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PubMed2000

Differential regulation of fos family genes in the ventrolateral and dorsomedial subdivisions of the rat suprachiasmatic nucleus.

Extensive studies have established that light regulates c-fos gene expression in the suprachiasmatic nucleus, the site of an endogenous circadian clock, but relatively little is known about the expression of genes structurally related to c-fos, including fra-1, fra-2 and fosB. We analysed the photic and temporal regulation of these genes at the messenger RNA and immunoreactive protein levels in rat suprachiasmatic nucleus, and we found different expression patterns after photic stimulation and depending on location in the ventrolateral or dorsomedial subdivisions. In the ventrolateral suprachiasmatic nucleus, c-fos, fra-2 and fosB expression was stimulated after a subjective-night (but not subjective-day) light pulse. Expression of the fra-2 gene was prolonged following photic stimulation, with elevated messenger RNA and protein levels that appeared unchanged for at least a few hours beyond the c-fos peak. Unlike c-fos and fra-2, the fosB gene appeared to be expressed constitutively in the ventrolateral suprachiasmatic nucleus throughout the circadian cycle; immunohistochemical analysis suggested that delta FosB was the protein product accounting for this constitutive expression, while FosB was induced by the subjective-night light pulse. In the dorsomedial suprachiasmatic nucleus, c-fos and fra-2 expression exhibited an endogenous circadian rhythm, with higher levels during the early subjective day, although the relative abundance was much lower than that measured after light pulses in the ventrolateral suprachiasmatic nucleus. Double-label immunohistochemistry suggested that some of the dorsomedial cells responsible for the circadian expression of c-Fos also synthesized arginine vasopressin. No evidence of suprachiasmatic nucleus fra-1 expression was found. In summary, fos family genes exhibit differences in their specific expression patterns in the suprachiasmatic nucleus, including their photic and circadian regulation in separate cell populations in the ventrolateral and dorsomedial subdivisions. The data, in combination with our previous results [Takeuchi J. et al. (1993) Neuron 11, 825-836], suggest that activator protein-1 binding sites on ventrolateral suprachiasmatic nucleus target genes are constitutively occupied by DeltaFosB/JunD complexes, and that c-Fos, Fra-2, FosB and JunB compete for binding after photic stimulation. The differential regulation of fos family genes in the ventrolateral and dorsomedial suprachiasmatic nucleus suggests that their circadian function(s) and downstream target(s) are likely to be cell specific.

Animals↗
PubMed2000

Neuroanatomical targets of anxiogenic drugs in the hindbrain as revealed by Fos immunocytochemistry.

It is speculated that specific hindbrain transmitter pathways centred on the periaqueductal gray and locus coeruleus are an important integrative neural substrate for the expression of anxiety and the somatic symptoms and cardiovascular changes that accompany severe anxiety states, such as in panic disorder. Here we investigated the effects of various drugs, known to induce panic in humans and to be anxiogenic in animals, on Fos expression in the periaqueductal gray, locus coeruleus and other parts of the rat hindbrain. The drugs tested were the benozodiazepine inverse agonist FG-7142, the alpha(2)-adrenoceptor antagonist yohimbine, the non-selective 5-hydroxytryptamine(2C) receptor agonist m-chlorophenyl piperazine, the adenosine antagonist caffeine and the cholecystokinin analogue BOC-CCK(4). A clear-cut finding was that administration of each anxiogenic drug caused a striking region-specific pattern of Fos expression within the hindbrain. In particular, the drugs commonly increased Fos-like immunoreactivity in the periaqueductal gray and locus coeruleus. Increased Fos expression in the periaqueductal gray was specific to the rostral dorsolateral and caudal ventrolateral regions. All the anxiogenic drugs also increased Fos-like immunoreactivity in the lateral parabrachial nucleus and nucleus of the solitary tract and all but one (BOC-CCK(4)) increased Fos in the dorsal raphe nucleus. Rats habituated to the test environment and injected with saline vehicle displayed little or no Fos-like immunoreactivity in the hindbrain areas investigated. In summary, each of the anxiogenic drugs tested (FG-7142, yohimbine, m-chlorophenyl piperazine, caffeine and BOC-CCK(4)) increased Fos expression in a restricted number of hindbrain regions, including the periaqueductal gray and locus coeruleus. Previous Fos studies have found that these same regions are activated by various fearful environmental stimuli. Therefore, a specific set of hindbrain circuits may be commonly involved in the processing of anxiety-related information evoked by pharmacological and environmental manipulation. The present findings also raise the possibility that measurement of the effect of anxiogenic drugs on Fos expression might be a useful way to model hindbrain pathways activated by anxiety and possibly panic.

Adrenergic alpha-Antagonists↗
PubMed2000

Maternal behaviour in lactating rats stimulates c-fos in glutamate decarboxylase-synthesizing neurons of the medial preoptic area, ventral bed nucleus of the stria terminalis, and ventrocaudal periaqueductal gray.

Increased activity of the immediate-early gene c-fos can be observed in many areas of the lactating rat brain after dams physically interact with pups and display maternal behaviour. These sites include the medial preoptic area, ventral bed nucleus of the stria terminalis, and the ventrolateral caudal periaqueductal gray, each of which is critical for the normal performance of particular maternal behaviours. The phenotype of cells in these areas that show increased c-fos activity after maternal behaviour, however, is unknown. Via double-label immunocytochemistry, we determined if the population of cells in these sites that express c-fos after maternal behaviour in lactating rats overlaps with the population that expresses the 67,000 mol. wt isoform of glutamate decarboxlyase, the synthesizing enzyme for the inhibitory neurotransmitter GABA. Lactating rats were separated from pups beginning on day 5 postpartum, and 48h later half were allowed to interact with a litter of pups for 60min whereas the other half were not. Dams re-exposed to pups were highly maternal, retrieving and licking them as well as displaying prolonged nursing behaviour that included milk letdown. Both groups of dams had a similar number of 67,000 mol. wt glutamate decarboxylase-immunoreactive cells in each site, although the number of 67,000 mol. wt glutamate decarboxylase-immunoreactive cells per microscopic field was significantly greater in the caudal ventrolateral periaqueductal gray than in the ventral bed nucleus of the stria terminalis, which in turn was greater than the medial preoptic area. In pup-stimulated dams, two to fourfold more Fos-immunoreactive cells were found in these three sites compared with non-stimulated controls. Labeling for Fos immunoreactivity and 67,000 mol. wt glutamate decarboxylase immunoreactivity was heterogeneous within each site. In the medial preoptic area, more Fos-immunoreactive and 67,000 mol. wt glutamate decarboxylase-immunoreactive cells (either single or dual-labeled) were found dorsally than ventrally. In the ventral bed nucleus of the stria terminalis, more Fos-immunoreactive and 67,000 mol. wt glutamate decarboxylase-immunoreactive cells were found medially than laterally. Within the caudal ventrolateral periaqueductal gray, 67,000 mol. wt glutamate decarboxylase-immunoreactive labeling was greatest ventromedially, while high numbers of Fos-immunoreactive nuclei were found both ventromedially and ventrolaterally. In pup-stimulated dams, more than half (53% in the medial preoptic area, 59% in the ventral bed nucleus of the stria terminalis, and 61% in the caudal ventrolateral periaqueductal gray) of the total population of Fos-immunoreactive cells also expressed 67,000 mol. wt glutamate decarboxylase. These results suggest that many of the neurons in these sites that show elevated c-fos activity after maternal behaviour are either local inhibitory interneurons or provide inhibitory input to other neural sites. These inhibitory mechanisms may be critical for the display of postpartum nurturance, possibly facilitating maternal behaviour by removing tonic inhibition on sites necessary for maternal responding or by restricting activity in neural sites that inhibit it.

Animals↗
PubMed2000

Long-term induction of Fos-related antigen-2 after methamphetamine-, methylenedioxymethamphetamine-, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine- and trimethyltin-induced brain injury.

A long-term induction of Fos-related antigens has been shown in neurons after brain injury, suggesting that Fos-related antigens are involved in enhancing the transcription of genes related to the process of regeneration and repair. In the present study, we report that levels of Fos-related antigen-2 are elevated in several models of chemically induced brain injury. Trimethyltin, which causes degeneration of neurons primarily in the hippocampus and other limbic regions, results in a five-fold induction of Fos-related antigen-2 immunoreactivity in neurons in the pyramidal and dentate layers of the hippocampus starting at seven days post-treatment and persisting for 60days. Methamphetamine and methylenedioxymethamphetamine, agents which cause degeneration of dopaminergic nerve terminals in the striatum of the mouse, cause an increase in Fos-related antigen-2 immunoreactivity which begins at three days post-treatment and returns to basal levels by days 5 and 15, respectively. Treatment with 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine elevated levels of Fos-related antigen-2 in the mouse striatum at three days post-treatment. This abbreviated time-course of Fos-related antigen-2 induction is consistent with less severe insult (terminal damage) relative to trimethyltin (cell death), but induction occurs during the period of regeneration and repair in both models. Dexfenfluramine, a non-neurotoxic amphetamine, does not induce Fos-related antigen-2 expression. Decreasing core temperature of the mouse, which blocks amphetamine-induced neurotoxicity, also blocks Fos-related antigen-2 induction. In summary, Fos-related antigen-2 is induced in models of both cell death and terminal degeneration, suggesting that this transcription factor may serve as a universal signal transduction molecule involved in the regulation of genes related to regeneration and repair in the CNS.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Parafascicular thalamic nucleus deafferentation reduces c-fos expression induced by dopamine D-1 receptor stimulation in rat striatum.

We investigated the role played by the parafascicular thalamostriatal pathway, one of the major excitatory inputs to the striatum, in the D-1 receptor induction of c-fos messenger RNA expression in the rat striatum. The full D-1 receptor agonist, SKF-82958 (0.05, 0.1, 0.5 and 1 mg/kg, s.c., 30 min), dose-dependently induced c-fos messenger RNA in naive rat striatum as determined by northern blot analysis. One day following electrolytic lesion of the parafascicular thalamostriatal nucleus, striatal c-fos signal by itself was not altered but the stimulated expression of c-fos was strongly decreased. Sections of sham-operated and acute-lesioned dorsal striata of vehicle- or SKF-82958-treated rats were processed for in situ hybridization histochemistry at the single-cell level with an RNA probe for c-fos. The basal expression of striatal c-fos was poorly detectable in sham and lesioned groups. Sections of dorsal striata from sham-operated rats treated with SKF-82958 showed two types of labeled neurons for c-fos: the lightly and the very densely labeled neurons which are few in number. Thalamic lesion strongly reduced SKF-82958 stimulated expression of c-fos RNA in both types of labeled cells. The frequency distribution of c-fos labeling per neuron in dorsal striata of lesioned rats treated with SKF-82958 was shifted to the left, and its median was lower than in the sham-operated striata treated with the D-1 receptor agonist. The results provide evidence that the excitatory projections from the parafascicular nucleus of the thalamus, thought to operate primarily through the N-methyl-D-aspartate receptors, exert a facilitatory control over D-1 receptor-induced c-fos gene expression specifically in the dorsal striatum.

Afferent Pathways↗
PubMed2001

Interactions between environmental stimulation and antipsychotic drug effects on forebrain c-fos activation.

The immediate-early gene product Fos is differentially induced in the rat brain by the antipsychotic drugs haloperidol and clozapine. It is often claimed that although both drugs induce Fos in the nucleus accumbens, haloperidol but not clozapine increases Fos-like immunoreactivity in the striatum, whereas clozapine but not haloperidol increases Fos-like immunoreactivity in prefrontal cortex. Investigations of antipsychotic drug effects on Fos have typically administered high doses with pronounced sedative effects to behaviorally naive animals. In the present study, we compared the effects of low doses of haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) on Fos-like immunoreactivity in rats which were either behaviorally naive, exposed to a novel environment or tested for two-way active avoidance. We determined that haloperidol increased Fos in the striatum and nucleus accumbens regardless of testing condition whereas clozapine markedly reduced the induction of Fos by behavioral testing in these regions; moreover, haloperidol dramatically increased prefrontal cortical Fos expression in animals placed in a novel environment, but not in testing-naive controls. From these results we suggest that antipsychotic drug-induced patterns of Fos expression in the rat are highly dependent on animals' concurrent behavioral status, perhaps reflecting neuroanatomically specific interactions between antipsychotic drugs and environmental stressors which also may occur in the schizophrenic condition.

Animals↗
PubMed1999

Blockade of cannabinoid receptors by SR141716 selectively increases Fos expression in rat mesocorticolimbic areas via reduced dopamine D2 function.

The present study investigated, in rats, whether blockade of cannabinoid CB1 receptors may alter Fos protein expression in a manner comparable to that observed with antipsychotic drugs. Intraperitoneal administration of the selective CB1 receptor antagonist, SR141716, dose-dependently (1.0, 3.0 and 10 mg/kg) increased Fos-like immunoreactivity in mesocorticolimbic areas (prefrontal cortex, ventrolateral septum, shell of the nucleus accumbens and dorsomedial caudate-putamen), while motor-related structures such as the core of the nucleus accumbens and the dorsolateral caudate-putamen were unaffected. In the ventrolateral septum, taken as a representative structure, the Fos-inducing effect of SR141716 (10 mg/kg) was maximal 2 h after injection and returned to near control levels by 4 h. Within the prefrontal cortex, SR141716 increased the number of Fos-positive cells predominantly in the infralimbic and prelimbic cortices, presumptive pyramidal cells being the major cell types in which Fos was induced. The D1-like receptor antagonist, SCH23390 (0.1 mg/kg), did not prevent the Fos-inducing effect of SR141716 in any brain region examined (prefrontal cortex, nucleus accumbens, ventrolateral septum and dorsomedial caudate-putamen), although SCH23390 significantly reduced Fos expression induced by cocaine (20 mg/kg) in all these regions. By contrast, the dopamine D2-like agonist, quinpirole (0.25 mg/ kg), counteracted SR141716-induced Fos-like immunoreactivity in the ventrolateral septum, the nucleus accumbens and the dorsomedial caudate-putamen, while no antagonism was observed in the prefrontal cortex. Microdialysis experiments in awake rats indicated that SR141716, at doses which increased Fos expression (3 and 10 mg/kg), did not alter dopamine release in the shell of the nucleus accumbens. Finally, SR141716 increased the levels of neurotensin-like immunoreactivity in the nucleus accumbens, but not in the caudate-putamen. Collectively, the present results show that blockade of cannabinoid receptors increases Fos- and neurotensin-like immunoreactivity with characteristics comparable to those reported for atypical neuroleptic drugs.

Animals↗
PubMed1999

Learning-related fos-like immunoreactivity in the chick brain: time-course and co-localization with GABA and parvalbumin.

Previous work has shown that, after domestic chicks have learned the characteristics of an object (visual imprinting), there is a learning-related increase in the numerical density of Fos-immunopositive neurons in the intermediate and medial part of the hyperstriatum ventrale, a forebrain region that is a site of recognition memory for the imprinted object. The present study describes the time-course of this effect and has used double-labelling immunocytochemistry to identify neuronal types in which the effect occurs. Chicks were trained by exposure for 1 h to an imprinting (training) stimulus and then given a preference test to determine the strength of imprinting (i.e. of learning). Strongly imprinted chicks were killed 2, 2.5, 3, 3.5 or 4 h (12 chicks in each group) after the start of training and a further group of 12 chicks remained untrained. Sections from the chicks' brains were stained for Fos-like immunoreactivity, and the numerical density of Fos-positive nuclei in the intermediate and medial part of the hyperstriatum ventrale was counted. Relative to untrained chicks, there was a 60% increase in the number of Fos-positive nuclei in the intermediate and medial part of the hyperstriatum ventrale 2 h after the start of training (P = 0.02), but not at any other time. Sections from 10 trained chicks, two killed at each of the above times after training, and from two untrained chicks were stained with anti-Fos antibody as before and also with an antibody against GABA. Approximately 95% of the Fos-positive neurons in the intermediate and medial part of the hyperstriatum ventrale were also immunopositive for GABA. In neurons immunopositive for GABA, there were significantly (P = 0.02) more Fos-positive nuclei in the intermediate and medial part of the hyperstriatum ventrale 2 h after the start of training than in untrained chicks. Five chicks killed 2 h after training and five untrained chicks yielded sections for the next experiment; sections were double labelled for (i) Fos and (ii) either Calbindin-D28k or parvalbumin. Training gave rise to a significant (P = 0.017) increase in numerical density of Fos-positive nuclei of neurons that were immunonegative for Calbindin-D28k. This increase occurred in neurons that were immunopositive for parvalbumin. The use of alternative antibodies for GABA, Calbindin-D28k and parvalbumin in trained and untrained chicks confirmed the double-staining pattern observed in the quantitative experiments. The results demonstrate that the learning-related increase in Fos-like immunoreactivity following training is transitory and have localized the increase to a population of neurons immunopositive for GABA and parvalbumin, but not Calbindin-D28k.

Animals↗
PubMed2000

Incipient cauda equina syndrome as a model of somatovisceral pain in dogs: spinal cord structures involved as revealed by the expression of c-fos and NADPH diaphorase activity.

Segmental and laminar distribution of Fos-like immunoreactive, reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd)-exhibiting and double-labeled (Fos-like immunoreactive and NADPHd-exhibiting) neurons was examined in lower lumbar and sacral segments of the dog spinal cord using the model of multiple cauda equina constrictions. NADPHd histochemistry was used as marker of nitric oxide synthase-containing neurons. The appearance and the time-course of Fos-like immunoreactive, NADPHd and double-labeled neurons was studied at 2 h and 8 h postconstriction characterized as the incipient phase of cauda equina syndrome. The occurrence of Fos-like immunoreactive and NADPHd-exhibiting neurons in fully developed cauda equina syndrome was studied at five days postconstriction. An increase in Fos-like immunoreactivity in superficial laminae (I-II) and an enhanced NADPHd staining of lamina VIII neurons were found. A statistically significant increase in Fos-like immunoreactive neurons was found in laminae I-II and VIII-X 8 h postconstriction, and in contrast, a prominent decrease in Fos-like immunoreactive neurons was found in laminae I-II, accompanied by a statistically significant increase in Fos-like immunoreactive neurons in more ventrally located laminae VII-X at five days postconstriction. Quantitative analysis of laminar distribution of constriction-induced NADPHd-exhibiting neurons revealed a considerable increase in these neurons in laminae VIII-IX 8 h postconstriction and a statistically highly significant increase in NADPHd-exhibiting neurons in laminae VII-X five days postconstriction. Concurrently, the number of NADPHd-exhibiting neurons in laminae I-II was greatly reduced. While a low number of double-labeled neurons was found throughout the gray matter of lower lumbar and sacral segments at 2 h postconstriction, a statistically significant number of double-labeled neurons was found in lamina X 8 h and in laminae VII-X five days postconstriction. The course and distribution of anterograde degeneration resulting five days after multiple cauda equina constrictions are compared with segmental and laminar distribution of Fos-like immunoreactive and NADPHd-exhibiting neurons. Prominent involvement of the spinal cord neurons appearing in the lumbosacral segments at the early beginning and in fully developed cauda equina syndrome results in a Fos-like immunoreactivity and strongly enhanced NADPHd staining of some neuronal pools. Under such circumstances, an early cauda equina decompression surgery is advisable aimed at decreasing or preventing the derangement of the neural circuits in the lumbosacral segments.

Animals↗
PubMed2000

Tachykinin receptor inhibition and c-Fos expression in the rat brain following formalin-induced pain.

Recent pharmacological evidence has implicated substance P and neurokinin A, natural ligands for neurokinin-1 and neurokinin-2 receptors, respectively, as neurotransmitters in brain neuronal circuits activated upon noxious stimulation. The expression of the inducible transcription factor, c-Fos, was used to identify areas in the brain activated by a noxious stimulus (the subcutaneous injection of formalin), and to investigate the effects of intracerebroventricular administration of selective, nonpeptide antagonists for neurokinin-1 and neurokinin-2 tachykinin receptors on the neural activity in these areas and on the behavioural response to formalin-induced pain. Formalin (5%, 50 microl), injected subcutaneously through a chronically implanted catheter in the region of the lower hindlimb, increased c-Fos expression in a number of brain areas related to nociceptive transmission or the integration of stress responses. Grooming behaviour, licking and biting directed to the injected site, was the most frequent behavioural response. Intracerebroventricular pretreatment of rats with either RP 67580 (500 pmol), the active enantiomer of a neurokinin-1 receptor antagonist, or with SR 48968 (500 pmol), the active enantiomer of a neurokinin-2 receptor antagonist, reduced the formalin-induced c-Fos staining in the prefrontal cortex, dorsomedial and ventromedial nuclei of the hypothalamus, the locus coeruleus and the periaqueductal gray. The neurokinin-1, but not the neurokinin-2, receptor antagonist attenuated the formalin-induced activation of c-Fos in the paraventricular nucleus of the hypothalamus. Simultaneous intracerebroventricular pretreatment with both neurokinin-1 and neurokinin-2 receptor antagonists did not produce any additional inhibitory effect on the post-formalin c-Fos expression. None of the tachykinin receptor antagonists had an effect on the formalin-induced c-Fos expression in the septohypothalamic nucleus, medial thalamus, parabrachial nucleus and central amygdaloid nucleus, indicating that neurotransmitters other than neurokinins are most probably responsible for the activation of these areas in response to noxious stimulation. While both tachykinin receptor antagonists reduced the grooming behaviour to formalin, the neurokinin-1 receptor antagonist was clearly more effective than the neurokinin-2 receptor antagonist. Intracerebroventricular pretreatment of rats with the inactive enantiomers of the tachykinin receptor antagonists, RP 68651 and SR 48965, was without effect. Our results show that (i) the modified formalin test elicited an intense grooming behaviour and expression of c-Fos in numerous forebrain and brainstem areas, (ii) both tachykinin receptor antagonists were able to attenuate the behavioural response to pain and to reduce the formalin-induced c-Fos expression in some, but not all, brain areas, and (iii) the neurokinin-1 antagonist, RP 67580, was more effective in inhibiting the behavioural response to formalin and the pain-induced activation of c-Fos than the antagonist for neurokinin-2 receptors, SR 48968, indicating that neurokinin-1 receptors are preferentially activated in neurokinin-containing pathways responding to noxious stimuli. Our results demonstrate that blockade of brain tachykinin receptors, especially of the neurokinin-1 receptor, reduces the behavioural response to pain and the pain-induced c-Fos activation in distinct brain areas which are intimately linked with nociceptive neurotransmission and the initiation and integration of central stress responses. Together with the previous findings of the inhibition of hypertensive and tachycardic responses to pain, the present data indicate that tachykinin receptor antagonists can effectively inhibit the generation of an integrated cardiovascular and behavioural response pattern to noxious stimuli.

Analgesics↗
PubMed1999

Quantitative analysis of the effects of lithium on the reverse tolerance and the c-Fos expression induced by methamphetamine in mice.

To elucidate the mechanism of psychostimulant-induced reverse tolerance [A. Kifune, S. Tadokoro, Modification of stereotype producing and ambulation-increasing effects following repeated administration of methamphetamine in rats, Jpn. J. Psychopharmacol. 11 (1991) 207-214 [11]; N.J. Leith, R. Kuczenski, Chronic amphetamine: tolerance and reverse tolerance reflect different behavioral actions of the dog, Pharmacol. Biochem. Behav. 15 (1981) 399-405 [13]; S. Tadokoro, H. Kuribara, Reverse tolerance to the ambulation-increasing effect of methamphetamine in mice as an animal model of amphetamine-psychosis, Psychopharmacol, Bull. 22 (1986) 757-762 [18]; S. Tadokoro, H. Kuribara, Modification of the behavioral effects of drugs after repeated administration: special reference to the reverse tolerance, Folia Pharmacologica Japonica 95 (1990) 229-238 [19]], the effects of lithium on ambulatory activity [P. Cappeliez, E. Moore, Effects of lithium on an amphetamine animal model of bipolar disorder, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 14 (1990) 347-358 [1]; M. Hirabayashi, M.K. Alam, Enhancing effect of methamphetamine on ambulatory activity produced by repeated administration on mice, Pharmacol. Biochem. Behav. 15 (1981) 925-932 [7]; M. Hirabayashi, S. Okada, S. Tadokoro, Comparison of sensitization to ambulation-increasing effects of cocaine and methamphetamine after repeated administration in mice, J. Pharm. Pharmacol. 43 (1991) 827-830 [8]; T. Miyauchi, K. Kikuchi, S. Satoh, Further studies on the potentiating effect of lithium chloride on methamphetamine-induced stereotypy in mice, Jpn. J. Pharmacol. 31 (1981) 61-68 [14]; H. Ozawa, T. Nozu, H. Aihara, F. Akiyama, M. Sasajima, Pharmacokinetics and general pharmacological actions of lithium salts administered singly or repeatedly, Folia Pharmacologica Japonica 72 (1976) 433-443 [15].] and cerebral c-Fos expression [S. Ceccatelli, M.J. Villar, M. Goldstein, T. Hokfelt, Expression of c-Fos immunoreactivity in transmitter-characterized neurons after stress, Proc. Natl. Acad. Sci. USA 86 (1989) 9569-9573 [2]; L. Giovannelli, P.J. Shiromani, G.F. Jirikoski, F.E. Bloom, Expression of c-fos protein by immunohistochemically identified oxytocin neurons in the rat hypothalamus upon osmotic stimulation, Brain Research 588 (1992) 41-48 [4]; B.T. Hope, H.E. Nye, M.B. Kelz, D.W. Self, M.J. Iadarola, Y. Nakabeppu, R.S. Duman, E.J. Nestler, Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments, Neuron 13 (1994) 1235-1244 [10]; T. Miyauchi, K. Kikuchi, S. Satoh, Further studies on the potentiating effect of lithium chloride on methamphetamine-induced stereotypy in mice, Jpn. J. Pharmacol. 31 (1981) 61-68 [14]; F.R. Sharp, S.M. Sager, K. Hicks, D. Lowenstein, K. Hisanaga, c-fos mRNA, Fos, and Fos-related antigen induction by hypertonic saline and stress, J. Neurosci. 11 (1991) 2321-2331 [16].] were investigated in mice injected with methamphetamine (2 mg/kg, s.c., one to five times). The ambulatory activity enhanced by either acute or chronic methamphetamine injection was delayed or diminished by lithium chloride (LiCl) pretreatment [R.G. Fessler, R.D. Sturgeon, S.F. London, H.Y. Meltzer, Effects of lithium on behaviour induced by phencyclidine and amphetamine in rats. Psychopharmacology 78 (1982) 373-376 [3].]. How the Li-sensitive c-Fos expression in the dorsolateral geniculate nucleus and striatum is related to methamphetamine-induced behavioral excitation is unclear. This protocol, in combination with c-Fos expression of mouse cerebral regions, may provide a useful tool for quantitation of ambulatory activity during c-Fos expression.

Animals↗
PubMed2004

Involvement of c-Fos in fenretinide-induced apoptosis in human ovarian carcinoma cells.

Fenretinide (HPR), a synthetic retinoid that exhibits lower toxicity than other retinoids, has shown preventive and therapeutic activity against ovarian tumors. Although the growth inhibitory effects of HPR have been ascribed to its ability to induce apoptosis, little is known about the molecular mechanisms involved. Since the proto-oncogene c-Fos has been implicated in apoptosis induction, we analyzed its role in mediating HPR response in a human ovarian carcinoma cell line (A2780) sensitive to HPR apoptotic effect. In these cells, HPR treatment caused induction of c-Fos expression, whereas such an effect was not observed in cells made resistant to HPR-induced apoptosis (A2780/HPR). Moreover, in a panel of other human ovarian carcinoma cell lines, c-Fos inducibility and HPR sensitivity were closely associated. Ceramide, which is involved in HPR-induced apoptosis, was also involved in c-Fos induction because its upregulation by HPR was reduced by fumonisin B(1), a ceramide synthase inhibitor. The causal relationship between c-Fos induction and apoptosis was established by the finding of an increased apoptotic rate in cells overexpressing c-Fos. Similarly to that observed for c-Fos expression, HPR treatment increased c-Jun expression in HPR-sensitive but not in HPR-resistant cells, suggesting the involvement of the transcription factor activating protein 1 (AP-1) in HPR-induced apoptosis. In gene reporter experiments, HPR stimulated AP-1 transcriptional activity and potentiated the AP-1 activity induced by 12-tetradecanoylphorbol 13-acetate. Furthermore, inhibition of AP-1 DNA binding, by transfecting A2780 cells with a dominant-negative Fos gene, caused decreased sensitivity to HPR apoptotic effects. Overall, the results indicate that c-Fos plays a role in mediating HPR-induced growth inhibition and apoptosis in ovarian cancer cells and suggest that c-Fos regulates these processes as a member of the AP-1 transcription factor.

Antineoplastic Agents↗
PubMed1997

The proto-oncogene c-fos increases the sensitivity of keratinocytes to apoptosis.

In human skin, most studies have suggested a role of c-fos or c-fos related genes in keratinocyte differentiation. The aim of our work was to more directly address this question by transfecting more or less differentiated keratinocyte cell lines (A431 and HaCaT) with constitutive expression vectors for c-Fos or c-Fos + c-Jun. Our results showed that c-Fos expression decreased keratinocyte growth, yet addition of c-Jun seemed to revert this c-Fos induced growth inhibition. Whereas no obvious differentiation program was turned on by c-Fos or c-Fos + c-Jun expression in our tissular model, apoptotic figures were observed and confirmed by in situ DNA fragmentation studies. These results do not rule out a role of c-Fos in keratinocyte differentiation but may indicate that the cell lines we used have reached an irreversible state of transformation so that they no longer respond to differentiation signals and rather die from apoptosis. These data add further evidence in favor of a role of c-Fos in epidermal homeostasis.

Apoptosis↗
PubMed1998

Suppression of c-Fos gene transcription with malignant transformation of human bronchial epithelial cells.

The Activator Protein-1 (AP-1) complex is a dimeric transcription factor composed of fos and jun proteins that regulates cellular growth and differentiation. We previously demonstrated a reduction in basal AP-1 transcriptional activity associated with the malignant transformation of human bronchial epithelial (HBE) cells that was, in part, a consequence of decreased c-fos expression. In this study, we investigated the mechanisms underlying the reduction in c-fos expression associated with the malignant transformation of HBE cells. c-Fos gene transcription was lower in tumorigenic HBE cells than in normal HBE cells, and the reduction in transcription involved c-fos gene promoter elements from -327 to +40. DNaseI footprinting and band shift analyses of motifs within this c-fos promoter region, including a cyclic AMP response element (CRE), serum response element (SRE), sis-inducible element (SIE), and a YY1 site, revealed that binding to these motifs was greater in tumorigenic HBE cells than in normal HBE cells. Site-directed mutagenesis of the CRE partially relieved the repression of c-fos promoter activity in tumorigenic HBE cells. Further, the activity of the Jun N-terminal Kinase (JNK)-dependent pathway, which was a positive regulator of the c-fos promoter, was greater in normal HBE cells than in tumorigenic HBE cells. These findings demonstrate a transcriptionally-mediated suppression of c-fos gene expression associated with the malignant transformation of HBE cells. The decreased activity of the c-fos promoter in tumorigenic 1170I cells appeared to involve suppression through a CRE site and reduced activation by JNK-dependent pathways.

Bronchi↗
PubMed2003

Interaction with GATA transcription factors provides a mechanism for cell-specific effects of c-Fos.

c-Fos is a multifunctional transcription factor that is involved in cellular proliferation, differentiation and apoptosis. c-Fos is rapidly induced by a variety of hormones, growth factors and other extracellular stimuli, resulting in cell-specific responses. One potential mechanism underlying the cell-specific effects of c-Fos may be its ability to regulate gene expression through interaction with tissue-restricted transcription factors. We report here that c-Fos interacts with the cell-specific GATA proteins to potentiate their ability to transactivate target promoters, via GATA-binding sites. c-Fos is recruited to GATA proteins through direct interaction with their N-terminal activation domain. Neither the leucine zipper nor the DNA-binding domain of c-Fos is required for physical interaction with GATA proteins. Instead, a C-terminal domain located between amino acids 235 and 296, which is conserved in FosB but not in the nontransforming Fos family members, FosB/SF or Fra-1, is essential for c-Fos-GATA interaction. These data suggest that c-Fos may act as an inducible cofactor for cell-specific transcription factors and unravel a novel mechanism for transcriptional regulation by c-Fos, independent of the well-studied AP-1 pathway. The results also raise the possibility that dysregulated interaction with cell-specific transcription factors may be an important component in cellular transformation by nuclear oncogenes.

Animals↗
PubMed2001

Immunohistochemical characterisation of Fos-positive cells in brainstem monoaminergic nuclei following intracranial self-stimulation of the medial forebrain bundle in the rat.

Fos immunostaining was used as a marker of neuronal activity following intracranial self-stimulation (ICSS) of the medial forebrain bundle (MFB) in the rat, and was combined with immunostaining for tyrosine hydroxylase (TH), serotonin (5-HT), gamma-aminobutyric acid (GABA), or NR1 (one of the glutamate N-methyl- D-aspartate receptor subunits) for purposes of neurochemical identification. ICSS induced a significant but different degree of increase in the number of Fos-immunopositive (Fos+) cells in the six brainstem monoaminergic nuclei examined, which included the ventral tegmental area (VTA), substantia nigra pars compacta (SNc), dorsal raphe nucleus (DR), median raphe nucleus (MR), locus coeruleus (LC), and A7 noradrenaline cells. Densely labelled Fos+ cells were observed in the LC following ICSS, and many of these Fos+ cells were colocalized with TH. Similarly, many of Fos+ cells in the A7 and DR/MR were colocalized with TH and 5-HT, respectively. By contrast, a smaller number of Fos+ cells was detected in the VTA and SNc following the ICSS, and in these regions the majority of Fos+ cells were not colocalized with TH. Although results among regions quantitatively differed, the ICSS induced a significant increase in the number of double-labelled cells (GABA+/Fos+ or NR1+/Fos+) in all of the VTA, DR, and LC, in which the ICSS produced an ipsilaterally weighted increase in Fos-like immunoreactivity. These results suggest that ICSS of the MFB induces differential Fos expression within monoaminergic and GABAergic neurons in brainstem monoaminergic nuclei under modulation by glutamatergic afferents.

Animals↗
PubMed2002

The expression of Fos following kainic acid-induced seizures is age-dependent.

The expression of limbic seizures following kainic acid (KA) administration starts at approximately postnatal day (P) 19 in rats. In this study we investigated whether the expression of Fos-like immunoreactivity (Fos-IR) in limbic regions occurs concomitantly with the behavioural expression of limbic seizures. Immunohistochemistry for c-Fos protein was examined 1, 2, 4, 12 and 24 h following seizure onset (KA-treated rats) or saline injections (controls) in immature and adult rats at P7, P13, P20 and P60. The expression of Fos-IR in limbic structures following KA-induced seizures is age-dependent. There is a strong and selective induction of Fos-IR in the CA3 region of the hippocampus following KA-induced seizures in rats at P7. However, the expression of Fos-IR in KA-treated rats at P13, P20 and P60 involved other hippocampal structures in addition to CA3. Abundant induction of Fos-IR was found in the CA1, CA3 and dentate gyrus (DG) in KA-treated rats at P13, P20 and P60. While immature rats at P7 and P13 showed very few or no Fos-IR neurons in most amygdala nuclei, rat pups at P20 showed strong induction of Fos-IR in the amygdala. Our results demonstrated that the induction of Fos-IR in most amygdala nuclei and the full expression of behavioural limbic seizures occur at the same developmental age, which is consistent with the idea that the amygdala may play a role in the modulation of limbic seizures.

Age Factors↗
PubMed1990

Luteinizing hormone-releasing hormone neurons express Fos protein during the proestrous surge of luteinizing hormone.

The ability of luteinizing hormone-releasing hormone (LHRH) neurons to express the oncogene c-fos was examined during the estrous cycle in rats. The immunocytochemical localization of the c-fos-encoded antigen, Fos, was coupled with the immunocytochemical localization of LHRH. LHRH neurons showed no Fos immunoreactivity during diestrus-1, diestrus-2, estrus, or the morning of proestrus. However, Fos was expressed in LHRH neurons from 1600 to 2200 hours during proestrus. The timing of onset of Fos expression in LHRH neurons during proestrus suggests a strong correlation with increased LH secretion. Pentobarbital, which blocks the preovulatory LH surge, blocked Fos expression in LHRH neurons, but the LHRH neurons expressed Fos on the following afternoon at the time of the expected delayed LH surge. Not all LHRH neurons expressed Fos during the LHRH surge. Approximately half of the LHRH neurons were activated in the preoptic area and anterior hypothalamus; more anteriorly positioned LHRH neurons did not express Fos, resulting in an overall stimulation of 40% of the LHRH neurons. These data provide direct evidence that stimulation of LHRH neurons during proestrus takes place at the LHRH cell bodies, and identify the specific population of LHRH neurons which are activated.

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