance of FOS technologies in complex SHM systems substantially difficult. A standard family for different FOS technologies is therefore being developed that should help to design SHM systems in an optimal way. International standardization activities take place in several standardization bodies such as IEC and ASTM, and within SHM societies such as ISHMII. The paper reports on activities in standardization of fiber-optic sensors, on results already achieved, and on newly started projects. Combined activities of fiber sensor experts and SHM experts from Civil Engineering are presented. These contributions should help owners of structures as well as developers of sensors and monitoring systems to select effective and validated sensing technologies. Using these standards, both parties find recommendations how to proceed in development of SHM systems to evaluate the structural behavior based on e.g. standardized fiber optic sensors, and to derive necessary measures, e.g. the optimal maintenance strategy.

  3. Guaranteed time observations support for Faint Object Spectrograph (FOS) on HST

    NASA Technical Reports Server (NTRS)

    Harms, Richard

    1994-01-01

    The goals of the GTO effort are for investigations defined in previous years by the IDT to be carried out as HST observations and for the results to be communicated to the scientific community and to the public. The search for possible black holes in the nuclei of both normal and active nucleus galaxies has had to be delayed to the post-servicing era. FOS spectropolarimetric observations of the nuclear region of the peculiar Seyfert galaxy Mrk 231 reveal that the continuum polarization peaks at 18% in the near UV and then declines rapidly toward shorter wavelengths. The papers on the absorption line analysis for our galactic halo address the spatial distribution of high and intermediate level ions in the halo and illustrate the patchy and heterogeneous nature of the halo. The papers on the scattering characteristics of the HST/FOS have provided us with data that shows that the HST mirror surfaces are quite smooth, even at the UV wavelengths. WF-PC and FOC images of the halo PN K648 have been fully analyzed.

  4. Transcription factor Fos-related antigen 1 is an effective target for a breast cancer vaccine

    NASA Astrophysics Data System (ADS)

    Luo, Yunping; Zhou, He; Mizutani, Masato; Mizutani, Noriko; Reisfeld, Ralph A.; Xiang, Rong

    2003-07-01

    Protection against breast cancer was achieved with a DNA vaccine against murine transcription factor Fos-related antigen 1, which is overexpressed in aggressively proliferating D2F2 murine breast carcinoma. Growth of primary s.c. tumor and dissemination of pulmonary metastases was markedly suppressed by this oral DNA vaccine, carried by attenuated Salmonella typhimurium, encoding murine Fos-related antigen 1, fused with mutant polyubiquitin, and cotransformed with secretory murine IL-18. The life span of 60% of vaccinated mice was tripled in the absence of detectable tumor growth after lethal tumor cell challenge. Immunological mechanisms involved activation of T, natural killer, and dendritic cells, as indicated by up-regulation of their activation markers and costimulatory molecules. Markedly increased specific target cell lysis was mediated by both MHC class I-restricted CD8+ T cells and natural killer cells isolated from splenocytes of vaccinated mice, including a significant release of proinflammatory cytokines IFN- and IL-2. Importantly, fluorescence analysis of fibroblast growth factor 2 and tumor cell-induced vessel growth in Matrigel plugs demonstrated marked suppression of angiogenesis only in vaccinated animals. Taken together, this multifunctional DNA vaccine proved effective in protecting against growth and metastases of breast cancer by combining the action of immune effector cells with suppression of tumor angiogenesis. vaccine | tumor | metastases | antiangiogenesis

  5. Effects of short-chain fructooligosaccharides (scFOS) and rearing temperature on growth performance and hepatic intermediary metabolism in gilthead sea bream (Sparus aurata) juveniles.

    PubMed

    Guerreiro, Inês; Enes, Paula; Oliva-Teles, Aires

    2015-10-01

    The effect of dietary short-chain fructooligosaccharides (scFOS) incorporation on growth, feed utilization, body composition, plasmatic metabolites and liver activity of key enzymes of lipogenic and amino acid catabolic pathways was evaluated in gilthead sea bream reared at 18 and 25 °C. Four practical diets containing plant ingredients and fish meal (50:50) as protein sources and supplemented with 0, 0.1, 0.25 and 0.5 % scFOS were fed to triplicate groups of fish for 8 weeks. Growth performance, feed efficiency and nitrogen retention were higher at 25 °C. In fish reared at 18 °C, there was a positive correlation between dietary scFOS concentration and growth. At 18 °C, liver glycogen was higher in fish fed the control diet, while at 25 °C it was higher in fish fed the 0.5 % scFOS diet. Plasma cholesterol LDL was lower in fish fed 0.25 % scFOS diet, and in fish reared at 18 °C plasma glucose was higher in fish fed the 0.1 % scFOS diet. Glucose 6-phosphate dehydrogenase, fatty acid synthetase and aspartate aminotransferase (ASAT) activities were higher in fish reared at 18 °C, whereas alanine aminotransferase activity was higher in fish reared at 25 °C. scFOS affected ASAT activity, which was lower in fish fed 0.25 % scFOS diet. Although, scFOS seemed to have no major effects on gilthead sea bream metabolism, the positive correlation between dietary prebiotic incorporation and growth at 18 °C indicates a beneficial effect of scFOS in fish reared at low temperatures.

  6. The Nuclear Receptor AhR Controls Bone Homeostasis by Regulating Osteoclast Differentiation via the RANK/c-Fos Signaling Axis

    PubMed Central

    Izawa, Takashi; Arakaki, Rieko; Mori, Hiroki; Tsunematsu, Takaaki; Kudo, Yasusei; Tanaka, Eiji

    2016-01-01

    The aryl hydrocarbon receptor (AhR) pathway plays a key role in receptor activator of NF-κB ligand (RANKL)–mediated osteoclastogenesis. However, the mechanism underlying the regulation of AhR expression in osteoclasts and the signaling pathway through which AhR controls osteoclastogenesis remain unclear. We found that the expression of AhR in bone marrow–derived osteoclasts was upregulated by RANKL at an earlier stage than was the expression of signature osteoclast genes such as those encoding cathepsin K and NFAT, cytoplasmic, calcineurin-dependent 1. In response to RANKL, bone marrow macrophages isolated from AhR−/− mice exhibited impaired phosphorylation of Akt and MAPK as well as NF-κB, whereas their response to M-CSF remained unchanged. Osteoclast differentiation mediated by the AhR signaling pathway was also regulated in an RANKL/c-Fos–dependent manner. Furthermore, ligand activation of AhR by the smoke toxin benzo[a]pyrene accelerated osteoclast differentiation in a receptor-dependent manner, and AhR-dependent regulation of mitochondrial biogenesis in osteoclasts was observed. Moreover, AhR−/− mice exhibited impaired bone healing with delayed endochondral ossification. Taken together, the present results suggest that the RANKL/AhR/c-Fos signaling axis plays a critical role in osteoclastogenesis, thereby identifying the potential of AhR in treating pathological, inflammatory, or metabolic disorders of the bone. PMID:27849171

  7. Prenatal ethanol exposure alters ethanol-induced Fos immunoreactivity and dopaminergic activity in the mesocorticolimbic pathway of the adolescent brain.

    PubMed

    Fabio, M C; Vivas, L M; Pautassi, R M

    2015-08-20

    Prenatal ethanol exposure (PEE) promotes alcohol intake during adolescence, as shown in clinical and pre-clinical animal models. The mechanisms underlying this effect of prenatal ethanol exposure on postnatal ethanol intake remain, however, mostly unknown. Few studies assessed the effects of moderate doses of prenatal ethanol on spontaneous and ethanol-induced brain activity on adolescence. This study measured, in adolescent (female) Wistar rats prenatally exposed to ethanol (0.0 or 2.0g/kg/day, gestational days 17-20) or non-manipulated (NM group) throughout pregnancy, baseline and ethanol-induced cathecolaminergic activity (i.e., colocalization of c-Fos and tyrosine hydroxylase) in ventral tegmental area (VTA), and baseline and ethanol-induced Fos immunoreactivity (ir) in nucleus accumbens shell and core (AcbSh and AcbC, respectively) and prelimbic (PrL) and infralimbic (IL) prefrontal cortex. The rats were challenged with ethanol (dose: 0.0, 1.25, 2.5 or 3.25g/kg, i.p.) at postnatal day 37. Rats exposed to vehicle prenatally (VE group) exhibited reduced baseline dopaminergic tone in VTA; an effect that was inhibited by prenatal ethanol exposure (PEE group). Dopaminergic activity in VTA after the postnatal ethanol challenge was greater in PEE than in VE or NM animals. Ethanol-induced Fos-ir at AcbSh was found after 1.25g/kg and 2.5g/kg ethanol, in VE and PEE rats, respectively. PEE did not alter ethanol-induced Fos-ir at IL but reduced ethanol-induced Fos-ir at PrL. These results suggest that prenatal ethanol exposure heightens dopaminergic activity in the VTA and alters the response of the mesocorticolimbic pathway to postnatal ethanol exposure. These effects may underlie the enhanced vulnerability to develop alcohol-use disorders of adolescents with a history of in utero ethanol exposure.

  8. Water deprivation increases Fos immunoreactivity in PVN autonomic neurons with projections to the spinal cord and rostral ventrolateral medulla.

    PubMed

    Stocker, Sean D; Cunningham, J Thomas; Toney, Glenn M

    2004-11-01

    The present study sought to determine whether water deprivation increases Fos immunoreactivity, a neuronal marker related to synaptic activation, in sympathetic-regulatory neurons of the hypothalamic paraventricular nucleus (PVN). Fluorogold (4%, 50 nl) and cholera toxin subunit B (0.25%, 20-30 nl) were microinjected into the spinal cord (T1-T3) and rostral ventrolateral medulla (RVLM), respectively. Rats were then deprived of water but not food for 48 h. Water deprivation significantly increased the number of Fos-positive nuclei throughout the dorsal, ventrolateral, and lateral parvocellular divisions of the PVN (water deprived, 215 +/- 23 cells; control, 45 +/- 7 cells, P < 0.01). Moreover, a significantly greater number of Fos-positive nuclei were localized in spinally projecting (11 +/- 3 vs. 2 +/- 1 cells, P < 0.025) and RVLM-projecting (45 +/- 7 vs. 7 +/- 1 cells, P < 0.025) neurons of the PVN in water-deprived vs. control rats, respectively. The majority of these double-labeled neurons was found in the ventrolateral and lateral parvocellular divisions of the ipsilateral PVN. Interestingly, a significantly greater percentage of RVLM-projecting PVN neurons were Fos positive compared with spinally projecting PVN neurons in the ventrolateral (25.8 +/- 0.7 vs. 8.0 +/- 1.5%, respectively, P < 0.01) and lateral (23.4 +/- 2.1 vs. 5.0 +/- 0.9%, respectively, P > 0.01) parvocellular divisions. In addition, we analyzed spinally projecting neurons of the RVLM and found a significantly greater percentage were Fos positive in water-deprived rats than in control rats (26 +/- 3 vs. 3 +/- 1%, respectively; P < 0.001). Collectively, the present findings indicate that water deprivation evokes a distinct cellular response in sympathetic-regulatory neurons of the PVN and RVLM.

  9. Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of ΔFosB.

    PubMed

    Vialou, Vincent; Bagot, Rosemary C; Cahill, Michael E; Ferguson, Deveroux; Robison, Alfred J; Dietz, David M; Fallon, Barbara; Mazei-Robison, Michelle; Ku, Stacy M; Harrigan, Eileen; Winstanley, Catherine A; Joshi, Tej; Feng, Jian; Berton, Olivier; Nestler, Eric J

    2014-03-12

    Decreased medial prefrontal cortex (mPFC) neuronal activity is associated with social defeat-induced depression- and anxiety-like behaviors in mice. However, the molecular mechanisms underlying the decreased mPFC activity and its prodepressant role remain unknown. We show here that induction of the transcription factor ΔFosB in mPFC, specifically in the prelimbic (PrL) area, mediates susceptibility to stress. ΔFosB induction in PrL occurred selectively in susceptible mice after chronic social defeat stress, and overexpression of ΔFosB in this region, but not in the nearby infralimbic (IL) area, enhanced stress susceptibility. ΔFosB produced these effects partly through induction of the cholecystokinin (CCK)-B receptor: CCKB blockade in mPFC induces a resilient phenotype, whereas CCK administration into mPFC mimics the anxiogenic- and depressant-like effects of social stress. We previously found that optogenetic stimulation of mPFC neurons in susceptible mice reverses several behavioral abnormalities seen after chronic social defeat stress. Therefore, we hypothesized that optogenetic stimulation of cortical projections would rescue the pathological effects of CCK in mPFC. After CCK infusion in mPFC, we optogenetically stimulated mPFC projections to basolateral amygdala or nucleus accumbens, two subcortical structures involved in mood regulation. Stimulation of corticoamygdala projections blocked the anxiogenic effect of CCK, although no effect was observed on other symptoms of social defeat. Conversely, stimulation of corticoaccumbens projections reversed CCK-induced social avoidance and sucrose preference deficits but not anxiogenic-like effects. Together, these results indicate that social stress-induced behavioral deficits are mediated partly by molecular adaptations in mPFC involving ΔFosB and CCK through cortical projections to distinct subcortical targets.